TW202539650A - Methods for the treatment of pain - Google Patents

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

Methods of treating pain

It is estimated that 50 million adults in the United States alone suffer from chronic pain. Despite the severity of the pain problem, many existing pain medications often carry serious risks, including gastrointestinal side effects, dependence risks, and overdose risks. Therefore, there is a need for innovative methods to treat pain.

In one embodiment, this article provides a method for treating pain in an individual using compounds provided herein. The pain may be acute inflammatory pain. The pain may be a symptom of an illness or condition in an individual experiencing the pain. For example, the pain may be a symptom of inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriasis arthritis), myofibrosis, lupus, surgery (e.g., postoperative 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 complicated regional pain syndrome (CRPS), or a combination of these. The pain may be associated with an underlying disease or condition in the individual experiencing it. Therefore, in some cases, the individual experiencing the pain may also have a disease or condition. Non-restrictive examples of diseases and conditions include inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriasis arthritis), myofibrosis, lupus, surgery (e.g., postoperative 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 complicated regional pain syndrome (CRPS).

In some embodiments, the compound is of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof: (I) Wherein: A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, 3- to 10-membered heterocyclic, or 5- to 6-membered monocyclic heteroaryl, each of which may be substituted by one or more ^{R6 groups} as required; X is CH or N; Y is NH; ^R1 is H; ^R2 is a _C1 - _C6 alkyl, _C3 - _C4 cycloalkyl, _C3 - _C8 heterocyclic, or 5- or 6-membered heteroaryl, each of which may be substituted by one or more substituents selected from halogen, hydroxyl, cyano, aminyl, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, and 3- to 8-membered heterocyclic groups as required; ^R3 is H; R ⁴ is selected from the following heteroaryl groups: 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, as needed, is derived from one or more groups selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, C2-C6 ynyl, _C1 - _C6 halogen, _{C3 - C8} cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _{C1 -} C6 cycloalkyl ... The substituted group is substituted with a _6- cyanoalkyl, 3- to 8-membered heterocyclic, _C3 - _C8 halogenated cycloalkyl, _C3 - _C8 aminoalkylcycloalkyl, _C3 - _C8 alkylcycloalkyl, 3- to 8-membered heterocyclic cycloalkyl, 3- to 8-membered alkyl heterocyclic cycloalkyl, 3- to 8-membered halogenated cycloalkyl and _C3 - _C8 halogenated cycloalkyl; ^R5 is H; and each ^R6 is independently halogenated, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, cyano, _C1 - _C6 hydroxyalkyl or _C1 - _C6 halogenated.

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).

In some embodiments, the compound is a compound of Table 1A. In some 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.

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

In some embodiments, the compound (e.g., compounds of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof) is administered orally. In some embodiments, the compound (e.g., compounds of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof) is provided in tablets, pills, or capsules. In some embodiments, the compound (e.g., compounds of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof) is administered in doses from about 0.5 mg to about 10 mg. In some embodiments, the compound (e.g., compounds of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof) is administered in doses from about 0.5 mg to about 5 mg. For example, the compound (e.g., compounds of formula (I), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof) is administered in doses of about 5 mg, about 4 mg, about 3 mg, about 2 mg, or about 0.5 mg.

Cross-reference to related applications This application claims the rights of U.S. Provisional Patent Application No. 63/625,217, filed January 25, 2024, and U.S. Provisional Patent Application No. 63/743,153, filed January 8, 2025, both of which are incorporated herein by reference in their entirety.

In one state, this article provides compounds as regulators of NLRP3 inflammasomes (a polymeric protein complex that acts as an intracellular sensor for various danger signals and responds by inducing inflammatory responses, including the release of pro-inflammatory intercytokines IL-1β and IL-18, and pyroptotic cell death).

In some embodiments, the compounds described herein demonstrated significant pain control in rat models of inflammatory pain, postoperative incision pain, and pain secondary to osteoarthritis driven by activation of the NLRP3 inflammasome. In a complete Freund’s adjuvant (CFA)-induced inflammatory pain model, treatment with single oral doses of the compounds described herein at 10 mg/kg and 30 mg/kg resulted in significant dose-dependent improvements in mechanical aalgesia and thermal hyperalgesia, with peak effects observed at 3 hours post-administration (p < 0.001 or better). In the Brennan incision pain model, when compared with the untreated control group, treatment with the compounds described herein at daily oral doses of 10 mg/kg and 30 mg/kg resulted in statistically significant improvements in claw retraction limit (PWT) and claw retraction latency (PWL) at all time points, and overall improvements in mechanical paresthesia and thermal hyperalgesia of 51% and 92%, respectively (p < 0.01 or better). In a surgically induced osteoarthritis model involving a combination of anterior cruciate ligamentectomy and partial internal meniscectomy, treatment with the compound described herein at a daily dose of 1 mg/kg resulted in statistically significant improvements in claw retraction limit (PWT) measured at 7, 14, 21, 28, and 35 days post-surgery (p < 0.05 or better) compared to the untreated control group, and ultimately an overall improvement of 18% in mechanical pain abnormalities (p < 0.01).

Therefore, this article provides methods for treating pain using the compounds disclosed herein. For example, compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI).

Unless otherwise defined, all technical terms , symbols, and other technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter pertains. In some cases, for clarity and/or ease of reference, terms are described herein that have the commonly understood meaning, and such terms should not necessarily be interpreted as representing a substantial difference from the generally understood meaning in the art.

As used in this specification, unless otherwise expressly indicated in the text, the singular forms "a," "an," and "the" include a plurality of indicators. For example, the term "sample" includes a plurality of samples, including mixtures thereof.

"Pharmaceutical composition" refers to the compounds of the present invention and formulations of media generally accepted in this art for delivering the compounds of the present invention to mammals (e.g., humans). Therefore, this media includes all pharmaceutically acceptable carriers, diluents or excipients.

"Pharmaceutical acceptable carriers, thinners, or excipients" include (but are not limited to) any adjuvants, carriers, excipients, glidants, sweeteners, thinners, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isointense agents, solvents, or emulsifiers.

"Amino group" refers to ˗NH ₂ group.

"Carboxy" or "carboxyl" refers to the ˗CO ₂ H group.

"Cyano" refers to 'CN'.

"Hydroxy" or "hydroxyl" refers to the ˗OH group.

"Nitro" refers to _NO2 group.

"Side group" refers to the =O substituent.

"Thiol group" refers to the ˗SH substituent.

"Thionyl group" refers to the =S substituent.

"Alkyl" refers to a saturated, straight-chain or branched hydrocarbon group consisting only of carbon and hydrogen atoms, having 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 similar, and being linked to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl and similar. The number of carbons mentioned refers to the carbon backbone and carbon branches but does not include carbon atoms belonging to any substituents. Unless otherwise expressly stated in this specification, alkyl groups are subject to substitution.

"Alkenyl" refers to an unsaturated, straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having two to twelve carbon atoms ( _C2 - _C12 alkenyl), two to eight carbon atoms ( _C2 - _C8 alkenyl), or two to six carbon atoms ( _C2 - _C6 alkenyl), or any value within these ranges, and being linked to the rest of the molecule by single bonds, such as vinyl, propenyl, butenyl, pentenyl, pent-1,4-dienyl, and similar groups. The number of carbons mentioned refers to the carbon backbone and carbon branches but does not include carbon atoms that are substituents. Unless expressly specified otherwise in this specification, alkenyl groups are substituted as necessary.

"Alynyl" means an unsaturated straight-chain or branched hydrocarbon having 2 to 12 carbon atoms ( _C2 - _C12 ynyl), two to nine carbon atoms ( _C2 - _C9 ynyl), or two to six carbon atoms ( _C2 - _C6 ynyl), or any value within these ranges, and having at least one carbon-carbon triple bond. Examples of ynyl may be selected from the group consisting of ethynyl, propynyl, but-1-ynyl, but-2-ynyl, and the like. The number of carbons mentioned refers to the carbon backbone and carbon branches but does not include carbon atoms that are substituents. Unless expressly specified otherwise in this specification, the ynyl group may be substituted as necessary.

"Alkoxy" refers to a group of the formula ˗OR _a , where _Ra is an alkyl group as defined 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 expressly specified otherwise in this specification, alkoxy groups are substituted as required.

"Amino" refers to a group of the formula _˗NRaRb , wherein _Ra and _{Rb are} each independently H or a _C1 - _C6 alkyl group as defined above. When either _Ra or _Rb is H, "aminyl" is the same as "amino" as defined above. Unless otherwise specified, the _C1 - _C6 alkyl portion of the amino group may be substituted as required.

"Aminoalkylcycloalkyl" refers to a group of the formula – _{Ra Rb NRc Rd} , wherein _{Ra is} a cycloalkyl group as defined herein, _Rb is a _C1 - _C6 alkyl group, _Rc is H or a _C1 - _C6 alkyl group, and _Rd is a _C1 - _C6 alkyl group as defined above. Unless otherwise specified, the cycloalkyl and each _C1 - _C6 alkyl portion of an aminoalkylcycloalkyl group may be substituted as required.

"Aromatic ring" refers to a planar cyclic molecule or a portion of a molecule (i.e., a group) that has a resonant ring, which exhibits increased stability relative to other arrangements of atoms with the same set of atoms. Generally, an aromatic ring contains a set of covalently bonded, coplanar atoms and includes an even number of π-electrons (e.g., alternating double and single bonds) (i.e., 4n + 2 π-electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include (but are not limited to) phenyl, naphthenyl, imidazolyl, pyrrole, pyridinyl, pyrimidine, pyrazinyl, pyridoneyl, dazinyl, and pyrimidinoneyl groups. Unless expressly specified otherwise in this specification, "aromatic ring" includes all groups that are substituted as necessary.

"Aryl" refers to a carbon ring system containing 6 to 18 carbon atoms (e.g., 6 to 10 carbon atoms ( _C6 - _C10 aryl)) and at least one carbon ring aromatic ring. For the purposes of this invention, aryl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include (but are not limited to) aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azurite, benzene, chrysene, 1,2-benzoacene, fen, asymmetric-dicyclopentadienzene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and terphenyl. Unless expressly specified in this specification, aryl groups may be substituted as necessary.

"Cyanoalkyl" means an alkyl group containing at least one cyano substituent. The -CN substituent may be on a primary, secondary, or tertiary carbon. Unless expressly specified otherwise in this specification, cyanoalkyl groups are substituted as required.

"Carbocyclic" or "carbocycle" refers to a ring system in which each of the ring atoms is carbon.

"Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbon-ring group consisting only of carbon and hydrogen atoms. It may include fused or bridged ring systems having three to fifteen ring carbon atoms ( _C3 - _C15 cycloalkyl), three to ten ring carbon atoms ( _C3 - _C10 cycloalkyl), or 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 is saturated or partially unsaturated and linked to the remainder of the molecule by single bonds. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, adalamyl, norbornel, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl and similar groups. Unless expressly specified otherwise in this specification, cycloalkyl groups are substituted as required.

"alkylcycloalkyl" refers to a group of the formula – _{Ra Rb} , where _Ra is cycloalkyl and _Rb is alkyl, as defined above. Unless expressly specified otherwise in this specification, alkylcycloalkyl groups are substituted as required.

"Fusion" refers to any ring structure described in this article that is fused into another ring structure.

"Halogen" refers to bromine, chlorine, fluorine, or iodine.

"Haldecyl" means an alkyl group as defined above, which is substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless expressly specified otherwise in this specification, haldecyl groups are substituted as necessary.

"Halcycloalkyl" means a cycloalkyl group as defined above, which is substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless expressly specified otherwise in this specification, halcycloalkyl groups are substituted as necessary.

"Haloxycycloalkyl" refers to a group of the formula – _{Ra Rb} , where _Ra is cycloalkyl and _Rb is haloxyalkyl, as defined above. Unless expressly specified otherwise in this specification, haloxycycloalkyl groups are substituted as required.

"Hydroalkyl" means an alkyl group as defined above, which is substituted with one or more hydroxyl groups. A hydroxyalkyl group is attached to the main chain by an alkyl carbon atom. Unless otherwise expressly specified in this specification, hydroxyalkyl groups are substituted as required.

"Heterocyclic group" refers to a 3- to 18-membered, such as 3- to 10-membered or 3- to 8-membered non-aromatic cyclic group having one to ten cyclic carbon atoms (e.g., two to ten) and one to six cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless expressly specified otherwise in this specification, a heterocyclic group is a partially or fully saturated monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic, and/or bridging ring systems. The nitrogen, carbon, and sulfur atoms in the heterocyclic group may be oxidized as required, and the nitrogen atom may be quaternized as required. Examples of such heterocyclic groups include (but are not limited to) dioxanecyclopentyl, thienyl[1,3]dithiayl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazodinyl, isothiazolinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrrolizinyl, 2-sideoxypiperazinyl, 2-sideoxypiperidinyl, 2-sideoxypyrrolidinyl, oxazolinyl, epoxyethyl, piperidinyl, piperazinyl, 4-piperidinoneyl, acridineyl, pyrrolidinyl, pyrazolidineyl. Quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropiperanyl, thiomorphinyl, thiamorphinyl, 1-epi-oxy-thiomorphinyl, and 1,1-di-epi-oxy-thiomorphinyl. Unless expressly specified otherwise in this specification, heterocyclic groups are substituted as required.

"Halogenated heterocyclic alkyl" refers to a group of the formula – _{Ra Rb} , where _Ra is an alkyl group and _Rb is a halogenated heterocyclic group, as defined herein. Unless expressly specified otherwise in this specification, halogenated heterocyclic alkyl groups are substituted as required.

"Heterocyclic alkyl" refers to a group of the formula – _{Ra Rb} , where _Ra is an alkyl group and _Rb is a heterocyclic group, as defined herein. Unless expressly specified otherwise in this specification, heterocyclic alkyl groups are substituted as required.

"Heteroaryl" refers to a 5- to 18-membered, such as 5- to 6-membered ring system group, which contains 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 can 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 may be oxidized as needed; the nitrogen atom may be quaternized as needed. Examples include (but are not limited to) aziridine, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[ b ][1,4]dioxanyl, 1,4-benzodioxane, benzonaphthofuranyl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxacyclohexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, and benzothienyl. (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, oxolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazoyl, indazole, indoleyl, indoleyl, isoindoleyl, indolinyl, isoindolinyl, isoquinolinyl, indoleazinyl, isoxazolyl, naphthidyl, oxadiazolyl, 2-sideoxy-nitropyridyl, oxazolyl, 1-oxo-ionylpyridyl, 1-oxo-ionylpyrazinyl, 1-oxo-ionylpyrazinyl, 1-oxo-ionyl-darazinyl, 1-phenyl- 1H -Pyrroleyl, benzymineyl, benzythiazinyl, benzyoxazinyl, phthalazinyl, pteridinyl, purineyl, pyrroleyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, darazinyl, quinazolinyl, quinoxolinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless expressly specified otherwise in this specification, heterocyclic groups are substituted as required.

The terms 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:

; ; ; ; ; ; ; ; ; ; ; ; and ,

Among them, 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, triazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl are derived from p-oxazolyl, isoxazolyl, 1 The carbon atom of one of the rings of 2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, triazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl is covalently bonded to the remaining part of the molecule.

The term "substituted" as used herein means any of the above-mentioned groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, cyanoalkyl, cycloalkyl, halogen, heterocyclic, alkylene-heterocyclic, heterocyclic alkyl, heteroaryl, heteroarylalkyl and/or hydroxyalkyl) wherein at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a non-hydrogen substituent. Examples of non-hydrogen substituents include (but are not limited to) amino, carboxyl, cyano, hydroxyl, halogen, nitro, lateral, thiol, thionyl, alkyl, alkenyl, alkyl carbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, halogenyl, heterocycloyl, heterocycloalkyl, heteroaryl, heteroaryl, heteroarylalkyl and/or hydroxyalkyl substituents, each of which may be substituted with one or more of the above substituents as needed.

In certain embodiments, the alternatives may be selected independently from the group consisting of halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 halogen, C3- _C8 cycloalkyl, _{C3 -C8 halogencycloalkyl} , _C6 - _C10 aryl, 5- or 6-membered heteroaryl, _C1 - _C6 alkoxy, and 3 to 8-membered heterocyclic groups.

"Effective amount" or "therapeutic effective amount" means the amount of the compound described herein that is sufficient to affect the intended application (including, but not limited to, pain treatment as defined below).

"Treatment" or "treating" refers to the methods used to achieve a beneficial or desired outcome in relation to a disease, ailment, or medical condition (including, but not limited to, pain).

"Medically acceptable salts" include acid and base addition salts.

"Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness of the free base and are biologically tolerable or otherwise biologically suitable for administration to an individual.

"Pharmaceutically acceptable alkali addition salts" refer to salts that retain the bioavailability of free acid and are biologically tolerable or otherwise biologically suitable for administration to an individual.

The terms "antagonist" and "inhibitor" are used interchangeably, and both refer to compounds that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of the protein (such as the NLRP3 inflammasome or NEK7) or the binding of the NLRP3 inflammasome to NEK7. Therefore, the terms "antagonist" and "inhibitor" can be defined within the text describing the biological action of the target protein.

The term "activator," as used herein, refers to a compound that has the ability to initiate or enhance the biological function of a target protein. Therefore, the term "activator" is defined within the context of the biological action of the target peptide. While preferred activators in this context interact specifically with the target (e.g., bind to the target), compounds that induce or enhance the biological activity of the target peptide through interactions with other members of the signaling pathway in which the target peptide is a member are also specifically included in this definition.

"Individual" refers to an animal, such as a mammal, like a human. The methods described herein can be used in human treatment and veterinary applications. In some embodiments, the individual is a mammal, and in some embodiments, the individual is a human.

"Mammalians" include both humans and livestock (such as laboratory animals and pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits)) and non-livestock (such as wild animals and similar animals).

Some embodiments also refer to the in vivo metabolites of the disclosed compounds. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amination, esterification, and the like, primarily by enzymatic processes of the administered compound. Thus, embodiments include compounds produced by processes involving administration of the present invention to mammals for a period sufficient to produce their metabolites. Such products are typically identified by administration of the radiolabeled compound of the present invention to animals (such as rats, mice, guinea pigs, monkeys) or humans at a detectable dose, allowing sufficient time for metabolism to occur, and by isolation of the metabolites from urine, blood, or other biological samples.

Crystallization often produces solvent compounds of the compounds disclosed herein. As used herein, the term "solvent compound" refers to an aggregate comprising one or more of the compounds of the invention and one or more solvent molecules. In some embodiments, the solvent is water, in which case the solvent compound is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Therefore, the compounds of the invention can exist as hydrates (including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates and similar, and corresponding solubilized forms). In some states, the compounds of the invention are true solvent compounds, while in others, the compounds of the invention retain only the indeterminate water and are a mixture of water and some indeterminate solvents.

"Stereoisomers" refer to compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This invention covers various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposed mirror images of each other.

The compounds of the present invention (compounds of formulas (I), (II), (III), (IV), (V), and (VI)) or their pharmaceutically acceptable salts may contain one or more geometrically asymmetric centers and may thus produce stereoisomers, such as enantiomers, diastereomers, and other stereoisomers defined in absolute stereochemistry as ( R )- or ( S )- or (D)- or (L)- for a specific amino acid. Therefore, embodiments 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 can be prepared using palmite synthons or palmite reagents or resolved using known techniques (e.g., chromatography and fractional crystallization). Known techniques for the preparation/separation of individual enantiomers include palmite synthesis from suitable optically pure precursors or resolution of racemic isomers (or racemic isomers of salts or derivatives) using, for example, palmite high-pressure liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetrical centers, it is desirable that such compounds include both E and Z geometric isomers, unless otherwise specified. Similarly, it is intended that all tautomers be included.

Embodiments of the present invention include all forms of rotational isomers and conformationally restricted states of the compounds of the present invention. Also included are turn-blocked isomers, which are stereoisomers resulting from blocked rotation around a single bond, wherein a rotational barrier is created by an energy difference due to steric strain or other contributing factors, the barrier being high enough to allow the separation of individual conformational isomers. As an example, certain compounds of the present invention may exist as mixtures of turn-blocked isomers or may be purified or enriched by the presence of one turn-blocked isomer.

In some embodiments, the compounds of formula (I), (II), (III), (IV), (V), or (VI) are mixtures of enantiomers or diastereomers. In other embodiments, the compounds of formula (I), (II), (III), (IV), (V), or (VI) are substantially a single enantiomer or diastereomer.

"Tautomerism" refers to a proton shift from one atom of a molecule to another atom of the same molecule. Therefore, embodiments include tautomers of the disclosed compounds.

The chemical nomenclature scheme and structural diagrams used in this paper are modified versions of the I.U.P.A.C. nomenclature system, using ACD/Name Version 9.07 software and/or ChemDraw Professional Version 17.0.0.206 software (CambridgeSoft). For complex chemical names used in this paper, substituents are usually named before the groups they are attached to. For example, cyclopropylethyl contains an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structural diagrams in this paper, except for some bonds on carbon atoms that are assumed to be bonded to a sufficient number of hydrogen atoms to complete the valence.

"Optional" or "as needed" means that the event or situation described thereafter may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "substituted aryl group as needed" means that the aryl group may or may not be substituted, and the description includes both substituted and unsubstituted aryl groups.

This invention provides that whenever an embodiment is described herein with the term "comprising," similar embodiments described with "consisting of" and/or "substantially consisting of" are also provided, unless otherwise explicitly provided. This invention further provides that whenever an embodiment is described herein with the phrase "substantially consisting of," similar embodiments described with "consisting of" are also provided. This invention also provides that whenever an embodiment is described herein with the phrase "consisting of," similar embodiments described with "substantially consisting of" are also provided.

The term "and/or," as used in phrases having a list of members, is intended to individually include all members and all combinations of the list of members, whether complete or partial. For example, phrases such as "A and/or B" are intended herein to include A and B; A or B; A (only); and B (only). Similarly, the term "and/or," as used in phrases such as "A, B and/or C," is intended to cover 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 (only); B (only); and C (only).

The chapter headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter.

Non-limiting compounds for use in methods of treating pain. This document describes methods of treating pain, which include administering to an individual in need a compound of formula (I), (II), (III), (IV), (V), or (Vi), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof. In some embodiments, compounds of formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts, stereoisomers, or solvents thereof, inhibit NEK7 and/or modulate the activity of the NLRP3 inflammasome. Pain may be acute inflammatory pain. Pain may be a symptom of a disease or condition in an individual experiencing pain. Pain may be associated with a disease or condition in an individual experiencing pain. Non-restrictive examples of diseases and conditions include inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriasis arthritis), myofibrosis, lupus, surgery (e.g., postoperative 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 complicated regional pain syndrome (CRPS).

The embodiments described herein provide a compound having formula (I): (I) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: A is a _C6 - _C10 aryl, C3- _C10 cycloalkyl, 3- to ₁₀ -membered heterocyclic, or 5- to 6-membered monocyclic heteroaryl, each of which may be substituted with one or more ^R6 groups as required; Y is NH; ^R1 is H or _C1 - _C6 alkyl; ^R2 is a _C1 -C6 alkyl, C2- _C6 alkenyl, _C2 - _C6 ynyl, C3- _C8 cycloalkyl, 3- to _8- membered heterocyclic, or 5- or 6-membered heteroaryl, each of which may be substituted with one or more R6 groups as required, selected from halogen, hydroxyl, cyano, amino, C1-C6 alkyl, _C2 - _C6 alkenyl, C2-C6 ynyl, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C3 - _C8 cycloalkyl, or C3 _- C8 heteroaryl. _{The 6-} alkoxy group is substituted with a 3- to 8-membered heterocyclic group; ^R3 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C3 - _C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 5- or 6-membered heteroaryl group, each of which may be substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, and _C1 - _C6 alkoxy groups as required; R ⁴ is selected from the following heteroaryl groups: 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, as needed, is derived from one or more groups selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, C2-C6 ynyl, _C1 - _C6 halogen, _{C3 - C8} cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _{C1 -} C6 cycloalkyl ... _6- Cyanoalkyl, 3- to 8-membered heterocyclic, _C3 - _C8 halogenated cycloalkyl, _C3 - _C8 aminoalkylcycloalkyl, _C3 - _C8 alkylcycloalkyl, 3- to 8-membered heterocyclic cycloalkyl, 3- to 8-membered alkyl heterocyclic cycloalkyl, 3- to 8-membered halogenated cycloalkyl and _C3 - _C8 halogenated cycloalkyl or combinations thereof are substituted; ^R5 is H, _C1 - _C6 alkyl, _C2 -C6 alkenyl, _C2 - _C6 ynyl, _{C3-C8 cycloalkyl} , 3- to 8 _- membered heterocyclic, _C6 - _C10 aryl or 5- or 6-membered heteroaryl, each of which, as required, is substituted with one or more groups selected from halogen, hydroxyl, cyano, amino, C The substituents are ₁ - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl and _C1 - _C6 alkoxy; and ^R6 is independently halogen, C1- _{C6 alkyl, cyano, C1-C6 hydroxyalkyl, C1-C6 alkoxy or C1 - C6 halogen in} each occurrence.

In some embodiments of compounds of formula (I): A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, 3 to 10-membered heterocyclic, or 5 to 6-membered monocyclic heteroaryl, each of which may be substituted with one or more ^R6 groups as desired; Y is NH; ^R1 is H or _C1 - _C6 alkyl; ^R2 is a _C1 - _C6 alkyl, C2-C6 alkenyl, _C2 - _C6 ynyl, _C3 - _C8 cycloalkyl, 3 to _8- membered heterocyclic, or 5- or 6-membered heteroaryl, each of which may be substituted with one or more R6 groups selected from halogen, hydroxyl, cyano, amino, _C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkyl, _C2 -C6 alkenyl, _C3 - _C6 ynyl, C4- _C6 alkyl, _C5 -C6 alkyl, C6- _C6 alkyl, C3-C6 alkyl, _C4 ... _{The 6-} alkoxy group is substituted with a 3- to 8-membered heterocyclic group; ^R3 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C3 - _C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 5- or 6-membered heteroaryl group, each of which may be substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, and _C1 - _C6 alkoxy groups as required; R ⁴ is a heteroaryl group selected from the following: 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 may be substituted as required by one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, and _C3 - _C8 halogen cycloalkyl; ^R5 is H, _C1 -C _R6 is substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, _{C1 - C6} alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl and _C1 - _C6 alkoxy, as required; and ^R6 is independently halogen, _C1 - _C6 alkyl or _{C1 - C6 alkyl} or _{C1 - C6 halogen} in each occurrence _.

In some embodiments of compounds of formula (I): A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, 3 to 10-membered heterocyclic, or 5 to 6-membered monocyclic heteroaryl, each of which may be substituted by one or more ^R6 groups as desired; X is CH or N; Y is NH; ^R1 is H or _C1 - _C6 alkyl; ^R2 is a C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C3 - _C8 cycloalkyl, 3 to 8-membered heterocyclic, or 5- or 6-membered heteroaryl, each of which may be substituted by one or more R6 groups selected from halogen, hydroxyl, cyano, amino, C1-C6 alkyl, _C2 - _C6 alkenyl, C2-C6 ynyl, _C1 -C6 alkyl, C2- _C6 alkenyl, C3-C6 ynyl, _C3 - _C6 alkyl, C2-C6 alkenyl, _C2 - _C6 ynyl, _C3 ... _{The 6-} alkoxy group is substituted with a 3- to 8-membered heterocyclic group; ^R3 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C3 - _C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 5- or 6-membered heteroaryl group, each of which may be substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, and _C1 - _C6 alkoxy groups as required; R ⁴ is selected from the following heteroaryl groups: 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, as needed, is derived from one or more groups selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, C2-C6 ynyl, _C1 - _C6 halogen, _{C3 - C8} cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _{C1 -} C6 cycloalkyl ... _6- Cyanoalkyl, 3- to 8-membered heterocyclic, _C3 - _C8 halogenated cycloalkyl, _C3 - _C8 aminoalkylcycloalkyl, _C3 - _C8 alkylcycloalkyl, 3- to 8-membered heterocyclic cycloalkyl, 3- to 8-membered alkyl heterocyclic cycloalkyl, 3- to 8-membered halogenated cycloalkyl and _C3 - _C8 halogenated cycloalkyl; ^R5 is H, _C1 - _C6 alkyl, C2-C6 alkenyl, _C2 - _C6 ynyl, _C3 - _C8 cycloalkyl, 3- to _8- membered heterocyclic, _C6 -C10 aryl or _5- or 6-membered heteroaryl, each of which, as required, is substituted with one or more groups selected from halogen, hydroxyl, cyano, amino, C1-C10, _C2 - _C10 , C3 ... The substituents R6 are _6- alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl and _C1 - _C6 alkoxy; and each time ^R6 appears, it is independently halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, cyano, _C1 - _C6 hydroxyalkyl or _C1 - _C6 halogen.

In some embodiments, A is any suitable functional group as described herein. In some embodiments, A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, 3- to 10-membered heterocyclic, or 5- to 6-membered monocyclic heteroaryl, each of which may be substituted with one or more ^{R6 groups} as desired; in some embodiments, A is a _C6 - _C10 aryl or 5- to 6-membered monocyclic heteroaryl, each of which may be substituted with one or more ^R6 groups as desired. In some embodiments, A is a _C6 - _C10 aryl group substituted with one or more ^R6 groups as desired. In some embodiments, A is a 5- to 6-membered monocyclic heteroaryl group substituted with one or more ^R6 groups as desired. In some embodiments, A is a _C3 - _C10 cycloalkyl. In some implementations, A is a 3 to 10-member heterocyclic base that is replaced by one or more R ⁶ as needed.

In some embodiments, A is a divalent, optionally substituted _{C6-10 aryl} group. In some embodiments, A is a divalent, optionally substituted 3- to 8-membered saturated or partially unsaturated carbon ring. In some embodiments, A is a divalent, optionally substituted 3- to 10-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, A is a divalent, optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, A is a divalent group selected from the following: phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0] dicyclooctyl, [4.3.0] dicyclononyl, [4.4.0] dicyclodecyl, [2.2.2] dicyclooctyl, fumonyl, indyl, tetrahydronaphthyl, acridineyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuran alkyl, benzothiophene, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolinyl, carbazole, NH-carbazole, carbolinyl, benzodiazonyl (chromanyl), benzopiperanyl (chromenyl), chlorolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazolidyl, imidazodinyl, imidazolinyl, imidazolyl, 1H-indazoleyl, indoleenyl, indole Dolinyl, indoleazinyl, indoleyl, 3-indoleyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isobenzodihydropiperanyl, isoindazoleyl, isoindolinyl, isoindoleyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, oxazolyl, pyrimidinyl, Phenyridyl, phenoxathiinyl, phenoxazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purine, piperanyl, pyrazinyl, pyrazolidine, pyrazolinyl, pyrazolyl, pyrazolyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridinyl, pyrimidinyl, pyrrolidine, pyrrolinyl, 2-pyrroleyl, pyrroleyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxathiinyl The following compounds are used: pyridyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, thiazolyl, thienenoyl, thieneno-thiazolyl, thieneno-imidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxadiazyl, acridineyl, and xanthenyl; each of which may be substituted as required.

In some embodiments, A is a divalent group selected from phenyl, pyridyl, cyclohexyl, and cyclohexenyl; each of these groups may be substituted as desired. In other embodiments, A is phenyl. In some embodiments, A is saturated or unsaturated cyclohexyl. In many more embodiments, A is pyridyl.

In some embodiments, A is a pyrimidine group, which may be substituted as needed.

In some embodiments, X is any suitable atom as defined herein. In some embodiments, X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

In some embodiments, Y is any suitable atomic linker as described herein. In some embodiments, Y is NH.

In some embodiments, ^R1 is any suitable functional group described herein. In some embodiments, ^R1 is H. In some embodiments, ^R1 is a _C1 - _C6 alkyl group. In some embodiments, ^R1 is methyl, ethyl, n-propyl, or isopropyl.

In some embodiments, ^R2 is any suitable functional group described herein. In some embodiments, ^R2 is a _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C3- _C8 cycloalkyl, 3- to ₈ -membered heterocyclic, or 5- or 6-membered heteroaryl, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 -C6 alkenyl, _{C2 -C6 alkynyl} , _C1 - _C6 alkoxy, and 3- to 8-membered heterocyclic. In some embodiments, ^R2 is a _C1 - _C6 alkyl, _C3 - _C4 cycloalkyl, _C3 - _C8 heterocyclic, or 5- or 6-membered heteroaryl, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, and 3- to 8-membered heterocyclic groups. In some embodiments, ^R2 is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, acridineyl, or oxocyclobutane, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 -C6 alkynyl, _{C1 -C6 alkoxy} , and 3- to 8-membered heterocyclic groups. In some embodiments, ^R2 is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxadicyclobutane, each of which may be substituted as required by one or ^more substituents selected from halogen, hydroxyl, cyano, _{amino, C1-C6 alkyl , C2 - C6} alkenyl, _{C2 - C6 alkynyl} , _{C1 - C6} alkoxy, and 3- _{to 8 -} membered heterocyclic groups. In some embodiments, ^R2 is cyclopropyl. In some embodiments, ^R2 is oxocyclobutane. In some embodiments, ^R2 is unsubstituted cyclopropyl or oxocyclobutane. In some embodiments, ^R2 is N-methyl-substituted pyrrolidyl. In some embodiments, ^R2 is unsubstituted cyclobutyl.

In some implementations, ^R² is: ; ; ; ; ; ; ; ; or .

In some implementations, ^R² is: ; or .

In some embodiments, ^R3 is any suitable functional group described herein. In some embodiments, ^R3 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C3 - _C8 cycloalkyl, 3- to 8-membered heterocyclic or 5- or 6-membered heteroaryl, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl and _C1 - _C6 alkoxy. In some embodiments, ^R3 is H or a _C1 - _C6 alkyl group, wherein the _C1 - _C6 alkyl group is substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, and _C1 - _C6 alkoxy. In some embodiments, ^R3 is H. In some embodiments, ^R3 is a _C1 - _C6 alkyl group. In some embodiments, ^R3 is methyl, ethyl, n-propyl, or isopropyl.

In some embodiments, ^R4 is any suitable functional group described herein. In some embodiments, ^R4 is selected from the following heteroaryl groups: 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, as desired, is derived from one or more groups selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, C2- _C6 ynyl, _C1 -C6 halogen, _C3 - _C8 cycloalkyl, cyano, _amino , _C1 - _C6 hydroxyalkyl, _{C1- C6} cycloalkyl ... Substituents of _6- cyanoalkyl, 3- to 8-membered heterocyclic, _C3 - _C8 halogenated cycloalkyl, _C3 - _C8 aminoalkylcycloalkyl, _C3 - _C8 alkylcycloalkyl, 3- to 8-membered heterocyclic alkyl, 3- to 8-membered alkyl heterocyclic cycloalkyl, 3- to 8-membered halogenated cycloalkyl and _C3 - _C8 halogenated cycloalkyl or combinations thereof. In some embodiments, ^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 wherein, as required, is derived from one or more groups selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, C1-C6 halogen, _C3 - _C8 cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _C1 - _C6 cyanoalkyl, 3- to 8- _{membered heterocyclic, C3-C8 halogen cycloalkyl , C3} - _C8 aminoalkyl cycloalkyl, _C3 -C Substituents of _8- alkylcycloalkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered alkyl heterocycloalkyl, 3- to 8-membered halogen heterocycloalkyl and _C3 - _C8 halogencycloalkyl and combinations thereof.

In some embodiments, ^R4 is oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, or 1,3,4-oxadiazolyl, each wherein, as desired, is derived from one or more groups selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, C2- _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _C1 - _C6 cyanoalkyl, 3- to 8-membered heterocyclic, _{C3 - C8} halogen cycloalkyl, _C3 - _C8 aminoalkyl cycloalkyl, _C3 -C The substituent is an _8- alkylcycloalkyl, a 3- to 8-membered heterocycloalkyl, a 3- to 8-membered alkyl heterocycloalkyl, a 3- to 8-membered halogen heterocycloalkyl, and a _C3 - _C8 halogencycloalkyl, or combinations thereof. In some embodiments, ^R4 is an isoxazolyl group, as desired, substituted with one or more substituents selected from halogen, _{C1 - C6} alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, C1- _C6 halogen, _C3 - _C8 cycloalkyl, and _C3 - _C8 halogencycloalkyl.

In some embodiments, ^{R4 is} an isoxazolyl group, as desired, substituted with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _{C1 - C6} cyanoalkyl, 3- to ₈ -membered heterocycloyl, _C3 - _{C8 halogen cycloalkyl, C3-C8 aminoalkyl cycloalkyl} , C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered alkyl heterocycloalkyl, 3- to 8-membered halogen heterocycloalkyl and _C3 - _C8 halogen cycloalkyl and combinations thereof.

In some embodiments, ^{R4 is} a thiazolyl group substituted as needed with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _C1 - _C6 cyanoalkyl, _3- to ₈ -membered heterocycloyl, C3-C8 halogen cycloalkyl, _C3 - _C8 aminoalkyl cycloalkyl, _C3 - _C8 alkyl cycloalkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered alkyl heterocycloalkyl, 3- to 8-membered halogen heterocycloalkyl and _C3 - _C8 halogen cycloalkyl and combinations thereof.

In some embodiments, ^{R4 is} an isothiazolyl group substituted as needed with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _C1 - _C6 cyanoalkyl, _3- to ₈ -membered heterocycloyl, C3-C8 halogen cycloalkyl, _C3 - _C8 aminoalkyl cycloalkyl, _C3 - _C8 alkyl cycloalkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered alkyl heterocycloalkyl, 3- to 8-membered halogen heterocycloalkyl and _C3 - _C8 halogen cycloalkyl and combinations thereof.

In some embodiments, ^{R4 is} , as needed, derived from one or more groups selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, C3- _C8 cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _{C1 - C6} cyanoalkyl, 3- to 8-membered heterocyclic, _C3 - _C8 halogen cycloalkyl, _C3 - _C8 aminoalkyl cycloalkyl, _C3 - _C8 alkyl cycloalkyl, 3- to 8-membered heterocyclic alkyl, 3- to 8-membered alkyl heterocyclic cycloalkyl, 3- to 8-membered halogen heterocyclic alkyl, and C3- _C6 cycloalkyl. _8- Halcycloalkyl groups and combinations thereof with substituents of 1,2,4-thiadiazole groups.

In some embodiments, ^{R4 is} , as needed, derived from one or more groups selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, C3- _C8 cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _{C1 - C6} cyanoalkyl, 3- to 8-membered heterocyclic, _C3 - _C8 halogen cycloalkyl, _C3 - _C8 aminoalkyl cycloalkyl, _C3 - _C8 alkyl cycloalkyl, 3- to 8-membered heterocyclic alkyl, 3- to 8-membered alkyl heterocyclic cycloalkyl, 3- to 8-membered halogen heterocyclic alkyl, and C3- _C6 cycloalkyl. _8- Halcycloalkyl groups and combinations thereof with substituents of 1,3,4-thiadiazole groups.

In some embodiments, ^{R4 is} a 1,2,4-triazolyl group substituted as desired with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _{C1 - C6} cyanoalkyl, 3- to ₈ -membered heterocycloyl, _C3 - _{C8 halogen cycloalkyl, C3-C8 aminoalkyl} cycloalkyl, C3-C8 alkyl cycloalkyl, _3- to 8-membered heterocycloalkyl, 3- to 8-membered alkyl heterocycloalkyl, 3- to 8-membered halogen heterocycloalkyl and _C3 - _C8 halogen cycloalkyl and combinations thereof.

In some embodiments, ^{R4 is} a 1,3,4-oxadiazolyl group substituted as desired with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, 3- to 8-membered heterocyclic and _C3 - _C8 halogencyclic or combinations thereof.

In some embodiments, ^R4 is substituted with _C1 - _C6 alkyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _C1 - _C6 cyanoalkyl, 3- to 8-membered heterocycloalkyl, _C3 - _C8 halogen cycloalkyl, C3- _C8 aminoalkyl cycloalkyl, _C3 - _C8 alkyl cycloalkyl, 3- to ₈ -membered heterocycloalkyl, 3- to 8-membered alkyl heterocycloalkyl, 3- to 8-membered halogen heterocycloalkyl and _C3 - _C8 halogen cycloalkyl and combinations thereof.

In some implementations, ^R4 is: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In some implementations, ^R4 is: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In some implementations, ^R4 is: ; ; ; ; ; ; ; ; ; ; or .

In some embodiments, ^R5 is any suitable functional group described herein. In some embodiments, ^R5 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C3 - _C8 cycloalkyl, 3- to 8-membered heterocyclic, _C6 - _C10 aryl, or 5- or 6-membered heteroaryl, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, and _C1 - _C6 alkoxy. In some embodiments, ^R5 is H or a _C1 - _C6 alkyl group, wherein the _C1 - _C6 alkyl group is substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, and _C1 - _C6 alkoxy. In some embodiments, ^R5 is H. In some embodiments, ^R5 is a _C1 - _C6 alkyl group. In some embodiments, ^R5 is methyl, ethyl, n-propyl, or isopropyl.

In some embodiments, each ^R6 is any suitable functional group described herein. In some embodiments, each ^R6 is independently a halogen, _C1 - _C6 alkyl, cyano, _C1 - _C6 hydroxyalkyl, C1- _C6 alkoxy, or _{C1 -C6 halogen} . In some embodiments, each ^R6 is chlorine or fluorine. In some embodiments, each ^R6 is fluorine. In some embodiments, each ^R6 is a _C1 - _C6 hydroxyalkyl. In some embodiments, each ^R6 is a _C1 - _C6 hydroxyalkyl. In some embodiments, each ^R6 is _{-CH₂CH₂OH} . In other embodiments, each ^R6 is a _cyano . In some embodiments, each ^R6 is a _C1 - _C6 alkoxy. In some embodiments, each ^R6 is a methoxy.

In some embodiments, A is: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In some embodiments, A is: ; ; ; or .

In some embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof: (Ia) wherein: ^R2a is a C3-C4 cycloalkyl group substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _{C6 alkynyl} , _C1 - _C6 alkoxy and 3 to 8 heterocyclic groups as needed; and ^R4a is an isoxazolyl group substituted with one or _more substituents selected from _C1 - _C6 halogen, _C3 - _C8 cycloalkyl or _C3 - _C8 halogen cycloalkyl as needed.

In some embodiments, ^R2a is a hydroxylated branched _C1 - _C6 alkyl group. In some embodiments, ^R2a is a _C3 - _C8 cycloalkyl group. In some embodiments, ^R2a is: or .

In some embodiments, R ^4a is an isoxazolyl group substituted with a _C3 - _C8 halogen-cycloalkyl group. In some embodiments, R ^4a is a _C3 - _C8 fluoroalkylcycloalkyl group. In some embodiments, R ^4a is a fluoroalkylcyclopropyl group or a fluoroalkylcyclobutyl group. In some embodiments, R ^4a is: or .

In some embodiments, the compound is a compound of formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof: (IB) Wherein: A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, 3- to 10-membered heterocyclic, or 5- to 6-membered monocyclic heteroaryl, each of which may be substituted with one or more ^R6 groups as required; X is CH or N; Y is NH; ^R1 is H or _C1 - _C6 alkyl; ^R2 is a _C1 -C6 alkyl, C2- _C6 alkenyl, _C2 -C6 ynyl, C3- _C8 cycloalkyl, 3- to _8- membered heterocyclic, or _5- or 6-membered heteroaryl, each of which may be substituted with one or more R6 groups selected from halogen, hydroxyl, cyano, amino, _C1 -C6 alkyl, _C2 -C6 alkenyl, C2-C6 ynyl, C1-C6 alkyl, _C2 - _C6 alkenyl, C2-C6 ynyl, _C3 - _C6 alkyl, C2-C6 alkenyl, C3-C6 alkyl, C2-C6 ynyl, _C3 - _C6 alkyl, _C2 ... _{The 6-} alkoxy group is substituted with a 3- to 8-membered heterocyclic group; ^R3 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C3 - _C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 5- or 6-membered heteroaryl group, each of which may be substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, and _C1 - _C6 alkoxy groups as required; R ⁴ is selected from the following heteroaryl groups: 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, as needed, is derived from one or more groups selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, C2-C6 ynyl, _C1 - _C6 halogen, _{C3 - C8} cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _{C1 -} C6 cycloalkyl ... _6- Cyanoalkyl, 3- to 8-membered heterocyclic, _C3 - _C8 halogenated cycloalkyl, _C3 - _C8 aminoalkylcycloalkyl, _C3 - _C8 alkylcycloalkyl, 3- to 8-membered heterocyclic cycloalkyl, 3- to 8-membered alkyl heterocyclic cycloalkyl, 3- to 8-membered halogenated cycloalkyl and _C3 - _C8 halogenated cycloalkyl; ^R5 is H, _C1 - _C6 alkyl, C2-C6 alkenyl, _C2 - _C6 ynyl, _C3 - _C8 cycloalkyl, 3- to _8- membered heterocyclic, C6- _C10 aryl or _5- or 6-membered heteroaryl, each of which, as required, is substituted with one or more groups selected from halogen, hydroxyl, cyano, amino, C1-C10, _C2 - _C10 , C3 ... The substituents R6 are _6- alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl and _C1 - _C6 alkoxy; and each time ^R6 appears, it is independently halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, cyano, _C1 - _C6 hydroxyalkyl or _C1 - _C6 halogen.

In some embodiments, the compound of formula (I) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of formula (I) is an inhibitor of NEK7 in a patient or 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 an individual's disease or condition. The pain may be associated with an individual's disease or condition. Non-restrictive examples of diseases and conditions include inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriasis arthritis), myofibrosis, lupus, surgery (e.g., postoperative 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 complicated regional pain syndrome (CRPS).

In various embodiments, the compound has one of the structures described in Table 1A below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

The compounds in Table 1A are prepared as described in the examples or methods known in the art and analyzed by mass spectrometry and/or ^1H NMR. Table 1A : Representative compounds of formula (I) Number Structure Name 1 1-(4-(4-amino-7-(oxocyclobutane-3-yl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea 2 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea 3 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)pyridin-2-yl)-3-(3-(tert-butyl)isoxazo-5-yl)urea 4 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(tert-butyl)isoxazo-3-yl)urea 5 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 6 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-cyclopropylisoxazo-3-yl)urea 7 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-methylisooxazol-5-yl)urea 8 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-methylisooxazol-3-yl)urea 9 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(2-fluoroprop-2-yl)isooxazol-5-yl)urea 10 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea 11 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-3-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 12 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazo-5-yl)urea 13 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea 14 1-(4-(4-amino-7-(2-hydroxy-2-methylpropyl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 15 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)cyclohexyl-3-en-1-yl)-3-(3-(tert-butyl)isoxazo-5-yl)urea 16 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)cyclohexyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea 17 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-methylcyclopropyl)isoxazo-5-yl)urea 18 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-(tert-butyl)thiazolyl-2-yl)urea 19 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)urea 20 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isothiazolyl-5-yl)urea twenty one 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)urea twenty two 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)urea twenty three 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)urea twenty four 1-(4-(4-amino-7-(pyridin-3-yl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 25 1-(4-(4-amino-7-(pyridin-4-yl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 26 1-(4-(4-amino-7-(1-methylpiperidin-4-yl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 27 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(3-methyloxacyclobutane-3-yl)isooxazol-5-yl)urea 28 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)isoxazo-5-yl)urea 29 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-hydroxy-2-methylpropyl-2-yl)isooxazol-5-yl)urea 30 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(dibutyl)isoxazo-5-yl)urea 31 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(pent-3-yl)isooxazol-5-yl)urea 32 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-isopropylisooxazol-5-yl)urea 33 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-ethylisoxazo-5-yl)urea 34 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-methylcyclobutyl)isoxazo-5-yl)urea 35 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(2-cyanopropyl-2-yl)isooxazol-5-yl)urea 36 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(hydroxymethyl)isooxazol-5-yl)urea 37 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)pyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 38 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methylphenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 39 1-(4-(4-amino-7-(3-hydroxycyclobutyl) -7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 40 1-(6-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-4-methylpyridin-3-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 41 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,6-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 42 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 43 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-3,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 44 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-3-fluoropyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 45 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclobutyl)isoxazo-5-yl)urea 46 1-(5-(4-amino-7-(2-hydroxy-2-methylpropyl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)pyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 47 1-(4-(4-amino-7-(2-hydroxy-2-methylpropyl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 48 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)pyrimidin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 49 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-(hydroxymethyl)phenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 50 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-cyanophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 51 1-(4-(4-amino-7-(2-methoxyethyl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 52 1-(4-(4-amino-7-(2-hydroxyethyl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 53 1-(4-(4-amino-7-cyclobutyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 54 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-chlorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 55 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methoxyphenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 56 1-(4-(4-amino-7-(1-methylpyrrolidin-3-yl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 57 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclobutyl)isoxazo-3-yl)urea 58 1-(4-(4-amino-7-cyclobutyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea 59 1-(6-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)pyridin-3-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 60 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,6-difluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea 61 1-(4-(4-amino-7-(2-hydroxyethyl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea 62 1-(4-(4-amino-1-cyclopropyl- 1H -pyrrolo[3,2-c]pyridin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 63 1-(4-(4-amino-7-(1-methylacetidin-3-yl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 64 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-(difluoromethyl)phenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea 65 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(1-((dimethylamino)methyl)cyclopropyl)isoxazo-5-yl)urea 66 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-((3,3-difluoroacetidin-1-yl)methyl)isoxazo-5-yl)urea

The embodiments described herein provide a compound having formula (II): (II) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: X is N or CH; A is _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, 3 to 10-membered heterocyclic, or 5 to 6-membered aryl; ^R1 is H, halogen, _C1 - _C6 alkyl, _C3 - _C10 cycloalkyl, or 3 to 10-membered heterocyclic; ^R2 is H, halogen, _C1 - _C6 alkyl, _C1 - _C6 halogen, _C3 - _C10 cycloalkyl, or 3 to 10-membered heterocyclic; R ³ is an aminoalkyl, a 3- to 10-membered heterocyclic, a 3- to 10-membered heterocyclic alkyl, a 3- to 10-membered heterocyclic carbonyl, a 3- to 10-membered heterocyclic alkenyl, a 3- to 10-membered N-heterocyclic oxy, or a 5- to 6-membered heteroaryl; or R3 is bonded to R4, which is attached to a carbon adjacent to the carbon to which R3 is attached, to form a C3-C8 cycloalkyl; ^R4 is independently halogen, cyano, _C1 - _C6 alkyl, _C1 - _C6 halogen, _C1 - _C6 alkoxy, _C1 - _C6 halogenalkoxy, _C3 - _C8 halogen cycloalkyl, or _C3 - _C8 cycloalkyl; and n is 0, 1, 2, 3, or 4.

In some embodiments, A is a _C6 - _C10 aryl group. In some embodiments, A is a phenyl group. In some particular embodiments, A is a 5- to 6-membered heteroaryl group. In some particular embodiments, A is a pyridyl group. In some more particular embodiments, A is a _C3 - _C10 cycloalkyl group or a 3- to 10-membered heterocyclic group.

In certain embodiments, A is substituted with one or more substituents selected from halogen, cyano, _C1 - _C6 alkyl, _C1 - _C6 halogen, _C1 - _C6 alkoxy, _C1 - _C6 halogenalkoxy, or _C3 - _C8 cycloalkyl. In some embodiments, A is substituted with one or more halogen substituents. In some embodiments, A is unsubstituted.

In some embodiments, ^R1 is H. In some embodiments, ^R1 is a _C1 - _C6 alkyl group. In some specific embodiments, ^R1 is methyl. In some embodiments, ^R1 is a _C3 - _C10 cycloalkyl group or a 3- to 10-membered heterocyclic group. In some embodiments, ^R1 is a halogen group (e.g., fluorine, chlorine, bromine, etc.).

In some embodiments, ^R2 is H. In some more specific embodiments, ^R2 is a halogen. In more specific embodiments, ^R2 is chlorine or fluorine. In some other embodiments, ^R2 is a _C3 - _C10 cycloalkyl (e.g., cyclopropyl). In some embodiments, ^R2 is a _C1 - _C6 alkyl, _C1 - _C6 halogen, or a 3- to 10-membered heterocyclic group. In some embodiments, ^R2 is a _C1 - _C6 alkyl (e.g., methyl).

In some embodiments, X is CH or ^CR3 . In some specific embodiments, the compound has the following structure (IIa): (IIa) or a medically acceptable salt, stereoisomer, or prodrug thereof.

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

In some embodiments, X is N. In some more specific embodiments, the compound has the following structure (IIc): (IIc) or a medically acceptable salt, stereoisomer, or prodrug thereof.

In some embodiments, the compound has the following structure (IId): (IId) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein R ^3a , each time it appears, is independently halogen, cyano, _C1 - _C6 alkyl, _C1 - _C6 halogen, C1- _{C6 alkoxy, C1-C6 halogenalkoxy ,} aminoalkyl, C3- _C8 cycloalkyl, 3 to ₁₀ -membered heterocyclic, 3 to 10 _- membered heterocyclic, 3 to 10-membered heterocyclic alkyl, 3 to 10-membered heterocyclic carbonyl, 3 to 10-membered heterocyclic alkenyl, 3 to 10-membered N-heterocyclic oxy or 5 to 6-membered heteroaryl; and m is 0, 1, 2, 3, or 4.

In some embodiments, R ^3a is independently a halogen or a 3 to 10-membered heterocyclic group each time it appears. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

In some embodiments, the compound has the following structure (IId1): (IId1) or its pharmaceutically acceptable salt, stereoisomer, or prodrug.

In some embodiments, ^R3 is substituted. In some embodiments, ^R3 is unsubstituted. In some embodiments, ^R3 is substituted with an alkyl (e.g., _C1 - _C6 alkyl), heterocyclic, halogen, halogen (e.g., _C1 - _C6 halogen), alkylcarbonyl (e.g., -C(=O) _CH3 ), hydroxyalkyl, alkoxyalkyl, cycloalkyl (e.g., _C3 - _C8 cycloalkyl), alkylamino, or combinations thereof.

In some of the above embodiments, ^R3 is an aminoalkyl group. In some embodiments, ^R3 has the following structure: .

In some embodiments, ^R3 is a 3- to 10-membered heterocyclic group. In some embodiments, ^R3 is a morpholino group. In some embodiments, ^R3 is a piperazine group. In certain embodiments, ^R3 has one of the following structures: or .

In some embodiments, ^R3 is a 3- to 10-membered heterocyclic alkyl group. In some more specific embodiments, ^R3 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In some embodiments, ^R3 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In some embodiments, ^R3 is a 3- to 10-membered heterocyclic carbonyl group. In a more specific embodiment, ^R3 has the following structure: .

In some embodiments, ^R3 is a 5- to 6-membered heteroaryl group. For example, in some embodiments, ^R3 has the following structure: .

In some embodiments, ^R3 is a 3- to 10-membered heterocyclic alkenyl group. In more specific embodiments, ^R3 has the following structure: .

In some embodiments, ^R3 is a 3 to 10-membered N-heterocyclic oxy group. In more specific embodiments, ^R3 has one of the following structures: ; ; or .

In some implementations, ^R3 has one of the following structures: ; ; ; ; ; or .

In some embodiments, n is 1 or 2. In some embodiments, n is 2. In some other embodiments, n is 1. In some specific embodiments, ^R4 is independently chlorine, fluorine, cyano, _C1 - _C6 alkyl, C1-C6 halogen, _C1 - _C6 alkoxy, _C1 - _C6 halogenalkoxy, _{C3 - C8} halogencycloalkyl, or _{C3 - C8} cycloalkyl each time it appears. In some embodiments, ^R4 is independently methyl, chlorine, fluorine, cyano, trifluoromethyl, methoxy, trifluoromethoxy, 2,2-difluorocyclopropyl, or cyclopropyl each time it appears. In some embodiments, ^R4 is independently methyl, chlorine, fluorine, cyano, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, 2,2-difluorocyclopropyl, or cyclopropyl each time it appears.

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.

In some embodiments, X is CH and n is 4. In some other embodiments, X is CH and 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.

In some embodiments, the compound of formula (II) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of formula (II) is an inhibitor of NEK7 in a patient or 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 may be acute inflammatory pain. The pain may be a symptom of an individual's disease or condition. The pain may be associated with an individual's disease or condition. Non-restrictive examples of diseases and conditions include inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriasis arthritis), myofibrosis, lupus, surgery (e.g., postoperative 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 complicated regional pain syndrome (CRPS).

In various embodiments, the compound has one of the structures described in Table 1B below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

The compounds in Table 1B are prepared as described in the examples or methods known in this art and analyzed by mass spectrometry and/or ^1H NMR. Table 1B : Representative compounds of formula (II) compound Structure Name II-1 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-2 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-fluoro-4-(morpholinylmethyl)phenyl)urea II-3 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-(4-methyl- 1H -imidazol-1-yl)-5-(trifluoromethyl)phenyl)urea II-4 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-(morpholinylmethyl)-3-(trifluoromethyl)phenyl)urea II-5 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea II-6 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)urea II-7 1-(4-((3-cyclopropyl- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-8 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)urea II-9 1-(4-(acetidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)-3-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)urea II-10 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((3-(dimethylamino)acridin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-11 1-(4-((3-chloro-2-methyl- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-12 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((3,3-difluoroacetidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-13 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-cyclopropylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-14 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((( 1R , 5S )-3-methyl-3,8-diazabiscyclic[3.2.1]oct-8-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-15 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((( 3aR , 6aS )-5-methylhexahydropyrrolo[3,4- c ]pyrrolo-2( 1H )-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-16 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-(1-(4-methylpiperazin-1-yl)ethyl)-3-(trifluoromethyl)phenyl)urea II-17 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-18 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((6-methyl-2,6-diazaspiro[3.3]hept-2-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-19 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-(4-methylpiperazin-1-carbonyl)-3-(trifluoromethyl)phenyl)urea II-20 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((7-methyl-4,7-diazaspiro[2,5]oct-4-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-21 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((5-methyl-2,5-diazabiscyclic[2.2.2]oct-2-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-22 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)urea II-23 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-methylphenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-24 1-(5-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)pyridin-2-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-25 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea II-26 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea II-27 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea II-28 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-29 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-30 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea II-31 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)urea II-32 1-(4-((3-chloro- 1H -pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-(4-methyl- 1H -imidazol-1-yl)-3-(trifluoromethyl)phenyl)urea II-33 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-methyl-1,4-diazacycloheptan-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-34 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-35 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-cyano-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea II-36 1-(2-fluoro-4-((3-methyl- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-37 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-38 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-isopropylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-39 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea II-40 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((1-methylpiperidine-4-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-41 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-(difluoromethyl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea II-42 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-(difluoromethyl)-4-((4-ethylpiperazin-1-yl)methyl)phenyl)urea II-43 1-(4-((2,3-dichloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-44 1-(4-((2,3-dichloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-methylphenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-45 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea II-46 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(6-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)pyridin-3-yl)urea II-47 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4,4-difluoropiperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-48 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((1-(oxocyclobutane-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea II-49 1-(4-((4-acetylopiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)urea II-50 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-(2-fluoroethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-51 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((3-fluoro-1-(oxocyclobutane-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea II-52 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((3-fluoropiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea II-53 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-(oxocyclobutane-3-yl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-54 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((2-fluoro-4-(oxocyclobutane-3-yl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-55 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-(piperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl)urea II-56 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-(2,2-difluorocyclopropyl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea II-57 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-(dimethylamino)piperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-58 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(6-((1-methylpiperidin-4-yl)oxy)-5-(trifluoromethyl)pyridin-3-yl)urea II-59 1-(4-((1-acetylopiridin-4-yl)oxy)-3-(trifluoromethyl)phenyl)-3-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)urea II-60 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-methyl-4,7-diazaspiro[2.5]oct-7-yl)methyl)-3-(trifluoromethyl)phenyl)urea II-61 1-(2-fluoro-4-((3-methyl- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)phenyl)-3-(6-((1-methylpiperidin-4-yl)oxy)-5-(trifluoromethyl)pyridin-3-yl)urea II-62 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethoxy)phenyl)urea II-63 1-(2-fluoro-4-((3-methyl- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)phenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea II-64 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea II-65 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)urea II-66 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(4-((3-fluoro-1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea II-67 1-(4-((3-chloro- 1H -pyrrolo[2,3- b ]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3,3-difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro- 1H -inden-5-yl)urea

The embodiments described herein provide a compound having formula (III): (III) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, 3-10-membered heterocyclic, or 5-6-membered heteroaryl; X is N or ^CR4 ; Y is N or CH; ^R1 is a _C1 - _C6 alkyl, _C1 - _C6 hydroxyalkyl, _C3 - _C10 cycloalkyl, or 3-10-membered heterocyclic; ^R2 is a 3-10-membered heterocyclic, 3-10-membered heterocyclic alkyl, 3-10-membered heterocyclic alkenyl, 3-10-membered heterocyclic carbonyl, 3-10-membered heterocyclic oxy, or 5-6-membered heteroaryl; or ^R2 is connected to R The carbon adjacent to the carbon atom ² is bonded to ^form a _C3 - _C8 cycloalkyl group; ^R3 is independently halogen, cyano, _C1 - _C6 alkyl, C1-C6 halogen, _C1 - _C6 alkoxy, _C1 - _C6 halogenalkoxy, or _C3 - _C8 cycloalkyl group each time it appears; ^R4 is H, _C1 - _{C6 alkyl, C1-C6 halogen ,} or _C3 - _C8 cycloalkyl group; and n is 0, 1, 2 _{, 3} , or 4.

In some embodiments, A is a _C6 - _C10 aryl group. In some particular embodiments, A is a phenyl group. In some embodiments, A is a 5- to 6-membered heteroaryl group. In some particular embodiments, A is a pyridyl group. In some embodiments, A is _{a C3} - _C10 cycloalkyl group or a 3- to 10-membered heterocycloalkyl group. In more particular embodiments, A is substituted with one or more substituents selected from halogen, cyano, _C1 - _C6 alkyl, _C1 - _C6 halogen, _C1 - _C6 alkoxy, _C1 - _C6 halogenalkoxy, or _C3 - _C8 cycloalkyl. In some more particular embodiments, A is substituted with one or more halogen substituents. In other embodiments, A is unsubstituted.

In some embodiments, X is ^CR4 . In more specific embodiments, ^R4 is H or a _C1 - _C6 alkyl group. In some embodiments, ^R4 is H. In some specific embodiments, X is N.

In some embodiments, ^R1 is a _C1 - _C6 alkyl group. In some more specific embodiments, ^R1 is methyl or isopropyl. In some embodiments, ^R1 is a _C1 - _C6 hydroxyalkyl group. In some more specific embodiments, ^R1 has one of the following structures: or .

In some implementations, ^R1 has one of the following structures: ; or .

In some embodiments, ^R1 is a _C1 - _C6 carboxyalkyl group. In more specific embodiments, ^R1 has one of the following structures: or .

In some embodiments, ^R1 is a _C1 - _C6 alkoxyalkyl group. In some embodiments, ^R1 has the following structure: .

In some embodiments, ^R1 is a _C3 - _C10 cycloalkyl group. In more specific embodiments, ^R1 is cyclopropyl or cyclobutyl. In some embodiments, ^R1 is a 3- to 10-membered heterocyclic group. In some embodiments, ^R1 is an oxadicyclobutane, pyrrolidone, or piperidinyl. In some embodiments, ^R1 is an oxadicyclobutane, pyrrolidone, acridine, or piperidinyl.

In some embodiments, ^R1 is a _C1 - _C6 ynyl group. In some embodiments, ^R1 has one of the following structures: or .

In some embodiments, ^R1 is substituted with one or more substituents selected from halogen, cyano, _C1 - _C6 alkyl, _C1 - _C6 halogen, _C1 - _C6 alkoxy, _C1 - _C6 halogenalkoxy, or _C3 - _C8 cycloalkyl. In some embodiments, ^R1 is substituted with one or more substituents selected from halogen, cyano, _C1 - _C6 alkyl, _C1 - _C6 halogen, _C1 - _C6 alkoxy, _C1 - _C6 halogenalkoxy, -S(O) _₂CH₃ , -S(O) _{₂cyclopropyl} , or _C3 - _C8 cycloalkyl. In _more specific embodiments, ^R1 is substituted with one or more _C1 - _C6 alkyl substituents. In other embodiments, ^R1 is unsubstituted.

In certain specific implementations, ^R1 has one of the following structures: ;-CH ₃ ; ; ; ; ; ; or .

In some implementations, ^R1 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ;-CH ₃ ; ; ; ; ; ; or .

In some specific embodiments, the compound has the following structure (IIIa): (IIIa) or a medically acceptable salt, stereoisomer, or prodrug thereof.

In some embodiments, Y is N. In other embodiments, Y is CH.

In certain specific embodiments, the compound has the following structure (IIIb): (IIIb) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

In some embodiments, ^R2 is a 3- to 10-membered heterocyclic group. In some specific embodiments, ^R2 is a morpholino group. In other specific embodiments, ^R2 is a piperazine group. In some even more specific embodiments, ^R2 has one of the following structures: or .

In some embodiments, ^R2 is a 3- to 10-membered heterocyclic alkyl group. In some more specific embodiments, ^R2 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In some more specific implementations, ^R2 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In some embodiments, ^R2 is a 3- to 10-membered heterocyclic carbonyl group. In some more specific embodiments, ^R2 has the following structure: .

In some embodiments, ^R2 is a 5- to 6-membered heteroaryl group. In some more specific embodiments, ^R2 has the following structure: .

In some embodiments, ^R2 is a 3- to 10-membered heterocyclic oxygen group. In some more specific embodiments, ^R2 has the following structure: .

In some implementations, ^R2 has one of the following structures: ; ; ; ; ; .

In some more specific implementations, ^R2 has the following structure: .

In some embodiments, n is 0. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, ^R3 is halogen, cyano, _C1 - _C6 alkyl, _C1 - _C6 halogen, _C1 - _C6 alkoxy, _C1 - _C6 halogenalkoxy, or _C3 - _C8 cycloalkyl. In certain embodiments, ^R3 is methyl, chloro, fluorine, cyano, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyclopropyl. In certain embodiments, n is 1 or 2 and ^R3 is halogen, _C1 - _C6 alkyl, _C1 - _C6 halogen, _{C1-C6 alkoxy, C1 - C6 halogenalkoxy} , or _C3 - _C8 cycloalkyl. In some embodiments, n is 1 and ^R3 is halogen, _C1 - _C6 alkyl, _C1 - _C6 halogen, _C1 - _C6 alkoxy, _C1 - _C6 halogenalkoxy, or _C3 - _C8 cycloalkyl. In some embodiments, n is 1 and ^R3 is methyl, chloro, fluorine, trifluoromethyl, methoxy, trifluoromethoxy, or cyclopropyl.

In some embodiments, the compound has the following structure (IIIc): (IIIc) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: R ^3a is a halogen or a 3 to 10-membered heterocyclic group; and n1 is 1, 2 or 3.

In some embodiments, R ^3a is fluoro or piperazine. In more specific embodiments, the compound has the following structure (IIIc1): (IIIc1) or its medically acceptable salt, stereoisomer, or prodrug.

In some other embodiments, the compound of formula (III) is a modulator of the NLRP3 inflammasome. In some other embodiments, the compound of formula (III) is an inhibitor of NEK7 in a patient or 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 an individual's disease or condition. The pain may be associated with an individual's disease or condition. Non-restrictive examples of diseases and conditions include inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriasis arthritis), myofibrosis, lupus, surgery (e.g., postoperative 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 complicated regional pain syndrome (CRPS).

In various embodiments, the compound has one of the structures described in Table 1C below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

The compounds in Table 1C are prepared as described in the examples or methods known in this art and analyzed by mass spectrometry and/or ^1H NMR. Table 1C : Representative compounds of structure (III) compound Structure Name III-1 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(2-fluoro-4-(metholinylmethyl)phenyl)urea III-2 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-fluoro-4-(metholinylmethyl)phenyl)urea III-3 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)urea III-4 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((3-methyl-3,8-diazabiscyclic[3.2.1]oct-8-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-5 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-(((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-6 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-(1-(4-methylpiperazin-1-yl)ethyl)-3-(trifluoromethyl)phenyl)urea III-7 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((6-methyl-2,6-diazaspiro[3.3]hept-2-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-8 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((7-methyl-4,7-diazaspiro[2,5]oct-4-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-9 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((5-methyl-2,5-diazabiscyclic[2.2.2]oct-2-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-10 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-(4-methylpiperazin-1-carbonyl)-3-(trifluoromethyl)phenyl)urea III-11 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-12 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)urea III-13 1-(4-(4-amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-14 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-15 1-(4-(4-amino-7-(2-hydroxy-2-methylpropyl) -7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-16 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)urea III-17 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-2-(trifluoromethoxy)phenyl)urea III-18 1-(4-(4-amino-7-methyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-19 1-(4-(4-amino-7-cyclobutyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-20 1-(4-(4-amino-7-(1-methylpyrrolidin-3-yl) -7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-21 1-(4-(4-amino-7-(1-methylpiperidin-4-yl) -7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-22 1-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(3-methyl-4-morpholinylphenyl)urea III-23 1-(4-(4-amino-1-(oxocyclobutane-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(3-methyl-4-morpholinylphenyl)urea III-24 1-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-25 1-(4-(4-amino-1-(oxocyclobutane-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)urea III-26 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(2-fluoro-4-(metholinylmethyl)phenyl)urea III-27 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea III-28 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-29 1-(4-(4-amino-1-(2-hydroxy-2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-30 1-(5-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-2-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-31 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-32 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-(morpholinylmethyl)-3-(trifluoromethyl)phenyl)urea III-33 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-methyl-4-morpholinylphenyl)urea III-34 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-35 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-chlorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-36 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea III-37 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea III-38 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea III-39 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea III-40 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea III-41 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-42 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-43 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-44 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methyl-1,4-diazacycloheptane-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-45 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-46 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)urea III-47 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea III-48 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-fluoro-4-(metholinylmethyl)phenyl)urea III-49 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-(4-methylpiperazin-1-carbonyl)-3-(trifluoromethyl)phenyl)urea III-50 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-51 1-(5-(4-amino-1-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)pyridin-2-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-52 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidine-4-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-53 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea III-54 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-cyano-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea III-55 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-chlorophenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-56 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-fluorophenyl)-3-(3-methyl-4-morpholinylphenyl)urea III-57 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea III-58 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)urea III-59 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(difluoromethyl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea III-60 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(difluoromethyl)-4-((4-ethylpiperazin-1-yl)methyl)phenyl)urea III-61 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(6-((1-methylpiperidin-4-yl)oxy)-5-(trifluoromethyl)pyridin-3-yl)urea III-62 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-cyclopropylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-63 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-isopropylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-64 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((5-methyl-2,5-diazabiscyclic[2.2.1]hept-2-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-65 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(2-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)urea III-66 1-(4-((4,7-diazaspiro[2.5]oct-4-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)urea III-67 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoropyridin-2-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-68 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(6-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)pyridin-3-yl)urea III-69 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-(dimethylamino)piperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-70 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((2,4-dimethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-71 1-(4-(4-amino-7-(2-hydroxyethyl) -7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-72 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-(difluoromethyl)-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)urea III-73 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methyl-4,7-diazaspiro[2,5]oct-7-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-74 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-(methylamino)piperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-75 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-aminopiperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-76 1-(4-(4-amino-1-(2-hydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-77 1-(4-(4-amino-1-(2-methoxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-78 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethoxy)phenyl)urea III-79 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-(piperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl)urea III-80 1-(4-((4-acetylopiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)urea III-81 1-(4-(4-amino-7-(2-methoxyethyl) -7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-82 1-(4-((1-acetylopiridin-4-yl)oxy)-3-(trifluoromethyl)phenyl)-3-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)urea III-83 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((1-(oxocyclobutane-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea III-84 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-(2-fluoroethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-85 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4,4-difluoropiperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-86 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-(oxocyclobutane-3-yl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-87 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)urea III-88 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea III-89 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((3-fluoro-1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (diastereomeric isomer #1) III-90 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((3-fluoro-1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (diastereomer #2) III-91 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((3-fluoro-1-(oxocyclobutane-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (diastereomeric #1) III-92 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((3-fluoro-1-(oxocyclobutane-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea (diastereomeric isomer #2) III-93 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)urea III-94 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(3,3-difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-yl)urea III-95 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-(piperidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)urea III-96 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-hydroxypiperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-97 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-(cyclopropylsulfonyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-98 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-(methylsulfonylmethane)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-99 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-(2-(methylsulfonylurea)ethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-100 2-(4-(4-(3-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)ureo)-2-(trifluoromethyl)benzyl)piperazin-1-yl)ethane-1-sulfonic acid III-101 1-(4-(4-amino-7-(1-(methylsulfonylmethane)piperidin-4-yl) -7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-102 1-(4-(4-amino-7-(1-(cyclopropylsulfonyl)piperidin-4-yl) -7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-103 1-(4-(4-amino-1-(5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-104 1-(4-(4-amino-7-(1-methylacetidin-3-yl) -7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-105 1-(4-(4-amino-7-isopropyl- 7H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-106 3-(4-amino-5-(3-fluoro-4-(3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureo)phenyl) -7H -pyrrolo[2,3-d]pyrimidin-7-yl)propionic acid III-107 4-(4-amino-5-(3-fluoro-4-(3-(4-(((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureo)phenyl) -7H -pyrrolo[2,3-d]pyrimidin-7-yl)butyric acid III-108 1-(4-(4-amino-1-(1-methylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-109 1-(4-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-110 1-(4-(4-amino-1-(1-methylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-111 1-(4-(4-amino-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-112 1-(4-(4-amino-1-(acetidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea III-113 1-(4-(4-amino-1-(1-methylacetidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea III-114 1-(4-(4-amino-1-(1-methylacetidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-115 1-(4-(4-amino-1-(prop-2-yn-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-116 1-(4-(4-amino-1-(prop-2-yn-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea III-117 1-(4-(4-amino-1-(but-3-yn-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea III-118 1-(4-(4-amino-1-(but-3-yn-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

The embodiments described herein provide a compound having formula (IV): (IV) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, 3- to 10-membered heterocyclic, or 5- to 6-membered monocyclic heteroaryl, each of which may be substituted with one or more ^{R5 groups} as required; X is N or ^CR1c ; Y is N or ^CR1d ; Z is C( ^R6 )( ^R7 ) or ^NR6 ; ^R1a , ^R1b , ^R1c , and ^R1d are each independently H, halogen, _C1 - _C6 alkyl, or _C3 - _C8 cycloalkyl; ^R2a and ^R2b are each independently H, halogen, cyano, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 R2a is a _C1-C6 halogenated, _C1 - _C6 alkoxy, _C1 - _C6 halogenated, _C3 - _C8 cycloalkyl, or _C3 - _C8 halogenated, provided that ^R2a and ^R2b are not both H; ^R3 is a _C1 - _C6 alkyl, C2-C6 alkenyl, _C2 - _C6 alkynyl, _{C3 -C8 cycloalkyl} , 3 to _10- membered heterocyclic, heteroaryl, or aryl group, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, and _C1 -C6 alkoxy; R4 is H, C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C8 cycloalkyl, C3- _C8 cycloalkyl, _C3 - _C8 cycloalkyl, ³ to _10- membered heterocyclic, heteroaryl, or aryl group. _R5 is substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, C2-C6 alkenyl, _C2 - _C6 alkynyl, and _C1 - _C6 alkoxy, as desired; R5 is independently substituted with H, C1-C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, or _C1 - _C6 halogen in each occurrence; ^R6 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, or _C1 - _C6 hydroxyalkyl; and ^R7 is H, OH, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 ^- _C6 alkynyl, or _{C1 - C6} hydroxyalkyl. _6- alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl or _C1 - _C6 hydroxyalkyl.

In some embodiments, A is a _C6 - _C10 aryl group. In some embodiments, A is a _C3 - _C10 cycloalkyl group. In some particular embodiments, A is a 3- to 10-membered heterocyclic group. In some particular embodiments, A is a 5- to 6-membered monocyclic heteroaryl group. In some more particular embodiments, A is substituted with one or more ^R5 groups. In some more particular embodiments, A is substituted with one or more ^R5 groups. In some embodiments, A is substituted with a substituent selected from halogens, _C1 - _C6 halogens, and combinations thereof. In some embodiments, A is substituted with a substituent selected from fluorines, trifluoromethyl groups, and combinations thereof. In more particular embodiments, A is unsubstituted.

In some embodiments, X is N. In some embodiments, X is CR ^1c . In some particular embodiments, R ^1c is H. In some more particular embodiments, R ^1c is halogen (e.g., R ^1c is chlorine). In some other embodiments, R ^1c is _C1 - _C6 alkyl (e.g., R ^1c is methyl). In some embodiments, R ^1c is _C3 - _C8 cycloalkyl (e.g., R ^1c is cyclopropyl).

In some embodiments, Y is N. In other embodiments, Y is CR ^1d . In some embodiments, R ^1d is H. In certain specific embodiments, R ^1d is halogen, _C1 - _C6 alkyl, or _C3 - _C8 cycloalkyl.

In some embodiments, Z is C( ^R6 )( ^R7 ). In more specific embodiments, ^R6 is H. In some embodiments, ^R7 is -OH, _C1 - _C6 alkyl, _C2 -C6 alkenyl, _C2 - _C6 alkynyl, or _C1 - _{C6 hydroxyalkyl} . In some specific embodiments, both ^R6 and ^R7 are H.

In some other embodiments, Z is NR ^6. In some other embodiments, R ⁶ is H. In some other embodiments, R ⁶ is _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl or _C1 - _C6 hydroxyalkyl.

In some embodiments, R ^1a is H. In some embodiments, R ^1a is a _C1 - _C6 alkyl group (e.g., R ^1a is methyl). In some embodiments, R ^1a is a halogen or a _C3 - _C8 cycloalkyl group.

In some embodiments, R ^1b is H. In some embodiments, R ^1b is halogen, _C1 - _C6 alkyl, or _C3 - _C8 cycloalkyl.

In some embodiments, R ^2a is a _C1 - _C6 alkyl group (e.g., R ^2a is tributyl or methyl). In some embodiments, R ^2a is a _C3 - _C8 cycloalkyl group. In more specific embodiments, R ^2a is cyclopropyl. In some embodiments, the cyclopropyl group is unsubstituted. In some embodiments, the cyclopropyl group is substituted with at least one halogen (e.g., trifluoromethyl). In some more specific embodiments, R ^2a has the following structure: .

In some embodiments, R ^2b is H. In some embodiments, R ^2b is halogen, cyano, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 -C6 halogen, _C1 - _C6 alkoxy, _{C1 -C6 halogenalkoxy} , _C3 - _C8 cycloalkyl, or _C3 - _C8 halogencycloalkyl.

In certain specific embodiments, ^R3 is a _C1 - _C6 alkyl group (e.g., ^R3 is a methyl group).

In some embodiments, ^R3 is an aryl group. For example, in some embodiments, ^R3 is a phenyl group. In some embodiments, the phenyl group is substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, and _C1 - _C6 alkoxy groups. In some other embodiments, the phenyl group is unsubstituted.

In some other embodiments, ^R3 is a 3- to 10-membered heterocyclic group. In more specific embodiments, ^R3 is piperidinyl. In certain specific embodiments, the piperidinyl group is substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _{C6 alkynyl, and C1-C6 alkoxy .} In certain embodiments, ^R3 has the following structure: .

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 to 8-membered heterocyclic, _C6 - _C10 aryl, or 5- or 6-membered heteroaryl.

In some other embodiments, the compound of formula (IV) is a modulator of the NLRP3 inflammasome. In some other embodiments, the compound of formula (IV) is an inhibitor of NEK7 in a patient or 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 an individual's disease or condition. The pain may be associated with an individual's disease or condition. Non-restrictive examples of diseases and conditions include inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriasis arthritis), myofibrosis, lupus, surgery (e.g., postoperative 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 complicated regional pain syndrome (CRPS).

In various embodiments, the compound has one of the structures described in Table 1D below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

The compounds in Table 1D are prepared as described in the examples or methods known in this art and analyzed by mass spectrometry and/or ^1H NMR. Table 1D : Representative compounds by structure (IV) compound Structure Name IV-1 1-(4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)urea IV-2 1-(4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-(trifluoromethyl)phenyl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)urea IV-3 1-(4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2-fluorophenyl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)urea IV-4 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)urea IV-5 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)urea IV-6 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)urea IV-7 1-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-3-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)urea IV-8 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2,6-difluorophenyl)urea IV-9 1-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(1-(4-cyanophenyl)-3-methyl-1H-pyrazol-5-yl)urea IV-10 1-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea IV-11 1-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)urea IV-12 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluorophenyl)urea IV-13 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(4-((5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2-fluorophenyl)urea IV-14 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(4-((3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)urea IV-15 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2,5-difluorophenyl)urea IV-16 1-(4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)cyclohexyl)-3-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)urea IV-17 1-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea IV-18 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(4-((3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)urea IV-19 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)oxy)phenyl)urea IV-20 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)cyclohexyl)urea IV-21 1-(3-(tert-butyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazol-5-yl)-3-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)urea IV-22 N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-2-(4-((3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluorophenyl)acetamide

The embodiments described herein provide a compound having formula (V): (V) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, 3- to 10-membered heterocyclic, or 5- to 6-membered monocyclic heteroaryl, each of which may be substituted with one or more ^R5 groups as desired; X is N or CH; Y is CHOH or NH; ^R1 is H or _C1 - _C6 alkyl; ^R2 is a _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, C3- _C8 cycloalkyl, 3- to 8 _- membered heterocyclic, or 5- or 6-membered heteroaryl, each of which may be substituted with one or more R5 groups selected from halogen, hydroxyl, cyano, amino, _C1 -C6 alkyl, C2- _C6 alkenyl, _C2 - _C8 alkyl, C3 _-C8 alkenyl ... _{The 6-} alkynyl group, _C1 - _C6 alkoxy group, and 3 to 8-membered heterocyclic group are substituents; ^R3 is a heteroaryl group selected from the following: 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, as desired, is substituent from one or more groups selected from amino, halogen, cyano, C1-C6 alkyl, _C2 -C6 alkenyl, C2- _C6 alkynyl, _C1 -C6 halogen, C3- _C6 alkyl, _C4 - _C6 alkyl, _C5 -C6 alkyl, _C6 -C6 alkyl, C4 _... Substituents of _8- cycloalkyl, _C3 - _C8 alkylcycloalkyl, _C3 - _C8 halogen cycloalkyl, _C3 - _C8 aminoalkylcycloalkyl, _C1 - _C6 cyanoalkyl, C1- _C6 amino, _C1 - _C6 hydroxyalkyl, 3- to 8-membered heterocycloalkyl, _3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered halogen heterocycloalkyl, 3- to 8-membered halogen heterocycloalkyl, _C3 - _C8 halogen cycloalkyl and _C3 - _C8 halogen cycloalkyl and combinations thereof; ^R4 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C3 -C ₈ -cycloalkyl, 3 to 8-membered heterocyclic, _C6 - _C10 aryl or 5- or 6-membered heteroaryl, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl and _C1 - _C6 alkoxy; and ^R5 is independently halogen, cyano, _C1 - _{C6 alkyl, C1-C6 hydroxyalkyl or C1} - _C6 halogen in each occurrence.

In some embodiments of structure (V), A is a _C6 - _C10 aryl, _C3 -C10 cycloalkyl, 3 to 10-membered heterocyclic, or 5 to 6-membered monocyclic heteroaryl, each of which may be substituted by one or more ^R5 groups as desired; X is N or CH; Y is CHOH or NH; R1 is H or _C1 - _C6 alkyl; ^R2 is ^C1 - _C6 alkyl, _C2 -C6 alkenyl, C2- _C6 ynyl, _C3 - _{C8 cycloalkyl, 3 to 8-membered heterocyclic, or 5- or 6-membered heteroaryl, each of which may be substituted by one or more R5 groups selected from halogen, hydroxyl, cyano, amino, C1-C6 alkyl , C2 -} C6 alkenyl, C2-C6 ynyl, C1-C6 alkyl, _C2 -C6 alkenyl, C2-C6 ynyl, C3-C6 alkyl, C2-C6 alkenyl, C3- _C6 ynyl, _C3 - _C6 alkyl, _C2 -C6 alkenyl, C2- _C6 ynyl, C3- _C6 alkyl ... _{The 6-} alkoxy group is substituted with a substituent of a 3- to 8-membered heterocyclic group; ^R3 is selected from the following heteroaryl groups: 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, triazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, each of which, as desired, is substituted with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _{C6 alkenyl, C2-C6 ynynyl , C1} - _C6 halogen, _C3 - _C8 cycloalkyl, and C3 _- C6 cycloalkyl. _{The 8-} halogenated cycloalkyl group is substituted; ^R4 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C3 - _C8 cycloalkyl, 3 to 8-membered heterocyclic, _C6 - _C10 aryl or 5- or 6-membered heteroaryl, each of which is substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl and _C1 - _C6 alkoxy; and ^R5 is independently halogen, _C1 - _C6 alkyl, _C1 - _C6 alkyl or _C1 - _C6 halogen in each occurrence.

One embodiment provides a compound of structure (I) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, 3- to 10-membered heterocyclic, or 5- to 6-membered monocyclic heteroaryl, each of which is substituted with one or more ^{R5 groups} as desired; X is N or CH; Y is CHOH or NH; ^R1 is H or _C1 - _C6 alkyl; R2 is H, C1-C6 alkyl, _C2 - _C6 alkenyl, C2-C6 alkynyl, _C3 - _C8 cycloalkyl, _3- to _8- membered heterocyclic, or 5- or 6-membered heteroaryl, ^each of which is substituted with one or more R5 groups selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, C2- _C6 alkyl, C3- _C8 cycloalkyl, 3- to 8-membered heterocyclic, or 5- or 6- _membered heteroaryl groups as desired. R3 is substituted with a substituent of _-C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 alkoxy, or a 3- to 8-membered heterocyclic group; ^R3 is a heteroaryl group selected from the following: 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 may be substituted with one or more substituents selected from amino, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, _C1 -C6 alkyl, C2-C6 alkenyl, C2- _C6 ynyl, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, C2 _-C6 alkyl ... Substituents of _6- halogenated, _C3 - _C8 cycloalkyl, _C3 - _C8 alkylcycloalkyl, _C3 - _C8 halogenated cycloalkyl, _C3 - _C8 aminoalkylcycloalkyl, _C1 - _C6 cyanoalkyl, C1-C6 amino, _{C1 -C6 hydroxyalkyl} , 3 to ₈ -membered heterocyclic, 3 to 8-membered heterocyclic alkyl, 3 to 8-membered heterocyclic cycloalkyl, 3 to 8-membered halogenated, ₃ to 8-membered halogenated cycloalkyl, C3- _C8 halogenated and _C3 - _C8 halogenated alkyl and combinations thereof; ^R4 is H, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C3 -C ₈ cycloalkyl, 3 to 8-membered heterocyclic, C ₆ -C ₁₀ aryl or 5- or 6-membered heteroaryl, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and C ₁ -C ₆ alkoxy; and R ⁵ is independently halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ halogen in each occurrence.

In some embodiments, ^R1 is H. In other embodiments, ^R1 is a _C1 - _C6 alkyl group, such as methyl.

In one embodiment, a compound with structure (I) is provided, wherein ^R2 is a branched _C4 - _C6 alkyl, _C3 - _C4 cycloalkyl, _C3 - _C8 heterocyclic or 5- or 6-membered heteroaryl, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _{C1 - C6} alkyl, C2 _{- C6} alkenyl, _C2 -C6 alkynyl, _C1 - _C6 alkoxy and 3- to 8-membered heterocyclic groups.

In another embodiment, a compound with structure (I) is provided, wherein ^R2 is a branched _C4 - _C6 alkyl, _C3 - _C4 cycloalkyl, or _C3 - _C8 heterocyclic group, each of which is substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, and 3- to 8-membered heterocyclic groups.

In a particular embodiment, ^R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _{C6 alkyl} , _C2 -C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, and 3- to 8-membered heterocyclic groups.

In various embodiments, ^R2 is methyl, isopropyl, 2-methylpropyl, or allyl, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, and 3- to 8-membered heterocyclic groups.

In various embodiments, ^R2 is methyl, ethyl, isopropyl, 2-methylpropyl, or allyl, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, and 3- to 8-membered heterocyclic groups.

In other embodiments, ^R2 is an oxocyclobutane, tetrahydrofuranyl, tetrahydropiperanyl, piperidinyl, or dioxonyltetrahydrothiophene, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, and 3- to 8-membered heterocyclic groups.

In other embodiments, ^R2 is an oxocyclobutane, tetrahydrofuranyl, tetrahydropiperanyl, piperidinyl, acridineyl, or dioxonyltetrahydrothiophene, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 -C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, and 3- to 8 _- membered heterocyclic groups.

In other embodiments, ^R2 is an oxocyclobutane, tetrahydrofuranyl, tetrahydropiperanyl, piperidinyl, acridineyl, pyrrolidinyl, or dioxonyltetrahydrothiopheneyl, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 -C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, and 3- to 8-membered heterocyclic groups _.

In several other embodiments, ^{R2 is} a pyridyl group substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy and 3- to 8-membered heterocyclic groups.

In any of the foregoing embodiments, ^R2 is unsubstituted. In other foregoing embodiments, ^R2 is substituted with one or more of a hydroxyl group and fluorine.

In any of the foregoing embodiments, ^R2 is unsubstituted. In other foregoing embodiments, ^R2 is substituted with one or more of hydroxyl, methyl, methoxy, and fluorine.

In more specific implementations, ^R2 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In a further specific embodiment, ^R2 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In a further specific embodiment, ^R2 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In some embodiments, ^R2 may be substituted, as required, with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl and 3 to 8 heterocyclic groups.

In some implementations, ^R2 does not have the following structure: or .

In any of the foregoing embodiments, ^R3 is an oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, or 1,3,4-oxadiazolyl group, each of which may be substituted as desired by one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogenyl, _C3 - _C8 cycloalkyl, and _C3 - _C8 halogenyl. For example, in some embodiments, ^R3 is an isoxazolyl group substituted as desired by one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogenyl, _C3 - _C8 cycloalkyl, and _C3 - _C8 halogenyl. In a further specific embodiment, ^R3 is substituted with a _C1 - _C6 alkyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, or _C3 - _C8 halogen cycloalkyl.

In a further embodiment, ^R3 is an 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 may be substituted as required by one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, C2- _C6 ynyl, _C1 -C6 halogen, _C3 - _C8 cycloalkyl, cyano, _{C1 - C6} amino, _C1 - _C6 hydroxyalkyl, 3 to 8 _- membered heterocyclic and _C3 - _C8 halogencycloalkyl or combinations thereof.

In some embodiments, ^{R3 is} an isoxazolyl group, as desired, substituted with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, _C1 - _C6 amino, _C1 - _C6 hydroxyalkyl, 3 to 8-membered heterocyclic and _C3 - _C8 halogencycloalkyl or combinations thereof.

In some embodiments, ^{R3 is} a thiazolyl group substituted as needed with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, _C1 - _C6 amino, _C1 - _C6 hydroxyalkyl, 3 to 8-membered heterocyclic and _C3 - _C8 halogencycloalkyl or combinations thereof.

In some embodiments, ^{R3 is} an isothiazolyl group substituted as needed with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, _C1 - _C6 amino, _C1 - _C6 hydroxyalkyl, 3 to 8-membered heterocyclic and _C3 - _C8 halogencycloalkyl or combinations thereof.

In some embodiments, ^{R3 is} a 1,2,4-thiadiazole group substituted as needed with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, _C1 - _C6 amino, _C1 - _C6 hydroxyalkyl, 3 to 8-membered heterocyclic and _C3 - _C8 halogencycloalkyl or combinations thereof.

In some embodiments, ^{R3 is} a 1,3,4-thiadiazole group substituted as desired with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, _C1 - _C6 amino, _C1 - _C6 hydroxyalkyl, 3 to 8-membered heterocyclic and _C3 - _C8 halogencycloalkyl or combinations thereof.

In some embodiments, ^{R3 is} a 1,3,4-oxadiazolyl group substituted as desired with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, _C1 - _C6 amino, _C1 - _C6 hydroxyalkyl, 3 to 8-membered heterocyclic and _C3 - _C8 halogencycloalkyl or combinations thereof.

In some embodiments, ^{R3 is} a 1,2,4-triazolyl group substituted as desired with one or more substituents selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 ynyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, _C1 - _C6 amino, _C1 - _C6 hydroxyalkyl, 3 to 8-membered heterocyclic and _C3 - _C8 halogencycloalkyl or combinations thereof.

In a further embodiment, ^R3 is substituted with a _C1 - _C6 alkyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, _C1 - _C6 amino, _C1 - _C6 hydroxyalkyl, 3 to 8-membered heterocyclic or _C3 - _C8 heterocyclic or a combination thereof.

In various embodiments, ^R3 has one of the following structures: ; ; ; ; ; ; ; ; ; ; or .

In a further embodiment, ^R3 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In a further embodiment, ^R3 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In other embodiments, ^R4 is H. In other embodiments, ^R4 is a _C1 - _C6 alkyl group, such as methyl.

In some embodiments, Y is CHOH. In other embodiments, Y is NH.

In other embodiments, X is N. In even more embodiments, X is CH.

In various embodiments, A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, or 5- to 6-membered monocyclic heteroaryl, each of which may be substituted with one or more ^R6 groups as required. It should be understood that A is a divalent group.

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

In some embodiments, A is a divalent group selected from phenyl, pyridyl, cyclohexyl and cyclohexenyl; each of which may be substituted as required.

In other embodiments, A is phenyl. In different embodiments, A is saturated or unsaturated cyclohexyl. In even more embodiments, A is pyridyl.

In a further embodiment, A is a pyrimidine group, which may be substituted as needed.

In any of the foregoing embodiments, A is not substituted. In different foregoing embodiments, A is substituted with one or more ^R5 groups. For example, in some embodiments, ^R5 is a halogen. In other embodiments, ^R5 is fluorine. In still other embodiments, ^R5 is chlorine.

In some embodiments, ^R5 is a cyano group. In some embodiments, ^R5 is a _C1 - _C6 alkyl group. In some embodiments, ^R5 is a methyl group. In some embodiments, ^R5 is a _C1 - _C6 halogenated group. In some embodiments, ^R5 is a difluoromethyl group. In further embodiments, ^R5 is a _C1 - _C6 hydroxyalkyl group. In some embodiments, ^R5 is _-CH2OH .

In some embodiments, A is a divalent group selected from the following: phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0] dicyclooctyl, [4.3.0] dicyclononyl, [4.4.0] dicyclodecyl, [2.2.2] dicyclooctyl, fumonyl, indyl, tetrahydronaphthyl, acridine, acridineyl, benzimidazolyl, benzofuranyl, benzothio Furanyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolinyl, carbazole, NH-carbazole, carbolinyl, benzodihydropiperanyl, benzopiperanyl, nitryl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazolidyl, imidazodinyl, imidazolinyl, imidazolyl, 1H-indazoleyl, indoleenyl, indolelinyl, indoleazinyl Indole, 3-indole, isonidolinyl, isonidolenyl, isobenzofuranyl, isonibenzodihydropiperanyl, isonidolyl, isonidolinyl, isonidolyl, isoniquinolinyl, isonithiazolyl, isonioxazolyl, morpholinyl, naphridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl Pyrimidinyl, phenidyl, phenorinyl, phenazinyl, phenthiazinyl, phenoxazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purine, piperanyl, pyrazinyl, pyrazolidine, pyrazolinyl, pyrazolyl, pyrazolyl, pyridoxazole, pyridoimidazole, pyridothiazazole, pyridinyl, pyridinyl, pyrrolidine, pyrrolinyl, 2-pyrroleyl, pyrroleyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxolinyl The following groups are included: pyridyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, thiazolyl, thienenoyl, thienenoxazolyl, thienenoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxadiazyl, acridineyl, and monyl; each of which may be substituted as required.

In a particular implementation, A has one of the following structures: ; ; ; ; or .

In other specific embodiments, A has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In some other embodiments, the compound of formula (V) is a modulator of the NLRP3 inflammasome. In some other embodiments, the compound of formula (V) is an inhibitor of NEK7 in a patient or 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 an individual's disease or condition. The pain may be associated with an individual's disease or condition. Non-restrictive examples of diseases and conditions include inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriasis arthritis), myofibrosis, lupus, surgery (e.g., postoperative 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 complicated regional pain syndrome (CRPS).

In various embodiments, the compound has one of the structures described in Table 1E below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

The compounds in Table 1E are prepared as described in the examples or methods known in this art and analyzed by mass spectrometry and/or ^1H NMR. Table 1E. Representative compounds with structure (V) Number Structure Name V-1 1-(4-(4-amino-1-isopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)phenyl)-3-(3-(tert-butyl)isooxazol-5-yl)urea V-2 1-(4-(4-amino-1-(oxocyclobutane-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)phenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-3 1-(4-(4-amino-1-(oxocyclobutane-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)phenyl)-3-(5-(tert-butyl)isoxazo-3-yl)urea V-4 1-(4-(4-amino-1-(tetrahydro- 2H -piperan-4-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)phenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-5 1-(4-(4-amino-1-(tetrahydrofuran-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)phenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-6 1-(4-(4-amino-1-isopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-chlorophenyl)-3-(3-(tert-butyl)isooxazol-5-yl)urea V-7 1-(4-(4-amino-1-cyclobutyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)phenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-8 1-(4-(4-amino-1-chlorobutyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-9 1-(4-(4-amino-1-(2-hydroxy-2-methylpropyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)phenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-10 1-(4-(4-amino-1-(2-hydroxy-2-methylpropyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-11 1-(4-(4-amino-1-isopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isooxazol-5-yl)urea V-12 1-(4-(4-amino-1-(oxocyclobutane-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-13 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-14 1-(4-(4-amino-1-(1-(oxocyclobutane-3-yl)piperidin-4-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-15 1-(4-(4-amino-1-(4-hydroxycyclohexyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-16 1-(4-(4-amino-1-(3,3-difluorocyclobutyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-17 1-(4-(4-amino-1-(pyridin-4-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-18 1-(4-(4-amino-1-(1,1-dioxo-tetrahydrothiophene-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-19 1-(4-(4-amino-1-(tetrahydro- 2H -piperan-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-20 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)phenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-21 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-22 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isooxazol-5-yl)urea V-23 1-(4-(4-amino-1-(oxocyclobutane-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(tert-butyl)isoxazo-3-yl)urea V-24 1-(4-(4-amino-1-(tetrahydrofuran-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-25 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-26 1-(4-(1-allyl-4-amino- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(tert-butyl)isoxazo-3-yl)urea V-27 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(2-fluoroprop-2-yl)isooxazol-5-yl)urea V-28 1-(4-(4-amino-1-methyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-chlorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-29 1-(4-(4-amino-1-methyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-30 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[4,3- c ]pyridin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-31 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[4,3- c ]pyridin-3-yl)phenyl)-3-(3-(tert-butyl)isoxazo-5-yl)urea V-32 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-methylcyclopropyl)isoxazo-5-yl)urea V-33 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)urea V-34 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(4-(tert-butyl)thiazolyl-2-yl)urea V-35 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)isothiazolyl-5-yl)urea V-36 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)urea V-37 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)urea V-38 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(1-(tert-butyl) -1H -1,2,4-triazol-3-yl)urea V-39 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)isoxazo-5-yl)urea V-40 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(pent-3-yl)isooxazol-5-yl)urea V-41 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-isopropylisooxazol-5-yl)urea V-42 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-ethylisooxazol-5-yl)urea V-43 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(dibutyl)isoxazo-5-yl)urea V-44 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-methylcyclobutyl)isoxazo-5-yl)urea V-45 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[4,3- c ]pyridin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-46 1-(4-(4-amino-1-(3-hydroxycyclobutyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-47 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)pyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-48 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-methylphenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-49 1-(4-(4-amino-1-(1-methylacetidin-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-50 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2,5-difluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-51 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-(hydroxymethyl)phenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-52 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(2-cyanopropyl-2-yl)isooxazol-5-yl)urea V-53 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(hydroxymethyl)isooxazol-5-yl)urea V-54 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[4,3- c ]pyridin-3-yl)pyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-55 1-(4-(4-amino-1-(2-hydroxyethyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-56 1-(4-(4-amino-1-(2-hydroxyethyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-57 1-(4-(4-amino-1-(2-methoxyethyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-58 1-(4-(4-amino-1-(2-methoxyethyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-59 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-methylphenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-60 1-(4-(4-amino-1-(3-hydroxycyclobutyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-61 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[4,3- c ]pyridin-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-62 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2,5-difluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-63 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-(hydroxymethyl)phenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isooxazol-3-yl)urea V-64 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)pyridin-2-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-65 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-4-methylisooxazol-5-yl)urea V-66 1-(4-(4-amino-1-(2-hydroxy-2-methylpropyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-67 1-(4-(4-amino-1-(2-hydroxy-2-methylpropyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-68 1-(4-(4-amino-1-(1-methylacetidin-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-69 1-(4-(4-amino- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-70 1-(4-(4-amino- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-71 1-(4-(4-amino-1-(1-methylpiperidin-4-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-72 1-(4-(4-amino-1-(1-methylpiperidin-4-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea V-73 1-(4-(4-amino-1-(1-methylpyrrolidin-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-74 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-(difluoromethyl)phenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-75 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-3-fluoropyridin-2-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea V-76 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-((dimethylamino)methyl)cyclopropyl)isoxazo-5-yl)urea V-77 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-((3,3-difluoroacetidin-1-yl)methyl)isoxazo-5-yl)urea V-78 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-(4-methylpiperazin-1-yl)cyclopropyl)isoxazo-5-yl)urea V-79 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(2-(4-methylpiperazin-1-yl)propyl-2-yl)isooxazol-5-yl)urea V-80 1-(4-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-hydroxy-2-methylpropyl-2-yl)isooxazol-5-yl)urea

The embodiments described herein provide a compound having formula (VI): (VI) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: This indicates that a double or single bond allows all valences to be satisfied; A is a 5- to 6-membered heterocyclic group, a 6-membered aryl group, or a 5- to 6-membered heteroaryl group, substituted as needed; X is N or ^CR3 ; Y is C or ^N ; W is CH or N; Z is CH or N; R1 is a _C1 - _C6 alkyl group, a _C1 - _C6 alkenyl group, a _C1 - _C6 alkynyl group, a _C1 - _{C6 hydroxyalkyl group, a C1-C6 alkoxyalkyl group} , a _C1 - _C6 carboxylalkyl group, a _C1 - _C6 halogenyl group, a _C3 - _C8 cycloalkyl group, or a _C6 -C6 cycloalkyl group, substituted as needed. _R10 is an aryl group, a 3- to 10-membered heterocyclic group substituted as desired, or a 5- to 10-membered heteroaryl group substituted as desired; ^R2 is an aryl group substituted as desired or a heteroaryl group substituted as desired; and ^R3 is a hydrogen, halogen, cyano, a _C1 - _C6 alkyl group substituted as desired, a _C1 - _C6 halogen group substituted as desired, a _C1 - _C6 alkoxy group substituted as desired, a _C1 - _C6 halogen alkoxy group substituted as desired, or a _C3 - _C8 cycloalkyl group substituted as desired.

In some implementations, Indicates a double key. In some other implementations, Indicates a single key.

In some embodiments, A is a 5-member heterocyclic group. In some embodiments, A is a 6-member heterocyclic group. In some embodiments, A is a 6-member heteroaryl group. In some embodiments, A is a 5-member heteroaryl group. In some embodiments, A is a 6-member aryl group.

In some embodiments, Y is N. In some embodiments, A is unsubstituted. In some embodiments, A is substituted. In some embodiments, A is substituted with one or more substituents selected from the group consisting of halogen, cyano, _C1 - _C6 alkyl, _C1 - _C6 halogen, _C1 - _C6 alkoxy, _C1 -C6 halogenalkoxy, or _{C3 -C8 cycloalkyl} .

In some embodiments, A is substituted by one or more substituents selected from the group consisting of a halogen, a _C1 - _C6 alkyl group substituted as desired, a _C1 - _C6 halogen group substituted as desired, a _C1 - _C6 alkoxy group substituted as desired, and a _C1 - _C6 halogen alkoxy group substituted as desired.

In some embodiments, A is substituted with one or more substituents selected from the group consisting of _C1 - _C6 alkyl, halogen, and _C1 - _C6 halogen. In some embodiments, A is substituted with one or more substituents selected from the group consisting of methyl, fluorine, and trifluoromethyl.

In some implementations, It has the following structure: ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

In some embodiments, Z is CH. In some embodiments, Z is N. In some embodiments, X is N. In some embodiments, X is ^CR3 . In some embodiments, ^R3 is hydrogen or, as desired, a substituted _C1 - _C6 alkyl group. In some embodiments, X is CH.

In some embodiments, ^R1 is a C1- _{C6 alkyl, C1-C6 alkenyl} , C1- _C6 alkynyl, _C1 - _C6 hydroxyalkyl, _C1 -C6 alkoxyalkyl, _C1 - _C6 carboxylalkyl, _C3 - _C8 cycloalkyl, 3- to 10-membered heterocyclic, or _5- to 10-membered heteroaryl. In some embodiments, ^R1 is a _C1 - _C6 alkyl. In some embodiments, ^R1 is methyl, ethyl, or isopropyl. In some embodiments, ^R1 is a _C1 - _C6 alkenyl or _{C1 - C6 alkynyl ,} depending on the substitution required. In some more specific implementations, ^R1 has the following structure: or .

In some embodiments, ^R1 is a _C1 - _C6 hydroxyalkyl group that is substituted as desired. In some embodiments, ^R1 has one of the following structures: or .

In some embodiments, ^R1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some more specific embodiments, ^R1 has one of the following structures: ; ; ; ; or .

In some embodiments, ^R1 is a 3- to 10-member heterocyclic basis that is replaced as needed. In some embodiments, ^R1 has the following structure: ; ; ; ; ; ; ; ; ; ; ; ; or .

In some embodiments, ^R1 is a substituted 5 to 10 heteroaryl group, depending on the requirements. In some embodiments, ^R1 is an unsubstituted pyridyl group. In some embodiments, ^R1 has one of the following structures: or .

In some embodiments, ^R1 is a _C1 - _C6 carboxyalkyl group that is substituted as desired. In some embodiments, ^R1 has the following structure: .

In some embodiments, ^R1 is a _C1 - _C6 alkoxyalkyl group that is substituted as desired. In some embodiments, ^R1 has the following structure: .

In some embodiments, ^R2 is a phenyl group that is substituted as desired, or a 5-membered heteroaryl group that is substituted as desired. In some embodiments, ^R2 is a phenyl group that is substituted as desired. In some embodiments, ^R2 is a 5-membered heteroaryl group that is substituted as desired. In some embodiments, ^R2 is an isoxazolyl group that is substituted as desired, or a pyrazolyl group that is substituted as desired. In some embodiments, ^R2 may be substituted as desired by one or more substituents selected from the group consisting of halogen, cyano, _C1 - _C6 alkyl, _C1 - _C6 halogen, _C1 - _C6 alkoxy, _C1 - _C6 halogenalkoxy, _C3 - _C8 cycloalkyl, 5- to 10-membered heterocyclic alkyl, 5- to 10-membered heterocyclic oxy, and _C6- to _C10 aryl groups.

In some embodiments, ^R2 may be substituted with one or more substituents selected from _the following structures: _-CH3 ; _-CH2CH3 ; ; ;-CF ₃ ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and .

In some implementations, ^R2 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;or .

In some implementations, ^R2 has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;or .

In various embodiments, the compound has one of the structures described in Table 1F below, or a stereoisomer, tautomer, or salt thereof. The compounds in Table 1F are prepared as described in examples or methods known in the art and analyzed by mass spectrometry and/or ^1H NMR. In some other embodiments, the compound of formula (VI) is a modulator of the NLRP3 inflammasome. In some other embodiments, the compound of formula (VI) is an inhibitor of NEK7 in a patient or 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 an individual's disease or condition. The pain may be associated with an individual's disease or condition. Non-restrictive examples of diseases and conditions include inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriasis arthritis), myofibrosis, lupus, surgery (e.g., postoperative 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 complicated regional pain syndrome (CRPS).

In various embodiments, the compound has one of the structures described in Table 1F below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

The compounds in Table 1F are prepared as described in the examples or methods known in this art and analyzed by mass spectrometry and/or ^1H NMR. Table 1F : Representative compounds of structure (VI) Number Structure Name VI-1 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)naphth-1-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea VI-2 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)quinoline-8-yl)-3-(3-(tert-butyl)isoxazo-5-yl)urea VI-3 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)quinoline-8-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea VI-4 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)quinoline-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-5 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)isoquinoline-8-yl)-3-(3-(tert-butyl)isooxazol-5-yl)urea VI-6 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)isoquinoline-8-yl)-3-(3-(1-methylcyclopropyl)isooxazol-5-yl)urea VI-7 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)isoquinoline-8-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isooxazol-5-yl)urea VI-8 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)isoquinoline-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isooxazol-3-yl)urea VI-9 1-(5-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)isoquinoline-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-10 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)isoquinoline-8-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-11 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2-a]pyridin-8-yl)-3-(3-(tert-butyl)-1-phenyl- 1H -pyrazol-5-yl)urea VI-12 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2-a]pyridin-8-yl)-3-(3-(tert-butyl)-1-(p-tolyl) -1H -pyrazol-5-yl)urea VI-13 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2-a]pyridin-8-yl)-3-(3-(tert-butyl)-1-(4-chlorophenyl) -1H -pyrazol-5-yl)urea VI-14 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(3-methylisooxazol-5-yl)urea VI-15 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(3-ethylisoxazo-5-yl)urea VI-16 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2-a]pyridin-8-yl)-3-(3-isopropylisooxazol-5-yl)urea VI-17 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2-a]pyridin-8-yl)-3-(3-(tert-butyl)isoxazo-5-yl)urea VI-18 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(3-(1-methylcyclopropyl)isoxazo-5-yl)urea VI-19 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(3-(1-methylcyclobutyl)isoxazo-5-yl)urea VI-20 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(3-(2-fluoroprop-2-yl)isooxazol-5-yl)urea VI-21 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isooxazol-5-yl)urea VI-22 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea VI-23 1-(5-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)imidazo[1,2-a]pyridin-8-yl)-3-(3-(1-(trifluoromethyl)cyclobutyl)isoxazo-5-yl)urea VI-24 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-methylisooxazol-3-yl)urea VI-25 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-ethylisoxazo-3-yl)urea VI-26 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-isopropylisooxazol-3-yl)urea VI-27 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(tert-butyl)isoxazo-3-yl)urea VI-28 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-methylcyclopropyl)isoxazo-3-yl)urea VI-29 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-methylcyclobutyl)isoxazo-3-yl)urea VI-30 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(2-fluoroprop-2-yl)isooxazol-3-yl)urea VI-31 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1,1,1-trifluoromethyl-2-methylpropyl-2-yl)isoxazo-3-yl)urea VI-32 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-33 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclobutyl)isoxazo-3-yl)urea VI-34 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-35 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-36 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)urea VI-37 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-38 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-39 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-40 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-41 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-(2-fluoroethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-42 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluoroimidozolo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-43 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-fluoroimidozolo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-44 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)-2-methylimidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-45 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methylimidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-46 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-(trifluoromethyl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-47 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)-2-(trifluoromethyl)imidazo[1,2 -a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-48 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)-3-methylimidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-49 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-3-methylimidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-50 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyrazin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-51 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyrazin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-52 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,3-dihydrobenzofuran-7-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-53 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,3-dihydrobenzofuran-7-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-54 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,3-dihydrobenzofuran-7-yl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-55 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,3-dihydrobenzofuran-7-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-56 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-57 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-58 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-59 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-60 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-61 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-62 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzofuran-7-yl)-3-(3-(tert-butyl)-1-phenyl- 1H -pyrazol-5-yl)urea VI-63 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzofuran-7-yl)-3-(3-(tert-butyl)isoxazo-5-yl)urea VI-64 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzofuran-7-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazo-5-yl)urea VI-65 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzofuran-7-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-66 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzofuran-7-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-67 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzofuran-7-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-68 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ d ]isooxazol-7-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isooxazol-3-yl)urea VI-69 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ d ]isooxazol-7-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-70 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ d ]isooxazol-7-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-71 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ d ]oxazol-7-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isooxazol-3-yl)urea VI-72 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ d ]oxazol-7-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-73 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)benzo[ d ]oxazol-7-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-74 1-(7-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ c ][1,2,5]oxadiazol-4-yl)-3-(3-(tert-butyl)isooxazol-5-yl)urea VI-75 1-(7-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ c ][1,2,5]oxadiazol-4-yl)-3-(3-(1-methylcyclopropyl)isooxazol-5-yl)urea VI-76 1-(7-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ c ][1,2,5]oxadiazol-4-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isooxazol-5-yl)urea VI-77 1-(7-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ c ][1,2,5]oxadiazol-4-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isooxazol-3-yl)urea VI-78 1-(7-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ c ][1,2,5]oxadiazol-4-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-79 1-(7-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ c ][1,2,5]oxadiazol-4-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-80 1-(5-(4-amino-1-cyclopropyl- 1H -pyrrolo[3,2- c ]pyridin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-81 1-(5-(4-amino-1-cyclopropyl- 1H -pyrrolo[3,2- c ]pyridin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-82 1-(5-(4-amino-1-cyclopropyl- 1H -pyrrolo[3,2- c ]pyridin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-83 1-(5-(4-amino-7-isopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isooxazol-3-yl)urea VI-84 1-(5-(4-amino-7-cyclobutyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-85 1-(5-(4-amino-7-(2-hydroxyethyl) -7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-86 1-(5-(4-amino-7-(2-hydroxy-2-methylpropyl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-87 1-(5-(4-amino-7-(3-hydroxycyclobutyl) -7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-88 3-(4-amino-5-(8-(3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)ureo)imidazo[1,2 -a ]pyridin-5-yl) -7H -pyrrolo[2,3- d ]pyrimidin-7-yl)propionic acid VI-89 1-(5-(4-amino-7-(2-methoxyethyl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-90 1-(5-(4-amino-7-(oxocyclobutane-3-yl) -7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-91 1-(5-(4-amino-7-(pyridin-3-yl) -7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-92 1-(5-(4-amino-7-(pyridin-4-yl) -7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-93 1-(5-(4-amino-7-(1-methylpyrrolidin-3-yl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-94 1-(5-(4-amino-7-(piperidin-4-yl) -7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-95 1-(5-(4-amino-7-(1-methylpiperidin-4-yl) -7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-96 1-(5-(4-amino-7-(1-(methanesulfonyl)piperidin-4-yl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-97 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4-d]pyrimidin-3-yl)imidazo[1,2-a]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-98 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4-d]pyrimidin-3-yl)imidazo[1,2-a]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-99 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4-d]pyrimidin-3-yl)imidazo[1,2-a]pyridin-8-yl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-100 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4-d]pyrimidin-3-yl)imidazo[1,2-a]pyridin-8-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-101 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[3,4-d]pyrimidin-3-yl)imidazo[1,2-a]pyridin-8-yl)-3-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-102 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[4,3-c]pyridin-3-yl)imidazo[1,2-a]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-103 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[4,3-c]pyridin-3-yl)imidazo[1,2-a]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-104 1-(5-(4-amino-1-cyclopropyl- 1H -pyrazolo[4,3-c]pyridin-3-yl)imidazo[1,2-a]pyridin-8-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-105 1-(5-(4-amino-1-methyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-106 1-(5-(4-amino-1-(3,3-difluorocyclobutyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-107 1-(5-(1-allyl-4-amino- 1H -pyrazolo[3,4- d ]pyrimidin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-108 1-(5-(4-amino-1-(but-3-yn-1-yl) -1H -pyrazolo[3,4 -d ]pyrimidin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-109 1-(5-(4-amino-1-(4-hydroxycyclohexyl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-110 1-(5-(4-amino-1-(tetrahydrofuran-3-yl) -1H -pyrazolo[3,4 -d ]pyrimidin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-111 1-(5-(4-amino-1-(tetrahydro- 2H -piperan-4-yl) -1H -pyrazolo[3,4 -d ]pyrimidin-3-yl)imidazo[1,2 -a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-112 1-(5-(4-amino-1-(tetrahydro- 2H -piperan-3-yl) -1H -pyrazolo[3,4 -d ]pyrimidin-3-yl)imidazo[1,2 -a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-113 1-(5-(4-amino-1-(1,1-dioxo-tetrahydrothiophene-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-114 1-(5-(4-amino-1-(acetidin-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-115 1-(5-(4-amino-1-(1-methylacetidin-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-116 1-(5-(4-amino-1-(piperidin-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)imidazo[1,2 -a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-117 1-(5-(4-amino-1-(1-methylpiperidin-3-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-118 1-(5-(4-amino-1-(1-(oxocyclobutane-3-yl)piperidin-4-yl) -1H -pyrazolo[3,4- d ]pyrimidin-3-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-119 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(3-cyclopropylisoxazo-5-yl)urea VI-120 1-(5-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-cyclopropylisoxazo-3-yl)urea VI-121 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-3-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-122 1-(4-(4-amino-7-cyclobutyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-123 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-3-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-124 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzofuran-7-yl)-3-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-125 1-(4-(4-amino-7-cyclopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)benzo[ d ]isooxazol-7-yl)-3-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-126 1-(5-(4-amino-7-methyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)urea VI-127 1-(5-(4-amino-7-methyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-128 1-(5-(4-amino-7-isopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-129 1-(5-(4-amino-7-cyclobutyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-130 1-(5-(4-amino-7-(2-hydroxyethyl) -7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-131 1-(5-(4-amino-7-(2-hydroxy-2-methylpropyl) -7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-132 1-(5-(4-amino-7-(3-hydroxycyclobutyl) -7H -pyrrolo[2,3 -d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-133 1-(5-(4-amino-7-(piperidin-4-yl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-134 1-(5-(4-amino-7-(1-methylpiperidin-4-yl) -7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea VI-135 1-(5-(4-amino-7-isopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-136 1-(5-(4-amino-7-isopropyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea VI-137 1-(5-(4-amino-7-cyclobutyl- 7H -pyrrolo[2,3- d ]pyrimidin-5-yl)imidazo[1,2- a ]pyridin-8-yl)-3-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)urea

The pharmaceutical composition is in one state. The compounds provided herein are formulated for use in a variety of applications, including (but not limited to) therapeutic methods, such as pharmaceutical compositions for the treatment of pain. The method of use can be in vitro, ex vivo, or in vivo. In various embodiments, the pharmaceutical composition is formulated for oral administration.

Pharmaceutical formulations may contain any pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" is a substance, formulation, or mediator that participates in carrying or transporting one tissue, organ, or part of the compound of interest to another tissue, organ, or part of the body. For example, a carrier may be a liquid or solid filler, thinner, excipient, solvent, or encapsulating substance, or a combination thereof. Each component of the carrier must be "pharmaceutically acceptable" because it must be compatible with the other components of the formulation. It must also be suitable for use in any tissue or organ it may come into contact with, meaning it will not carry the risk of toxicity, irritation, allergic reactions, immunogenicity, or any other complication that exceeds its therapeutic benefit.

In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 10 mg of a compound of formula (I), (II), (III), (IV), (V), or (VI). In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 5 mg of a compound of formula (I), (II), (III), (IV), (V), or (VI). In some embodiments, the pharmaceutical composition comprises about 10 mg of a compound of formula (I), (II), (III), (IV), (V), or (VI). In some embodiments, the pharmaceutical composition comprises about 5 mg of a compound of formula (I), (II), (III), (IV), (V), or (VI). In some embodiments, the pharmaceutical composition comprises about 4 mg of a compound of formula (I), (II), (III), (IV), (V), or (VI). In some embodiments, the pharmaceutical composition comprises about 3 mg of a compound of formula (I), (II), (III), (IV), (V), or (VI). In some embodiments, the pharmaceutical composition comprises about 2 mg of a compound of formula (I), (II), (III), (IV), (V), or (VI). In some embodiments, the pharmaceutical composition comprises about 1 mg of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 0.5 mg of a compound of formula (I), (II), (III), (IV), (V), or (VI).

In some embodiments, the pharmaceutical composition of the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI) is a modulator of the NLRP3 inflammasome. In some embodiments, the pharmaceutical composition of the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI) inhibits NEK7 when administered to a patient or biological sample.

In some embodiments, capsule compositions containing compounds of active ingredients of formula (I), (II), (III), (IV), (V), or (VI) are given in Table 2. In some embodiments, capsule compositions containing compounds of active ingredients of formula (I), (II), (III), (IV), (V), or (VI) are given in Table 3. In some embodiments, capsule compositions containing compounds of active ingredients of formula (I), (II), (III), (IV), (V), or (VI) are given in Table 4.

In some embodiments, the composition comprises a compound containing an active ingredient of formula (I), (II), (III), (IV), (V), or (VI); and one or more excipients listed in Table 2 (e.g., sodium lauryl sulfate (Kolliphore SLS fine), partially pregelatinized corn starch (Starch 1500), microcrystalline cellulose (Avicel PH 101), sodium glycolate (type A), HPC LF (Klucel LH Pharma), Aerosil Pharma 200, magnesium stearate). One or more excipients may be present in the tablet in the amounts shown in Table 2. One or more excipients may be present in the tablet in the weight percentages shown in Table 2.

In some embodiments, the composition comprises a compound containing an active ingredient of formula (I), (II), (III), (IV), (V), or (VI); and one or more excipients listed in Table 3 (e.g., sodium lauryl sulfate (Kolliphore SLS fine), partially pregelatinized corn starch (Starch 1500), microcrystalline cellulose (Avicel PH 101), sodium glycolate (type A), HPC LF (Klucel LH Pharma), Aerosil Pharma 200, magnesium stearate). One or more excipients may be present in the tablet in the amounts shown in Table 3. One or more excipients may be present in the tablet in the weight percentages shown in Table 3.

In some embodiments, the composition comprises a compound containing an active ingredient of formula (I), (II), (III), (IV), (V), or (VI); and one or more excipients listed in Table 3 (e.g., sodium lauryl sulfate (Kolliphore SLS fine), partially pregelatinized corn starch (Starch 1500), microcrystalline cellulose (Avicel PH 101), sodium glycolate (type A), HPC LF (Klucel LH Pharma), Aerosil Pharma 200, magnesium stearate). One or more excipients may be present in the tablet in the amounts shown in Table 3. One or more excipients may be present in the tablet in the weight percentages shown in Table 3.

In some embodiments, the composition of capsules containing the active ingredient (I) is given in Table 2. In some embodiments, the composition of capsules containing the active ingredient (I) is given in Table 3. In some embodiments, the composition of capsules containing the active ingredient (I) is given in Table 4.

In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 10 mg of compound (I). In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 5 mg of compound (I). In some embodiments, the pharmaceutical composition comprises about 10 mg of compound (I). In some embodiments, the pharmaceutical composition comprises about 5 mg of compound (I). In some embodiments, the pharmaceutical composition comprises about 4 mg of compound (I). In some embodiments, the pharmaceutical composition comprises about 3 mg of compound (I). In some embodiments, the pharmaceutical composition comprises about 2 mg of compound (I). In some embodiments, the pharmaceutical composition comprises about 1 mg of compound (I). In some embodiments, the pharmaceutical composition comprises about 0.5 mg of compound (I).

In some embodiments, the pharmaceutical composition of compound (I) is a modulator of the NLRP3 inflammasome. In some embodiments, the pharmaceutical composition of compound (I) inhibits NEK7 when administered to a patient or biological sample.

In some embodiments, the composition of capsules containing the active ingredient (I) is given in Table 2. In some embodiments, the composition of capsules containing the active ingredient (I) is given in Table 3. In some embodiments, the composition of capsules containing the active ingredient (I) is given in Table 4. Table 2. Composition of capsules containing compound (I) (0.5 mg) Element mg/ capsule %w/w Compound 10 0.5 0.36 Sodium lauryl sulfate (Kolliphore SLS fine) 0.05 0.04 Partially pregelatinized corn starch (Starch 1500) 61.0 43.57 Microcrystalline cellulose (Avicel PH 101) 66.81 47.72 Sodium glycolate (Type A) 5.00 3.57 HPC LF (Klucel LH Pharma) 3.64 2.60 Aerosil Pharma 200 1.5 1.07 Magnesium stearate 1.5 1.07 Total 140.0 100% Capsule HG, size "3", white, opaque NA NA Total capsule weight 187 mg NA Table 3. Composition of Compound (I) ( 2 mg) Capsules Element mg/capsule %w/w Compound 10 2.0 1.43 Sodium lauryl sulfate (Kolliphore SLS fine) 0.050 0.04 Partially pregelatinized corn starch (Starch 1500) 61.00 43.57 Microcrystalline cellulose (Avicel PH 101) 65.31 46.65 Sodium glycolate (Type A) 5.0 3.57 HPC LF (Klucel LH Pharma) 3.64 2.60 Aerosil Pharma 200 1.500 1.07 Magnesium stearate 1.500 1.07 Total 140.00 100% Capsule HG, size "3", white, opaque NA NA Total capsule weight 187 mg NA Table 4. Composition of Compound 10 Capsules ( 5 mg) Element mg/ capsule %w/w Compound 10 5.0 3.57 Sodium lauryl sulfate (Kolliphore SLS fine) 0.050 0.04 Partially pregelatinized corn starch (Starch 1500) 61.00 43.57 Microcrystalline cellulose (Avicel PH 101) 62.31 44.51 Sodium glycolate (Type A) 5.00 3.57 HPC LF (Klucel LH Pharma) 3.64 2.60 Aerosil Pharma 200 1.50 1.07 Magnesium stearate 1.50 1.07 Total 140.00 100% Capsule HG, size "3", white, opaque NA NA Total capsule weight 187 mg NA

Treatment Methods This article provides methods for treating pain in an individual by administering a compound of formula (I), (II), (III), (IV), (V), or (VI) to that individual. Pain includes (but is not limited to) acute pain, chronic pain, and sudden onset pain. Pain includes (but is not limited to) nociceptive pain, neuropathic pain, and nerve root pain. Pain includes (but is not limited to) pain caused by arthritis, osteoarthritis, rheumatoid arthritis, psoriasis arthritis, myofiarism, lupus, postoperative pain, acute inflammatory pain, peritonitis, and any combination thereof.

Pain can be a symptom of an illness or condition in an individual who experiences pain. For example, pain can be a symptom of inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriasis arthritis), myofibrosis, lupus, surgery (e.g., postoperative 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 complicated regional pain syndrome (CRPS), or two or more of these conditions.

Pain can be associated with an individual's underlying disease or condition. Therefore, in some cases, an individual experiencing pain may also have a disease or condition. Non-restrictive examples of diseases and conditions include inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriasis arthritis), myofibrosis, lupus, surgery (e.g., postoperative 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 complicated regional pain syndrome (CRPS).

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered in doses from about 0.5 mg to about 10 mg. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered in doses from about 0.5 mg to about 5 mg. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered in doses of about 5 mg. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered in doses of about 4 mg. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered at a dose of about 3 mg. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered at a dose of about 2 mg. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered at a dose of about 0.5 mg.

In some embodiments, the compound of formula (I) described herein, or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, may be administered via any of the appropriate administration schedules described herein. In some embodiments, the compound of formula (I) described herein, or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered before and after surgery.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent compound thereof, is administered at least one day prior to surgery.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent compound thereof, is administered one day prior to surgery.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent compound thereof, is administered on the day of surgery.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 1 to 6 hours prior to surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 1 to 3 hours prior to surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 2 to 4 hours prior to surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 2 to 5 hours prior to surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 3 to 6 hours prior to surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 6 hours prior to surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 5 hours prior to surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 4 hours prior to surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 3 hours prior to surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 2 hours prior to surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 1 hour prior to surgery.

In some embodiments, the compound of formula (I), or its pharmaceutically acceptable salt, stereoisomer, or solvent compound, is administered starting one day after surgery.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 1 day post-surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 2 days post-surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 3 days post-surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 4 days post-surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 5 days post-surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 6 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 7 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 8 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 9 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 10 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 11 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 12 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 13 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 14 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 15 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 16 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 17 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 18 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 19 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 20 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 21 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 22 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 23 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 24 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 25 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 26 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 27 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 28 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 29 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 30 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 1 to 7 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 1 to 10 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 1 to 20 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 1 to 30 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 10 to 20 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 10 to 30 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered 20 to 30 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered for at least 10 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered for at least 20 days postoperatively. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered for at least 30 days postoperatively.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered one day before surgery and for at least one day after surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered one day before surgery and for at least five days after surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered one day before surgery and for at least ten days after surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered one day before surgery and for at least twenty days after surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent compound thereof, is administered one day before surgery and for at least 30 days after surgery.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered on the day of surgery and for at least one day post-surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered on the day of surgery and for at least five days post-surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered on the day of surgery and for at least ten days post-surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered on the day of surgery and for at least twenty days post-surgery. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent compound thereof, is administered on the day of surgery and for at least 30 days post-surgery.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered to an individual daily. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered to an individual once daily.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered to an individual every other day. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered to an individual once every other day.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered to the individual weekly. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered to the individual once weekly.

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

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered to an individual for at least 5 days. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered for at least 10 days. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered for at least 20 days. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, is administered for at least 30 days.

In some embodiments, compound (I) is administered to an individual for at least 2 weeks. In some embodiments, compound (I) is administered for at least 4 weeks. In some embodiments, compound (I) is administered for at least 8 weeks. In some embodiments, compound (I) is administered for at least 12 weeks. In some embodiments, compound (I) is administered for 16 weeks. In some embodiments, compound (I) is administered for 20 weeks. In some embodiments, compound (I) is administered for 24 weeks. In some embodiments, compound (I) is administered for 28 weeks. In some embodiments, compound (I) is administered for 32 weeks. In some embodiments, compound (I) is administered for 1 to 12 weeks. In some embodiments, compound (I) is administered for more than 12 weeks.

Examples are provided below to illustrate the embodiments described herein and should not be construed as limiting the scope of the invention. References to specific substances are for illustrative purposes only and are not intended to be restrictive. Those skilled in the art can develop equivalent means or reactants without employing inventive capabilities and without departing from the scope of the invention.

Example 1 : Synthesis Scheme The following general reaction scheme illustrates an example of a compound with structure (I): (I) or its pharmaceutically acceptable salt, stereoisomer or prodrug, wherein each of A, X, Y, ^R1 , ^R2 , ^R3 , ^R4 and ^R5 is as defined herein.

The following general reaction scheme (where ^X1 and ^X2 are halogens independently, and X, ^R1 , ^R2 , ^R3 , and A have the meanings described herein) illustrates an example of a method for preparing amine intermediate D: As shown in general reaction scheme 1, alkylation of pyrimidine/pyridinepyrrole (i.e., intermediate A) with a borate cycloalkyl ester or a suitable electrophile in the presence of an alkali provides intermediate B. The precursor is then treated with ammonium hydroxide to form a pyrrolopyrimidine/pyridine-4-amine derivative intermediate C. The resulting intermediate C can then undergo palladium-catalyzed arylation to form intermediate D.

General Reaction Scheme 2 : The following general reaction scheme illustrates an example of a method for preparing carbamate intermediate E: As shown in general reaction scheme 2, intermediate E can be prepared in the presence of alkali by reacting phenyl chloroformate with an indicator heteroarylamine (an analogue of amine substitution of ^R4 ). General reaction scheme 2 describes the preparation of a compound in which ^R5 is H; however, compounds in which ^R5 is not H can be prepared by a similar method by introducing ^R5 after the preparation of intermediate E or by using a suitably substituted heteroarylamine.

The following general reaction scheme 3 illustrates an example of a method for preparing a compound with structure (I): Intermediates D and E are treated with alkalis contained in THF (e.g., trimethylamine, DIPEA, DMAP, and similar substances) to provide a compound with structure (I).

The following general reaction scheme 4 illustrates an example of a method for preparing a compound with structure (I): Intermediate D is reacted with the phenyl chloroformate shown under suitable conditions to produce intermediate E. Intermediate E is then coupled to an amine using a suitable alkali contained in THF (e.g., trimethylamine, DIPEA, DMAP, and the like) to provide a compound with structure (I).

Any of the above reaction schemes may be modified at any step to add and/or modify substituents, which may be appropriately added or modified during any stage of the overall synthesis of the desired compound.

Intermediate A1 (4-chloro-5-iodo-7h-pyrrolo[2,3-d]pyrimidine) The preparation was 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. After the reaction was complete (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 provide the title compound (1.7 g, 93% yield) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ = 12.96 (bs, 1H), 8.60 (s, 1H), 7.95 (d, J = 2.40 Hz, 1H); LCMS: 279.9 [M+H].

Intermediate B1 (4-chloro-7-cyclopropyl-5-iodo-7h-pyrrolo[2,3-d]pyrimidine) The reaction mixture was 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 (Al, 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 an oxygen atmosphere for 12 h. After the reaction was complete (as indicated by TLC), the reaction mixture was filtered through a diatomaceous earth mat, and then the diatomaceous earth mat was rinsed with DCM (2 x 20 mL). The combined filtrate was washed with water (20 mL) and brine (25 mL), _dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by rapid chromatography (silicone 230-400 mesh, eluted with 15% EtOAc in petroleum ether) to give the title compound as a grayish-white solid (0.7 g, 61% yield). ¹H NMR (400 MHz, DMSO-d₆) δ = 8.67 (s, 1H), 7.96 (s, 1H), 3.63–3.69 (m, 1H), 1.06–1.10 (m, 4H). LCMS: 319.9 [M+H].

Intermediate C1 (7-cyclopropyl-5-iodo-7h-pyrrolo[2,3-d]pyrimidine-4-amine) The compound was 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. After the reaction was complete (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to provide the title compound as a grayish-white solid (0.75 g, 80% yield). ¹H NMR (400 MHz, DMSO-d6) δ = 8.12 (s, 1H), 7.39 (s, 1H), 6.57 (bs, 2H), 3.48–3.54 (m, 1H), 0.97–1.01 (m, 4H). LCMS: 301.0 [M+H].

Intermediate D1 (5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7h-pyrrolo[2,3-d]pyrimidine-4-amine) The reaction mixture was prepared as follows: 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-dioxoboronyl-2-yl)aniline (0.190 g, 0.800 mmol), and _K₂CO₃ (0.221 g, 1.599 mmol) were contained in 1,4- _dioxane (1 mL) and water (0.3 mL) and purified with _N₂ for 10 min. Then, Pd( _PPh₃ ) _₄ (0.062 g, 0.053 mmol) was added, and the reaction mixture was stirred at 100 °C for 12 h. After the reaction was complete (as indicated by TLC), the mixture was filtered through a diatomaceous earth mat, which was then rinsed with EtOAc (2 x 10 mL). The combined filtrate was concentrated under reduced pressure to produce a crude product, which was purified by rapid chromatography (silicone 230 to 400 mesh, eluted with 3% MeOH contained in DCM) to give the title compound as a yellow solid (0.110 g, 73% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 7.13 (s, 1H), 7.05-7.09 (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].

Compound 10 ( Following the order of 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.10 g, 0.35 mmol) and (5-(1-(trifluoromethyl)cyclopropyl)isoxazo-3-yl)aminocarbamate (0.11 g, 0.35 mmol) (E1)) is prepared using the general procedure for urea formation starting from the initial stage:

Specifically, triethylamine (2.0 equivalents) was added to a mixture of D1 (1.0 equivalents) and E1 (1.0 equivalents) contained in THF (10 volumes), and the resulting mixture was stirred in a sealed tube at 60°C for 12 h. After the reaction was complete (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by reversed-phase preparative HPLC to obtain the desired product. Compound 10 was obtained as a grayish-white solid (0.010 g, 6% yield). 1H NMR (400 MHz, DMSO-d6) δ = 9.99 (bs, 1H), 8.86 (bs, 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. The free base of compound 10 was formulated into oral capsules with 0.5 mg, 2 mg, and 5 mg capsule strengths, in a similar form to the admixtures shown in Table 5. Compound 10 can also be formulated into tablets. For example, the tablets may contain the excipients listed in Table 5. Table 5. Composition of admixtures for 0.5 , 2 , and 5 mg strength capsules. Element Dopant composition (mg) 0.5 mg capsules 2 mg capsules 5 mg capsules Compound 10 (active ingredient) 0.50 2.00 5.00 Sodium lauryl sulfate (Kolliphor SLS fine) 0.05 0.05 0.05 Partially pregelatinized corn starch (Starch 1500) 61.00 61.00 61.00 Microcrystalline cellulose (Avicel PH 101) 66.81 65.31 62.31 Sodium glycolate (Type A) 5.00 5.00 5.00 HPC LF (Klucel LH Pharma) 3.64 3.64 3.64 Aerosil Pharma 200 1.50 1.5 1.50 Magnesium stearate 1.50 1.50 1.50 Total 140.00 140.00 140.00 Capsule color White (opaque) Swedish Orange dark green

Example 3 : CFA -induced inflammatory pain model in rats . CFA (a water-in-oil emulsion containing inactive mycobacteria) was injected into the paws of rodents to induce inflammatory pain, which was converted into increased sensitivity to thermal and mechanical tactile stimuli.

In this model, male Wistar rats (n=10 rats/group, group details in Table 6) were injected with CFA into the plantar surface of their right hind paw (day 0). Twenty-four hours later (day 1, t = 0 h), the animals were treated with a single oral dose of compound 10 (10 or 30 mg/kg) or the control drug diclofenac (30 mg/kg). Mechanical aorticism was assessed by measuring plantar tactile tachycardia (PWT) using a dynamic plantar aesthesiometer at 0, 1, 3, 6, 9, 12, and 24 hours post-administration, and thermal hyperalgesia was assessed by measuring plantar tactile tachycardia (PWL) using a Hargreaves apparatus. Results are shown in Figures 1A to 1C. Table 6. Detailed information on the CFA-induced inflammatory pain model Group Number of animals Pain Induction Drug treatment Dosage Investment and Pathways 1 - Fake Comparison 10 without Mediator n/a PO 2 - No treatment control 10 CFA Mediator n/a PO 3-Diclofenac 10 CFA diclofenac 30 mg/kg, once PO 4 - Compound 10, low dose 10 CFA Compound 10 10 mg/kg, once PO 5 - Compound 10, high dose 10 CFA Compound 10 30 mg/kg, once PO

Animals in the untreated control group showed statistically significant reductions in PWT and PWL at all time points compared to the sham control (p < 0.0001), indicating successful induction of inflammatory pain 24 to 48 hours after CFA injection (0 to 24 hours on day 1). Treatment with the nonsteroidal anti-inflammatory drug diclofenac (30 mg/kg) resulted in statistically significant improvements in mechanical aalgesia and thermal hyperalgesia, with peak effects observed at 3 hours post-administration (p < 0.0001 for both PWT and PWL) and efficacy extended to 12 hours (PWT) or 24 hours (PWL) post-administration. When compared with the untreated control group, diclofenac treatment resulted in a 39% improvement in mechanical pain abnormalities and a 42% improvement in thermal hyperalgesia over 24 hours (p < 0.0001 for both).

Treatment with compound 10 also resulted in a significant dose-dependent improvement in mechanical analgesia and thermal hyperalgesia, with peak effects observed at 3 hours post-administration (p < 0.001 or better). In the high-dose group, the efficacy against mechanical analgesia was significant up to 9 hours post-administration (p < 0.01 or better), while in the low-dose group, the efficacy against thermal hyperalgesia was prolonged to 12 hours post-administration and in the high-dose group, it was prolonged to 24 hours post-administration (p < 0.05 or better). Overall, when compared with the untreated control group over a 24-hour period, treatment with low-dose compound 10 resulted in a 14% improvement in mechanical pain abnormalities and a 24% improvement in thermal hyperalgesia (p < 0.0001), while treatment with high-dose compound 10 resulted in a 30% improvement in mechanical pain abnormalities and a 34% improvement in thermal hyperalgesia (p < 0.0001 for both).

These data indicate that in a rat model of CFA-induced inflammatory pain, compound 10 provides sustained pain control at oral doses as low as 10 mg/kg.

Example 4 : The Brennan Incision Pain Model in Rats. In this study, mechanical analgesia and thermal hyperalgesia were assessed in male SD rats (n=8/group, group details in Table 7) at baseline (day -1). Surgery was performed on day 0 (a 1 cm longitudinal incision was made through the skin, fascia, and plantar muscles of the right hind paw, followed by wound closure). From day 1 to day 3, the animals received an oral dose of compound 10 (10 mg/kg) or the control drug indomethacin (30 mg/kg), and mechanical analgesia and thermal hyperalgesia were assessed 2 hours after drug administration (at t = 24, 48, and 72 hours post-surgery). The results are shown in Figures 2A to 2B. Table 7. Detailed information on the Brennan incision pain model Group Number of animals Operation Drug treatment Dosage Investment and Pathways 1 - Fake Comparison 8 without Mediator n/a PO 2 - No treatment control 8 Claw cut Mediator n/a PO 3-Indomethacin 8 Claw cut Indomethacin 30 mg/kg QD PO 4 - Compound 10 8 Claw cut Compound 10 10 mg/kg QD PO

Animals in the untreated control group showed statistically significant reductions in PWT and PWL at all time points (p < 0.001) (expected outcome of postoperative pain), while their body weight increased slightly over 5 days. Compared with the untreated control group, treatment with nonsteroidal anti-inflammatory indomethacin (30 mg/kg PO daily) resulted in statistically significant improvements in PWT and PWL at all time points, with overall improvements of 87% and 93% in mechanical dysphagia and thermal hyperalgesia, respectively (p < 0.001 or better). However, on day 2 (after administration of a single dose of indomethacin), signs of GI and overall toxicity, including discolored feces, weakness, and weight loss, were observed. Ultimately, on day 3, one animal died and the entire group experienced a 9.1% weight loss (p < 0.0001), indicating that although effective, daily oral treatment with 30 mg/kg indomethacin was intolerable.

Compared with the untreated control group, treatment with compound 10 (10 mg/kg PO daily) also resulted in statistically significant improvements in PWT and PWL at all time points, with overall improvements of 51% and 92% in mechanical paresthesia and thermal hyperalgesia, respectively (p < 0.01 or better). Rats treated with compound 10 did not exhibit any obvious signs of toxicity, and their body weight remained stable throughout the study.

These data indicate that compound 10, administered orally at a daily dose of 10 mg/kg, was well tolerated and effectively controlled postoperative incision pain in rats, essentially restoring full function of the affected limb.

Example 5 : Surgically Induced Osteoarthritis Model in Rats. Osteoarthritis can be induced in rats by surgical induction or acceleration of joint degeneration. Specifically, the combination of preoperative cruciate ligament transection (ACLT) and partial internal meniscectomy (pMMx) leads to time-dependent pathological changes such as articular cartilage degradation, subchondral sclerosis, osteophyte formation, and inflammatory pain.

In this model, male Wistar rats (n=8 or 10 per group, group details in Table 8) underwent ACLT+pMMx surgery (day 0), followed by treatment with oral doses of compound 10 (1 mg/kg/day) or the control drug dexamethasone (0.1 mg/kg/day) for 5 weeks. Body weight was collected daily, and pain was assessed weekly for 5 weeks post-surgery by measuring mechanical aches and pain (using a dynamic plantar tactile meter to quantify the claw retraction threshold, PWT). Results are shown in Figures 3A to 3B. Table 8. Group details of the surgically induced osteoarthritis rat model. Group Number of animals Operation Drug treatment Dosage Investment channels 1 - Fake Comparison 8 without Mediator n/a PO 2 - No treatment control 10 ACLT + pMMx Mediator n/a PO 3 - Dexamethasone 10 ACLT + pMMx Dexamethasone 1 mg/kg/day from day 0 to day 35 PO 5 - Compound 10 10 ACLT + pMMx Compound 10 0.1 mg/kg/day from day 0 to day 35 PO

Postoperatively, animals in the untreated control group showed a statistically significant reduction in PWT (p < 0.0001 at all time points) and no recovery within 5 weeks (a result of untreated severe joint instability and postoperative pain). After a 3.9% postoperative weight loss, animals from the untreated control group regained their pre-treatment weight by day 13. They experienced a total weight gain compared to the sham control group (9.4% vs. 13.6%).

Animals treated with the potent anti-inflammatory corticosteroid dexamethasone (0.1 mg/kg PO daily) experienced only mild (3%) weight loss and showed no statistically significant improvement in PWT over 5 weeks compared to the untreated group. Furthermore, significant weight loss was observed in the dexamethasone group, peaking at 10.9% after 2 weeks with limited recovery over the following 3 weeks, resulting in a mean weight loss of 7.1% at 5 weeks (p < 0.0001). These data indicate that treatment with dexamethasone (0.1 mg/kg daily) after ACLT+MMx surgery is poorly tolerated in rats and fails to restore function of the affected limbs.

In contrast, animals treated with compound 10 (1 mg/kg PO daily) experienced steady-state and continuous improvement in PWT at each weekly measurement compared to the untreated group, ultimately achieving an 18% improvement in PWT over 5 weeks (p < 0.01). Furthermore, following postoperative weight loss, animals in these groups showed similar weight gains to those in the pseudocontrol group (12.7% vs. 13.6%).

These data indicate that compound 10 was well tolerated after oral administration at 1 mg/kg daily for 5 weeks and provided sustained pain control and partial functional recovery for affected limbs in a rat model of surgically induced osteoarthritis.

Example 6 : Phase I Data – Safety Receptor Screening This study screened 44 receptors and enzymes for compound 10, which are known to contribute to adverse drug reactions in clinical practice. At a concentration of 10 μM, significant 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 Screening Results for Compound 10 Target species agonist / antagonist % inhibition at 10 µM IC ₅₀ (µM) 5-HT _1B human Antagonist 79.3 1.6 5-HT _2A human activator 75.2 5.5 5-HT _2B human activator 95.6 0.25 A2A human activator 80.2 nd ^Ca²⁺ channel (L, dihydropyridine site) - Antagonist 83.4 5.3 D ₁ human Antagonist 76.2 5.1 Dopamine transporter human Antagonist 75 5.6 H ₁ human Antagonist 75.4 3.1 Lck kinase human - 91.6 1.1 Na ⁺ channel (bit 2) - Antagonist 90.6 4.3 Norepinephrine transporter human Antagonist 67.1 6.4 Potassium channel hERG human - 68.3 nd δ (DOP) human activator 78.5 4.2 μ (MOP) human activator 73.8 6.3 nd: Value not determined

All targets except serotonin receptor 5-HT _2B showed _IC50 ≥ 1 µM, which was considered to be outside the relevant pharmacological range of compound 10, indicating no significant toxicity concerns were expected from the observed off-target receptor activity.

The efficacy of compound 10 in hERG channel function was evaluated in vitro to inhibit the transport of ions via the human Ether-à-go-go-associated gene (hERG). Compared to the mediator control current, compound 10 at concentrations of 0.78, 3, 10, and 30 µM inhibited hERG current by 12.93%, 19.39%, 40.34%, and 52.95%, respectively. The calculated _IC50 value of compound 10 was 23.10 µM, making it a low-potency inhibitor of hERG current.

The Functional Observational Battery (FOB) assay evaluated the effects of compound 10 on the central nervous system in male Sprague Dawley rats. Following single oral doses (1, 3, and 10 mg/kg), compound 10 was found to have no effect on any CNS function as tested by the FOB. Therefore, the no-observed-effect level (NOEL) for compound 10 in altering neurobehavioral function after a single oral dose in rats was 10 mg/kg (the highest dose tested).

The respiratory system was assessed using head-out plethysmography to evaluate the effects of compound 10 on respiratory function in conscious male Spriggdalee rats. Following single oral doses (1, 3, and 10 mg/kg), compound 10 was found to have no effect on any of the respiratory functions tested in this study. Therefore, the NOEL (noise of exhaustion) of compound 10 for altering respiratory function in rats after a single oral dose was 10 mg/kg (the highest dose tested).

Cardiovascular effects of compound 10 were evaluated in instrumented male beagle dogs. The no-effect level (NOEL) was found to be 4 mg/kg (the highest dose tested).

In vitro permeability and drug transporter effects were assessed in a two-way Caco-2 assay for the permeability of compound 10. Compound 10 was found to be moderately permeable in the absorption direction (Papp 2.55 x 10⁻⁶ cm/sec) with an efflux ratio of 2.0. Transporter studies showed moderate activity of BCRP as a transporter, with a smaller effect than that of P-gp.

Caco-2 screening studies with and without selective P-gp and BCRP inhibitors showed moderate permeability and no efflux concern (ER < 2) for compound 10, indicating that it is not a recipient of P-gp and BCRP transporters. To confirm this finding, bidirectional permeability was evaluated in MCDK-II cells transfected with either the MDR1 or MDCK gene. Permeability (A > B) was found to be extremely 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 indicates that compound 10 is a recipient of P-gp and BCRP transporters.

A Phase 1, randomized, placebo-controlled, single-center, single- and multiple-addition-dose study of compound 10 in humans has been initiated and designed to evaluate its safety, tolerability, pharmacokinetic (PK), and PD in healthy human individuals. 48 individuals have been enrolled in this study. Eight (8) individuals were enrolled in each cohort, with two receiving a placebo. Therefore, a total of 36 individuals in this study have received compound 10. Safety data were available from the 32 individuals enrolled in the single-addition-dose (SAD) portion of the study completed on October 29, 2022. The multiple-addition-dose (MAD) portion of this study is ongoing. To date, compound 10 has been administered in six different dosage groups [1 mg single dose (SD), 2 mg SD, 3 mg SD, 4 mg SD, 1 mg QD, 2 mg QD]. No serious adverse events (SAEs) have been reported to date, and no treatment-emergent AEs of grade ≥CTCAE 3 have occurred.

Potential risks and side effects of compound 10 have been evaluated in 36 individuals, with safety data available in 32 individuals. No SAEs have been observed to date, and no treatment-emergent adverse events (AEs) of grade ≥CTCAE 3 have occurred. Based on animal studies, anticipated potential side effects include transaminitis (reversible) and gastrointestinal toxicity (such as diarrhea).

In vivo, compound 10 demonstrated significant pain control in rat models of inflammatory pain and incision pain driven by activation of the NLRP3 inflammasome. In a fully Freund's adjuvant (CFA)-induced inflammatory pain model, treatment with single doses of compound 10 mg/kg and 30 mg/kg resulted in significant dose-dependent improvement in mechanical aalgesia and thermal hyperalgesia, with peak effects observed at 3 hours post-administration (p < 0.001 or better). In the Brennan incision pain model, when compared with the untreated control group, treatment with daily doses of compound 10 at 10 mg/kg and 30 mg/kg resulted in statistically significant improvements in claw retraction limit (PWT) and claw retraction latency (PWL) at all time points, and overall improvements in mechanical aches and pains and thermal hyperalgesia of 51% and 92%, respectively (p < 0.01 or better).

Example 7 : Phase II clinical trial : A phase II, randomized, placebo-controlled, double-blind, parallel-group study was conducted to evaluate the ability of compound 10 to reduce diagnostic biomarkers of acute inflammation after surgery and to manage pain after third molar extraction in adult patients.

Eighty (80) patients will be enrolled and randomly assigned in a 1:1 ratio to either the study drug compound 10 or a matched placebo. A single 4 mg dose of the randomized study drug will be administered 3 hours (± 15 minutes) prior to surgery. If pain persists, a rescue analgesic (acetaminophen or ibuprofen) may be used.

The primary biomarker endpoint and overall primary endpoint of this study was the maximum observed increase in CRP (ΔCRP) prior to auto-administration. The primary safety endpoint was the incidence of adverse events (AEs) and sarcopenic erythematosus (SAEs). Key secondary efficacy endpoints included the levels of ESR, IL-1β, IL-6, and TNF-α (following a definition similar to ΔCRP), the area under the time-dependent categorical pain intensity curve (AUC _e , AUC ₆ , and AUC ₈ ) from the initial pain intensity rating to 4, 6, and 8 hours post-surgery, the time to rescue analgesia, the proportion of patients requiring rescue analgesia within 4, 6, and 8 hours post-surgery, the patient rating of pain intensity on the 11-point NPRS at 60, 90, 120, and 150 minutes, and 3, 4, 5, 6, 7, and 8 hours post-surgery (i.e., the time of the final suture), and the overall stratification of the study drug.

Safety Conclusions: During this study period, a total of 14 individuals (34.1%) in the compound 10 group and 13 individuals (32.5%) in the placebo group reported at least one TEAE. 11 individuals (26.8%) in the compound 10 group and 7 individuals (17.5%) in the placebo group reported at least one TEAE judged to be possibly or highly probable to be related to the investigational drug; however, only 1 individual (2.5%) in the placebo group (and none in the compound 10 group) reported at least one TEAE judged to be highly probable to be related to the investigational drug. The only TEAE occurring in ≥10% of individuals in either treatment group was headache, which occurred in 14.6% of compound 10 individuals and 0% of placebo individuals, and nausea, which occurred in 7.3% of compound 10 individuals and 10.0% of placebo individuals.

The majority of TEAEs in each treatment group were of mild severity (92.9% of events in the compound 10 group and 76.9% of events in the placebo group). No serious TEAEs were reported. The only TEAE (by severity) occurring in ≥10% of individuals in any treatment group was mild headache, occurring in 12.2% of compound 10 individuals and 0% of placebo individuals, and mild nausea, occurring in 7.3% of compound 10 individuals and 10.0% of placebo individuals.

26.8% of compound 10 individuals and 17.5% of placebo individuals reported treatment-emergent adverse events (TEAEs) that were possibly or highly probable to be related to the investigational drug. The most common treatment-emergent adverse events (TEAEs) considered possibly or highly probable to be related to the investigational drug (>2.5% of individuals in either treatment) were nausea (7.3% and 5.0% in compound 10 and placebo, respectively), headache (9.8% and 0%, respectively), increased CRP (4.9% and 2.5%), and vomiting (0% and 5.0%).

There were no reported adverse events (AEs) leading to death, no reported serious AEs, and no reported AEs leading to the discontinuation or termination of the investigational drug.

Regarding laboratory parameters, neutrophil and mononuclear globulin concentrations increased on day 3 in both groups relative to pre-screening and pre-operative levels, although none of these increases were ≥1.5-fold. At the assessed post-operative time points, amylase concentrations decreased in both groups, although none of these decreases were ≥1.5-fold. Additionally, only one potentially clinically significant laboratory value (≥ grade 3 CTCAE) is reported.

There was no group bias or significant difference between groups in vital sign measurements. Overall, compound 10 was safe and well-tolerated when compared to placebo.

The efficacy conclusions were based on a full efficacy analysis of the safety cohort, which consisted of 81 individuals (41 compound individuals, 10 compound individuals, and 40 placebo individuals).

The primary endpoint of the observed increase in CRP from the baseline was not significantly different among the groups (p = 0.815).

Secondary power endpoints were analyzed in a stratified closed-loop test procedure. Secondary endpoints were not considered for statistical significance because the primary power endpoints were not statistically significant.

Pain intensity AUC was also assessed as a secondary efficacy endpoint. Pain intensity was assessed hourly at 60, 90, 120, and 150 minutes and 3 to 8 hours after the end of surgery (i.e., the time of the final suture). For all time frames, the time-based AUC of "claw" pain intensity was lower in the compound 10 group than in the placebo group. For all time frames, the time-based AUC of "SAP" pain intensity was lower in the compound 10 group than in the placebo group. Similarly, for all time frames, the time-based AUC of "FDA" pain intensity was also lower in the compound 10 group than in the placebo group.

Within 8 hours of the end of surgery (i.e., the time of the final suture), the time to rescue analgesia and the need for rescue analgesia, including further secondary efficacy endpoints, were recorded for each individual. At 4 hours, more individuals in the placebo group (43.9%) had not yet taken rescue analgesia compared to the placebo group (30.0%), while more individuals in the placebo group (67.5%) had taken first-tier rescue analgesia compared to the compound group (51.2%). At 6 hours, compared to the placebo group (17.5%), more individuals in the placebo group (29.3%) had not yet taken a rescue analgesic (CRA), while compared to the compound group (61.0%), more individuals in the placebo group had taken a CRA (75.0%). There was no significant difference between the treatment groups in taking a CRA at 4 or 6 hours post-surgery, and no significant difference between the rescue groups at 8 hours post-surgery. In the compound 10 treatment group, only 2 individuals did not require a rescue analgesic; a total of 39/41 (95%) individuals in the compound 10 group required a rescue analgesic, and 40/40 (100%) individuals in the placebo group required a rescue analgesic.

For the ultimate secondary efficacy endpoint, individuals assessed overall satisfaction with the study drug using a 5-point Likert scale during FU1. Overall, fewer individuals rated "very disappointed" or "somewhat disappointed" with the study drug in the compound 10 group (7.3% and 29.3%, respectively) than in the placebo group (17.5% and 37.5%, respectively); more individuals rated "extremely satisfied" with the study drug in the compound 10 group (17.1%) than in the placebo group (2.5%); and the proportions of individuals rating "neutral" or "somewhat satisfied" with the study drug were similar in both treatment groups (31.7% and 27.5% neutral in compound 10 and placebo, respectively, and 14.6% and 15.0% quite satisfied, respectively).

The fundamental principle and objective of unspecified exploratory analyses, in addition to the predefined primary and secondary endpoints of this clinical study, is to investigate additional outcomes and potential relationships that may provide further insights into the safety and activity of the investigational therapy. Methods

The same dataset used for both primary and secondary endpoints is also used for exploratory analyses that are not pre-specified. Where possible, these exploratory analyses are supported by statistical techniques used to assess primary and secondary outcomes (Student's t-test is the most common of these methods).

The early versus late response was substratified, with early time points assessed at 4 and 8 hours post-surgery and late time points at 24 and 48 hours post-surgery. C-reactive protein (CRP) levels were reviewed at early time points after compound 10 administration to match its expected peak plasma concentration ( _Cmax ), which, based on early clinical data, occurred approximately 2 to 3 hours post-administration. To more fully capture the maximum pharmacokinetic effect of compound 10, biomarker and pain assessments were subsequently reviewed at earlier (4 and 8 hours) time points to explore whether a decrease in CRP levels at these time points would provide further insight into the role of compound 10 in alleviating inflammation. The observed convergence of results at 24 and 48-hour time points between the treatment and placebo groups would support the hypothesis of a weaning biological effect of compound 10, since the drug may now be present only at a sub-effective level.

The data illustrated in Figure 4 show increased CRP levels in the placebo group at 4 and 8 hours, reflecting the expected postoperative inflammatory response. In contrast to the placebo group, the compound 10 treatment group showed inhibition of CRP levels at 4 and 8 hours. This decrease in CRP levels relative to the placebo indicates inhibition of the inflammatory response in the compound 10 treatment group (1).

Figure 5 confirms that CRP levels measured at baseline, 4 and 8 hours post-surgery, and at two follow-up time points (follow-up visit 1 at 24 hours [FU1] and follow-up visit 2 at 48 hours [FU2]) showed significant increases in both groups. This may indicate a transient effect of compound 10 when administered as a single dose, as the drug's effect in inhibiting CRP levels may decrease at later time points. This also coincided with lower plasma concentrations of compound 10.

The importance of prognostic factors for pain after third molar extraction was used in the randomization timetable for assigning treatment to individuals by a two-variable classification stratification based on the number of partially or completely impacted third molars to be extracted (1 relative to more than 1). The basic principle of the stratification was to ensure a balance of important prognostic factors for pain after third molar extraction between individuals randomly assigned to compound 10 and those randomly assigned to placebo. Prophylactic administration of the study drug required individuals to be randomly assigned to the study drug prior to the actual surgical procedure; therefore, the stratification variable was the number of partially or completely impacted third molars to be extracted. Of the 81 individuals, only 1 was randomly assigned to the "1 impacted third molar" stratification, and 80 were randomly assigned to the ">1 impacted third molar" stratification. Therefore, a two-way ANOVA, identified as the primary efficacy analysis model from the protocol and statistical analysis plan (SAP), was used to eliminate the fixed effects of the stratification variables in the randomization. Thus, the conclusion is based on a one-way ANOVA with a fixed effect on the study drug, equivalent to Stuttgart's t-test. Unfortunately, the revised analytical method did not account for the imbalance of prognostic factors regarding post-oral surgery pain between treatment groups.

Randomization failed to produce homogeneous groups of individuals among the treatment groups regarding important prognostic factors for postoperative pain following third molar extraction. For example, the percentage of individuals who had a fully impacted left mandibular third molar extracted during the study differed between the treatment groups (58.5% [24 of 41 individuals] vs. 40.0% [16 of 40 individuals] for Compound 10), as did the percentage of individuals with a fully impacted right mandibular third molar (51.2% [21 of 41 individuals] vs. 42.5% [17 of 40 individuals] for Compound 10).

Given the observed heterogeneity among treatment groups regarding the number of fully impacted third molars extracted, an ad hoc statistical comparison using analysis of covariance (ANCOVA) was performed on the area under the pain rating curve (AUC). The objective of this analysis was to compare the effects of self-treatment and eliminate the effects of prognostic factors; therefore, the ANCOVA model included the number of impacted mandibular third molars extracted, randomized treatment groups, and bidirectional interactions as covariates. Covariates are tabulated by treatment in the table below. Overview of the number of impacted molars by treatment group. Number of impacted third mandibular molars removed Treatment Group 0 1 2 Compound 10 13 (31.7%) 11 (26.8%) 17 (41.5%) placebo 18 (45.0%) 11 (27.5%) 11 (27.5%)

As shown in Figure 6, the p-value for the difference in pain intensity AUC (estimated by SAP) between compound 10 and placebo at 1 to 4 hours post-surgery was 0.021, which was below the nominal threshold for statistical significance. Low p-values were also observed for pain intensity AUC at 1 to 6 hours and 1 to 8 hours post-surgery (Figure 6; p-values were 0.053 and 0.137, respectively). Notably, as an inverse univariate measure of compound 10's reduction of acute pain, the p-value increased consecutively at greater distances from the study drug, supporting the hypothesis that increased or longer exposure to compound 10 may increase its analgesic effect and duration. While these results are promising and require further investigation, statistical significance cannot be declared due to the lack of control over multiple comparisons and the ad hoc nature of this test.

Given the heterogeneity of observed treatment effects potentially influenced by prognostic factors, we examined whether incompletely impacted molars were associated with a reduced need for opioid analgesics postoperatively. Figure 7 presents a comparative analysis of tablet-like use in the compound 10 and placebo groups, highlighting the frequency achieved during the 8-hour observation period and throughout the 48-hour study duration up to FU2.

In the compound 10 treatment group, there was a significant tendency for less analgesic use (especially opioids) when individuals did not have fully impacted third molars removed. This may indicate that the effectiveness of compound 10 in this study may be affected by the number of impacted molars. This could indicate the presence of a pain threshold effect, where the difference (regardless of the amount) between partially impacted and fully impacted molars becomes a significant contributing factor to exceeding the threshold for enhanced analgesia (a threshold required to clearly benefit from the analgesic effect of compound 10).

Summary of Findings from the Unspecified Analysis In summary, the following findings were obtained from the aforementioned unspecified analysis: 1. Postoperative pain intensity: Individuals receiving compound 10 reported lower pain intensity at 4 and 8 hours postoperatively compared to those receiving a placebo. The compound 10 group consistently had lower pain scores, indicating enhanced analgesia. Importantly, the observed differences in pain intensity between the treatment and placebo groups became more pronounced when stratified by prognostic variables such as the severity of the surgical procedure and the number of impacted molars removed. 2. Use of rescue analgesics : The compound 10 group demonstrated a delayed time to first use of rescue analgesics and a reduced total amount of rescue analgesics used. This further supports the potential analgesic effect observed with treatment using compound 10.

Conclusion: The findings of this study’s unspecified analysis highlight the potential anti-inflammatory effects of compound 10 and warrant further investigation as a potential analgesic in the context of third molar extraction. The observed reductions in inflammatory markers, pain intensity, and reliance on rescue analgesics further suggest that compound 10 may contribute to the mechanisms involved in managing postoperative 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 reduce diagnostic biomarkers of acute inflammation after surgery and to manage pain following third molar extraction. Compared to the placebo group, the compound 10 treatment group did not show a significantly different increase in maximum CRP from baseline. Therefore, the primary endpoint was not met. Several secondary endpoints (pain intensity AUC, time to rescue analgesia (TTR), proportion of individuals requiring rescue analgesia, and overall satisfaction with the study drug) were not considered for statistical significance because the primary efficacy endpoint was not statistically significant. However, it is noteworthy that pain intensity was lower in the compound 10 treatment group than in the placebo group at almost all time points; although descriptive, analysis of overall satisfaction with the study drug indicates that individuals receiving compound 10 were generally more satisfied with the treatment than those receiving the placebo. Furthermore, a post-operative review of CRP levels at earlier (4 and 8 hours) post-operative time points revealed that the inhibition of CRP levels occurred only at these earlier time points following a single dose of compound 10, indicating a transient drug effect. These post-operative findings point to an emerging hypothesis that increased or prolonged exposure to compound 10 may enhance its analgesic effect. This hypothesis was further supported by the observed divergence of pain scores in placebo and compound 10 individuals, where the pain level was lower in compound 10 individuals and the first use of rescue analgesics was delayed and the total amount of rescue analgesics was lower.

Overall, treatment with compound 10 resulted in an acceptable safety profile for single-dose exposure in the study population. The incidence of treatment-associated adverse events (TEAEs) was similar between the compound 10 and placebo groups. The only TEAE occurring in ≥10% of individuals in either treatment group was headache (14.6% of compound 10 individuals and 0% of placebo individuals) and nausea (7.3% of compound 10 individuals and 10.0% of placebo individuals). Most reported TEAEs were mild, and no serious TEAEs were reported. No AEs leading to death, no serious AEs, and no AEs leading to discontinuation or termination of the study drug were reported.

Clinical laboratory parameters were similar across groups, and only one potentially clinically significant laboratory value was reported. There was no treatment group bias or significant difference in vital sign measures between groups. In conclusion, while compound 10 was generally safe and well-tolerated, the effectiveness of a single 4 mg dose of compound 10 in reducing diagnostic biomarkers of acute inflammation postoperatively and in managing pain after third molar extraction relative to placebo did not reach statistical significance; however, based on findings from an unspecified analysis, further investigation of compound 10 as a potential analgesic is warranted. That is, compound 10 may impart bioefficacy to the mechanisms involved in managing postoperative inflammation and pain.

The foregoing description of various embodiments known to the applicant at the time of filing this application is presented and intended for illustrative and descriptive purposes. This description is not intended to be exhaustive or limited to the precise forms disclosed, and many modifications and variations are possible in light of the foregoing teachings. The described embodiments are intended to explain the principles and practical applications, and to enable those skilled in the art to utilize the various embodiments, along with modifications as needed to suit the particular intended use. Therefore, it is intended that the invention is not limited to the specific embodiments disclosed.

Exemplary embodiments are illustrated in the referenced diagrams. It is intended that the embodiments and diagrams disclosed herein be regarded as illustrative rather than restrictive.

Figures 1A to 1C depict the regulation of mechanical aalgesia (measured by the claw retraction threshold: Figure 1A (left), Figure 1B (top), Figure 1C (left)) and thermal hyperalgesia (measured by the claw retraction latency: Figure 1A (right), Figure 1B (bottom), Figure 1C (right)) in a rat model of CFA-induced inflammatory pain.

Figures 2A to 2B depict the regulation of mechanical pain abnormalities (measured by the claw retraction threshold) and thermal hyperalgesia (measured by the claw retraction latency) by compound 10 in a rat model of postoperative incision pain.

Figures 3A to 3B depict the regulation of weight and mechanical pain abnormalities (measured by the claw retraction threshold) in a rat model of surgically induced osteoarthritis (a combination of anterior cruciate ligament transection and partial internal meniscectomy) by compound 10.

Figure 4 shows the effect of sufficient exposure to compound 10 on CRP levels (CRP = C-reactive protein; Hr = hour) in a phase 2b human study of third molar extraction.

Figure 5 shows the effect of trough compound 10 exposure to CRP levels in a phase 2b human study of third molar extraction. (CRP = C-reactive protein; Hr = hours; FU1 = follow-up visit 1; FU2 = follow-up visit 2; PK = pharmacokinetics; Note: Dashed lines show plasma concentrations of compound 10 in the compound 10 treatment group at baseline before FU1 treatment, at 4 hours, and at 24 hours.)

Figure 6 shows the area under the curve (AUC) of SAP pain intensity over time in the human phase 2b study of third molar extraction – p-value of the Full ANCOVA model. (ANCOVA = ANOVA; AUC = area under the curve; SAP = statistical analysis plan. The time-based SAP pain intensity AUC was calculated by replacing the pain intensity rating with the highest score of 10 after administration of rescue analgesia (according to the statistical analysis plan). The p-value is from the ANCOVA model, which includes the number of impacted mandibular third molars extracted as covariates, randomized treatment group, and bidirectional interaction. The error is ±1 standard error.)

Figure 7 shows the use of analgesics in individuals with non-impacted molars in the Phase 2b human study of third molar extraction. (FU2 = Follow-up visit 2.)

Claims (50)

A method for treating pain, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof to an individual in need: (I) Wherein: A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, 3- to 10-membered heterocyclic, or 5- to 6-membered monocyclic heteroaryl, each of which may be substituted by one or more ^{R6 groups} as required; X is CH or N; Y is NH; ^R1 is H; ^R2 is a _C1 - _C6 alkyl, _C3 - _C4 cycloalkyl, _C3 - _C8 heterocyclic, or 5- or 6-membered heteroaryl, each of which may be substituted by one or more substituents selected from halogen, hydroxyl, cyano, aminyl, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, and 3- to 8-membered heterocyclic groups as required; ^R3 is H; R ⁴ is selected from the following heteroaryl groups: 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, as needed, is derived from one or more groups selected from halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, C2-C6 ynyl, _C1 - _C6 halogen, _{C3 - C8} cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _{C1 -} C6 cycloalkyl ... The substituted group is substituted with a _6- cyanoalkyl, 3- to 8-membered heterocyclic, _C3 - _C8 halogenated cycloalkyl, _C3 - _C8 aminoalkylcycloalkyl, _C3 - _C8 alkylcycloalkyl, 3- to 8-membered heterocyclic cycloalkyl, 3- to 8-membered alkyl heterocyclic cycloalkyl, 3- to 8-membered halogenated cycloalkyl and _C3 - _C8 halogenated cycloalkyl; ^R5 is H; and each ^R6 is independently halogenated, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, cyano, _C1 - _C6 hydroxyalkyl or _C1 - _C6 halogenated. The method of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent thereof is administered in a dose of about 0.5 mg to about 5 mg. The method of Request 1 or Request 2, wherein the pain is a symptom of arthritis and/or a symptom related to arthritis. The method of claim 3, wherein the arthritis is rheumatoid arthritis. The method of request item 3, wherein the arthritis is osteoarthritis. The method of claim 3, wherein the arthritis is psoriasis arthritis. The method of Request 1 or Request 2, wherein the pain is a symptom of myofibrosis and/or a symptom related to myofibrosis. The method of Request 1 or Request 2, wherein the pain is a symptom of lupus and/or a symptom related to lupus. The method of request 1 or request 2, wherein the pain is acute inflammatory pain. The method of request 1 or request 2, wherein the pain is a symptom of peritonitis and/or a symptom related to peritonitis. The method of Request 1 or Request 2, wherein the pain is a symptom of cancer or its treatment and/or a symptom related to cancer or its treatment. The method of Request 1 or Request 2, wherein the pain is a symptom of systemic sclerosis and/or a symptom related to systemic sclerosis. The method of Request 1 or Request 2, wherein the pain is a symptom of psoriasis and/or a symptom related to psoriasis. The method of claim 13, wherein the psoriasis is psoriasis arthritis. The method of Request 1 or Request 2, wherein the pain is a symptom of atopic dermatitis or hidradenitis suppurativa and/or a symptom associated with atopic dermatitis or hidradenitis suppurativa. The method of Request 1 or Request 2, wherein the pain is a symptom of inflammatory bowel disease (IBD) and/or a symptom associated with inflammatory bowel disease (IBD). The method of claim 16, wherein the IBD is colitis. The method of claim 16, wherein the IBD is Crohn's disease. The method of request 1 or request 2, wherein the pain is a symptom of endometriosis and/or a symptom related to endometriosis. The method of Request 1 or Request 2, wherein the pain is a symptom of complex regional pain syndrome (CRPS) and/or a symptom associated with complex regional pain syndrome (CRPS). The method of request 1 or request 2, wherein the pain is postoperative pain. The method of any of claims 1 to 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent compound thereof is administered orally. The method of any of claims 1 to 22, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent thereof is provided in tablet, pill or capsule form. The method of any of claims 1 to 23, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent thereof is administered in a dose of about 5 mg. The method of any of claims 1 to 23, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent thereof is administered in a dose of about 4 mg. The method of any of claims 1 to 23, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent thereof is administered in a dose of about 3 mg. The method of any of claims 1 to 23, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent thereof is administered in a dose of about 2 mg. The method of any of claims 1 to 23, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent thereof is administered at a dose of about 0.5 mg. The method of any one of claims 1 to 28, wherein ^R2 is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, acridineyl, or oxocyclobutane, each of which may be substituted as required by one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 -C6 alkenyl, _{C2 -C6 alkynyl} , _C1 - _C6 alkoxy, and 3- to 8-membered heterocyclic groups. If the method is any one of requests 1 to 29, where R ² is: ; ; ; ; ; ; ; ; or . The method of any of claims 1 to 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 wherein, as required, is derived from one or more of a halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, C2-C6 ynyl, _C1 - _C6 halogen, _{C3 - C8} cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _C1 - _C6 cyanoalkyl, 3- _to 8-membered heterocyclic, _C3 - _C8 halogen cycloalkyl, _C3 - _C8 aminoalkyl cycloalkyl, _C3 -C Substituents of _8- alkylcycloalkyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered alkyl heterocycloalkyl, 3- to 8-membered halogen heterocycloalkyl and _C3 - _C8 halogencycloalkyl and combinations thereof. The method of any one of claims 1 to 31, wherein ^R4 is substituted with _C1 - _C6 alkyl, _C1 - _C6 halogen, _C3 - _C8 cycloalkyl, cyano, amino, _C1 - _C6 hydroxyalkyl, _C1 - _C6 cyanoalkyl, 3- to 8-membered heterocyclic, _C3 - _C8 halogen cycloalkyl, _C3 - _C8 aminoalkyl cycloalkyl, _C3 - _C8 alkyl cycloalkyl, 3- to 8-membered heterocyclic alkyl, 3- to 8-membered alkyl heterocyclic cycloalkyl, 3- to 8-membered halogen heterocyclic alkyl or _C3 - _C8 halogen cycloalkyl or combinations thereof. The method of any of the claims 1 to 32, wherein R ⁴ has one of the following structures: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or . The method of any of claims 1 to 33, wherein A is a _C6 - _C10 aryl, _C3 - _C10 cycloalkyl, or 5 to 6-membered monocyclic heteroaryl, each of which is substituted with one or more ^R6 as required. The method of any of claims 1 to 34, wherein A is cyclohexyl, cyclohexenyl, phenyl, pyridyl or pyrimidinyl. The method of any one of claims 1 to 35, wherein A is phenyl. The method of any one of the requests 1 to 36 is requested, where A is not replaced. The method of any of the requests 1 to 36, wherein A is replaced by one or more R ⁶ . The method of any one of claims 1 to 36 or 38, wherein R ⁶ is chlorine, fluorine, -CHF ₂ , -CH ₂ CH ₂ OH, cyano or methoxy. If the method is requested for any one of items 1 to 35, where A is: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or . The method of any one of claims 1 to 36 or 38 to 40, wherein the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof: (Ia) wherein: ^R2a is a C3-C4 cycloalkyl group substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _{C6 alkynyl} , _C1 - _C6 alkoxy and 3 to 8 heterocyclic groups as needed; and ^R4a is an isoxazolyl group substituted with one or _more substituents selected from _C1 - _C6 halogen, _C3 - _C8 cycloalkyl or _C3 - _C8 halogen cycloalkyl as needed. The method of claim 41, wherein R ^2a is cyclopropyl. For example, the method of request item 41 or 42, where R ^4a is: or . The method of any of claims 1 to 28, wherein the compound of formula (I) is listed in Table 1A, or a pharmaceutically acceptable salt or solvent thereof. The method of any one of claims 1 to 36 or 38 to 44, wherein the compound of formula (I) is Or a medically acceptable salt or solvent compound thereof. The method of any of the claims 1 to 45, wherein the pain is a symptom of inflammation and/or a symptom related to inflammation. The method of any of claims 1 to 46, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent thereof is an inhibitor of NEK7 kinase. The method of any of claims 1 to 47, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent thereof is a modulator of the NLRP3 inflammasome. The method of any one of claims 1 to 48, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent thereof is an inhibitor of NLRP3 (protein)-NEK7 (protein) interaction. The method of any one of claims 1 to 49, wherein the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvent thereof is a compound that modulates the priming step of the NLRP3 inflammasome and inhibits the formation of the NLRP3 (protein)-NEK7 (protein) interaction.