Methods for the treatment or prevention of biological aging

Abstract

Described herein are methods of treating the symptom of biological aging, including improving and / or restoring muscle function, improving and / or restoring cognition and improving and / or restoring immune function, and methods of preventing the symptom of biological aging, the methods comprising administering an inflammasome modulator. In some embodiments the method of treatment comprises administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein.

Description

Attorney Docket No. 63243-710.601METHODS FOR THE TREATMENT OR PREVENTION OF BIOLOGICAL AGING CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Patent Application No. 63 / 747,821, filed January 21, 2025, which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Biological aging and symptoms thereof include the reduction of function of the muscle, cognition, and immune systems.SUMMARY OF THE INVENTION

[0003] In one aspect, provided herein are compositions and methods of treating or preventing a symptom of biological aging in a subject. In some embodiments, the methods herein comprise treatment with an inflammasome modulator. In some embodiments, the methods herein comprise treatment with a modulator of the NOD-, LRR- and pyrin domaincontaining protein 3 (NLRP3) inflammasome. In some embodiments, the methods herein comprise treatment with an inhibitor of NEK7 kinase. In some embodiments, the methods herein comprise treatment with an inhibitor of the NLRP3 (protein)-NEK7 (protein) interaction. In some embodiments, the inflammasome modulator inhibits the priming step of the NLRP3 inflammasome. In some embodiments, the inflammasome modulator inhibits signaling downstream of members of the TLR (toll-like receptor) family, IL-1R (interleukin 1 receptor) family, and / or TNFR1 / 2 (tumor necrosis factor receptor 1 / 2). In some embodiments, the inflammasome modulator prevents the activation of NF-kB (nuclear factor kappa-beta). In some embodiments, the administering reduces the level of TNF-a, IL-6, or the components of the NLRP3 inflammasome (e.g., NLRP3, pro-IL-1β (pro-interleukin-1beta), pro-IL18 (pro-interleukin- 18)), or a combination thereof, in the subject. In some embodiments, the inflammasome modulator inhibits the assembly and activation step of the NLRP3 inflammasome. In some embodiments, the inflammasome modulator inhibits the formation of a NLRP3 (protein)-NEK7 (protein) interaction. In some embodiments, the inflammasome modulator inhibits the formation of the ASC speck and the NLRP3 inflammasome. In some embodiments, the inflammasome modulator prevents caspase-1 activation. In some embodiments, the inflammasome modulator inhibits the production of IL-1β. In some embodiments, the inflammasome modulator inhibits the production of IL-18. In some embodiments, the inflammasome modulator inhibits the cleavage of gasdermin D. In some embodiments, the inflammasome modulator prevents pyroptotic cell death. In someAttorney Docket No. 63243-710.601embodiments, the methods herein comprise treatment with a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). In some embodiments, the methods herein comprise treatment with a compound of Formula (I).

[0004] Provided herein is a method of treating, preventing, slowing, and / or decreasing biological aging or a symptom of biological aging, restoring muscle function, restoring cognition, or improving immune function, or any combination thereof, comprising administering to a subject in need thereof an inflammasome modulator. Provided herein is a method of slowing biological aging or decreasing a symptom of biological aging, restoring muscle function, restoring cognition, or improving immune function, or any combination thereof, comprising administering to a subject in need thereof an inflammasome modulator. In some embodiments, the administering comprises administering about 0.5 mg to about 10 mg of the inflammasome modulator to the subject. In some embodiments, the administering comprises administering the inflammasome modulator to the subject every day, every other day, every two days, every three days, every four days, every five days, every six days, once a week, five days on and two days off, once every two weeks, or once a month. In some embodiments, the administering comprises administering the inflammasome modulator to the subject five days on and two days off. In some embodiments, the administering comprises orally administering to the subject the inflammasome modulator. In some embodiments, the inflammasome modulator is in the form of a tablet, capsule, or pill.

[0005] Provided herein is a method of treating or preventing the symptom of biological aging, comprising administering to a subject in need thereof a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (I)wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;Xis CH orN;YisNH;Attorney Docket No. 63243-710.601R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl;Formula (II) wherein:X is N or CH;A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;R1is H, halo, Ci-Ce alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R3is aminylalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N-heterocyclyloxy, or 5-6 membered heteroaryl; orAttorney Docket No. 63243-710.601R3joins with an occurrence of R4attached to a carbon adjacent to a carbon to which R3is attached to form a C3-C8 cycloalkyl;R4is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci- Ce alkoxy, Ci-Ce haloalkoxy, Cs-Cs halocycloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4;Formula (III)wherein:A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;Xis N or CR4;Y is N or CH;R1is Ci-Ce alkyl, Ci-Ce hydroxylalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl; orR2joins with an occurrence of R3attached to a carbon adjacent to a carbon to which R2is attached to form a C3-C8 cycloalkyl;R3is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl;R4is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4;R3Formula (IV)Attorney Docket No. 63243-710.601wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;Xis N or CR1C;Y is N or CRld;Z is C(R6)(R7) or NR6;R1a, R1b, R1c, and R1dare each independently H, halo, Ci-Ce alkyl, or C3-C8 cycloalkyl;R2aand R2bare each independently H, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl, provided that R2aand R2bare not both H;R3is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R5is, at each occurrence, independently halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;R6is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl; and R7is H, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl;A N NH2R4N IIR2Formula (V)wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Attorney Docket No. 63243-710.601Yis CHOH orNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl;O HN^2 / N^( * VARH W NH2zNR1Formula (VI)wherein:represents a double or a single bond such that all valences are satisfied;Attorney Docket No. 63243-710.601A is an optionally substituted 5-6-membered heterocyclyl, an optionally substituted 6-membered aryl, or an optionally substituted 5-6-membered heteroaryl;Xis N or CR3;Y is C or N;W is CH or N;Z is CH or N;R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;R2is optionally substituted aryl or optionally substituted heteroaryl; andR3is hydrogen, halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.

[0006] As a non-limiting example embodiment, the method of treating or preventing the symptom of biological aging, comprises administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:VR4NH2R5Njl y- R3X N(I)wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;Xis CH orN;YisNH;R1is H;Attorney Docket No. 63243-710.601R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0007] In some embodiments, R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0008] In some embodiments, R2is:

[0009] In some embodiments, R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3-to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-Attorney Docket No. 63243-710.601Cs halocycloalkyl, and combinations thereof.

[0010] In some embodiments, R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, Cs-Cs haloalkylcycloalkyl, Cs-Cs aminylalkylcycloalkyl, Cs-Cs alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or Cs-Cs halocycloalkyl, or combinations thereof.

[0011] In some embodiments, R4has one of the following structures:

[0012] In some embodiments, A is C6-C10aryl, C3-C10cycloalkyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6.

[0013] In some embodiments, A is cyclohexyl, cyclohexenyl, phenyl, pyridinyl, or pyrimidinyl.

[0014] In some embodiments, A is phenyl. In some embodiments, A is unsubstituted.Attorney Docket No. 63243-710.601

[0015] In some embodiments, A is substituted with one or more R6.

[0016] In some embodiments, R6is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy.

[0017] In some embodiments, A is:\ Cl 0 FF F F

[0018] In some embodiments, the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci- Ce haloalkyl, C3-C8 cycloalkyl or Cs-Cs haloalkyl cycloalkyl.

[0019] In some embodiments, R2ais cyclopropyl.

[0020] In some embodiments, R4ais:Attorney Docket No. 63243-710.601 / ___ / 'CF3 / ~CF3-tx zN AA „00 orN

[0021] In some embodiments, the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0022] In some embodiments, the compound of Formula (I) isO / L" CF3cHN-XF\ VA / NH' NNI-'0O NH2\===^|i JL / , or a pharmaceutically acceptable salt or solvate thereof.

[0023] In some embodiments, the method comprises the treating or preventing the symptom of biological aging. In some embodiments, the symptom of biological aging comprises loss of muscle function. In some embodiments, the method comprises the restoring muscle function in the subject. In some embodiments, the method restores glucose tolerance and insulin sensitivity. In some embodiments, the method reduces protein catabolism. In some embodiments, the method reduces muscle atrophy. In some embodiments, the symptom of biological aging comprises reduction of immune function. In some embodiments, the method comprises the improving immune function in the subject. In some embodiments, the method reduces the amount of SASP biomarkers in the subject. In some embodiments, the method reduces ILlb in the subject. In some embodiments, the method reduces IL6 in the subject. In some embodiments, the method reduces IL8 in the subject. In some embodiments, the symptom of biological aging comprises a reduction of neurological function. In some embodiments, the method comprises restoring cognition in the subject. In some embodiments, the method reduces obesity-related chronic inflammation. In some embodiments, the method protects the blood-brain barrier (BBB). In some embodiments, the method prevents obesity-related cognitive decline. In some embodiments, the subject has clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP). In some embodiments, the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 2% or greater, in the absence of cytopenia. In some embodiments, the subject has the presence of acquired mutations inAttorney Docket No. 63243-710.601genes associated with myeloid malignancies at a variant allele fraction (VAF) of 1% or greater, in the absence of cytopenia. In some embodiments, the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 3% or greater, in the absence of cytopenia. In some embodiments, the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 4% or greater, in the absence of cytopenia. In some embodiments, the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 5% or greater, in the absence of cytopenia. In some embodiments, the subject has somatic mutations in normal dividing cells. In some embodiments, the subject has clonal cytopenias of undetermined significance (CCUS). In some embodiments, the subject is 25 years old or older. In some embodiments, the subject is 30 years old or older. In some embodiments, the subject is 35 years old or older. In some embodiments, the subject is 40 years old or older. In some embodiments, the subject is 45 years old or older. In some embodiments, the subject is 50 years old or older. In some embodiments, the subject is 55 years old or older. In some embodiments, the subject is 60 years old or older. In some embodiments, the subject is 65 years old or older. In some embodiments, the subject is 70 years old or older. In some embodiments, the subject is 75 years old or older.DETAILED DESCRIPTION OF THE INVENTION

[0024] In one aspect, provided herein are methods of treating or preventing the symptom of biological aging with a compound disclosed herein. In one aspect, provided herein are methods of delaying the development of a symptom of biological aging with a compound disclosed herein. In one aspect, provided herein are methods of slowing the development of a symptom of biological aging with a compound disclosed herein. The compound disclosed herein is, for example, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI).Terms

[0025] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are described herein for clarity and / or for ready reference, and the inclusion of such should not necessarily be construed to represent a substantial difference over what is generally understood in the art.Attorney Docket No. 63243-710.601

[0026] As used in the specification, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0027] A “pharmaceutical composition” refers to formulations of compounds of the disclosure and a medium generally accepted in the art for the delivery of compounds of the disclosure to mammals, c.g, humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefore.

[0028] “Pharmaceutically acceptable carrier, diluent or excipient” includes, without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier.

[0029] Amino” refers to the -NH2 radical.

[0030] “Carboxy” or "carboxyl" refers to the -CO2H radical.

[0031] “Cyano” refers to the -CN radical.

[0032] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0033] “Nitro” refers to the -NO2 radical.

[0034] Oxo” refers to the =0 substituent.

[0035] Thiol” refers to the -SH substituent.

[0036] Thioxo” refers to the =S substituent.

[0037] “Alkyl” refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (Ci-Cs alkyl) or one to six carbon atoms (Ci-Ce alkyl), or any value within these ranges, such as C4-C6 alkyl and the like, and which is attached to the rest of the molecule by a single bond, c.g, methyl, ethyl, / / -propyl,1 -methylethyl ( / .w-propyl), / -butyl, / / -pentyl, 1,1 -dimethylethyl ( / -butyl), 3 -methyl hexyl, 2-methylhexyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted.

[0038] “Alkenyl” refers to an unsaturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbonAttorney Docket No. 63243-710.601double bonds, having from 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 which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted.

[0039] “Alkynyl” refers to unsaturated straight or branched hydrocarbon radical, having 2 to 12 carbon atoms (C2-C12 alkynyl), two to nine carbon atoms (C2-C9 alkynyl), or two to six carbon atoms (C2-C6 alkynyl), or any value within these ranges, and having at least one carbon- carbon triple bond. Examples of alkynyl groups may be selected from the group consisting of ethynyl, propargyl, but-l-ynyl, but-2-ynyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted.

[0040] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above containing one to twelve carbon atoms (C1-C12 alkoxy), one to eight carbon atoms (Ci-Cs alkoxy) or one to six carbon atoms (Ci-Ce alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0041] “Aminyl” refers to a radical of the formula -NRaRb, where Ra and Rb are each independently H or Ci-Ce alkyl as defined above. When both of Raand Rb are H, an "aminyl" group is the same as an "amino" group as defined above. The Ci-Ce alkyl portion of an aminyl group is optionally substituted unless stated otherwise.

[0042] “ Aminylalkylcycloalkyl” refers to a radical of the formula -RaRbNRcRd where Ra is cycloalkyl as defined herein, Rb is Ci-Ce alkyl, Rc is H or Ci-Ce alkyl and Rd is Ci-Ce alkyl as defined above. The cycloalkyl and each Ci-Ce alkyl portion of an aminylalkylcycloalkyl group are optionally substituted unless stated otherwise.

[0043] Aromatic ring” refers to a cyclic planar molecule or portion of a molecule ( / .<., a radical) with a ring of resonance bonds that exhibits increased stability relative to other connective arrangements with the same sets of atoms. Generally, aromatic rings contain a set of covalently bound co-planar atoms and comprises a number of ^-electrons (for example, alternating double and single bonds) that is even but not a multiple of 4 ( / .<., 4n + 27t-Attorney Docket No. 63243-710.601electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, pyrimidonyl. Unless stated otherwise specifically in the specification, an "aromatic ring" includes all radicals that are optionally substituted.

[0044] “Aryl” refers to a carbocyclic ring system radical comprising 6 to 18 carbon atoms, for example 6 to 10 carbon atoms (Ce-Cio aryl) and at least one carbocyclic aromatic ring. For purposes of embodiments of this invention, the aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, -indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group is optionally substituted.

[0045] “Cyanoalkyl” refers to an alkyl group comprising at least one cyano substituent. The -CN substituent may be on a primary, secondary, or tertiary carbon. Unless stated otherwise specifically in the specification, a cyanoalkyl group is optionally substituted.

[0046] " Carbocyclic" or "carbocycle" refers to a ring system, wherein each of the ring atoms are carbon.

[0047] “Cycloalkyl” refers to a non-aromatic monocyclic or polycyclic carbocyclic radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C3-C15 cycloalkyl), from three to ten ring carbon atoms (C3-C10 cycloalkyl), or from three to eight ring carbon atoms (C3-C8 cycloalkyl), or any value within these ranges such as three to four carbon atoms (C3-C4 cycloalkyl), and which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group is optionally substituted.

[0048] “Alkylcycloalkyl” refers to a radical group of the formula -RaRb where Ra is a cycloalkyl group and Rb is an alkyl group as defined above. Unless otherwise stated specifically in the specification, an alkylcycloalkyl group is optionally substituted.

[0049] “Fused” refers to any ring structure described herein which is fused to another ring structure.Attorney Docket No. 63243-710.601

[0050] Halo" refers to bromo, chloro, fluoro, or iodo.

[0051] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl,tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0052] “Halocycloalkyl” refers to a cycloalkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl,3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a halocycloalkyl group is optionally substituted.

[0053] “Haloalkylcycloalkyl” refers to a radical group of the formula -RaRb where Ra is a cycloalkyl group and Rb is a haloalkyl group as defined above. Unless otherwise stated specifically in the specification, a haloalkylcycloalkyl group is optionally substituted.

[0054] “Hydroxylalkyl” refers to an alkyl radical, as defined above that is substituted by one or more hydroxyl radical. The hydroxyalkyl radical is joined at the main chain through the alkyl carbon atom. Unless stated otherwise specifically in the specification, a hydroxylalkyl group is optionally substituted.

[0055] “Heterocyclyl” refers to a 3 - to 18-membered, for example 3- to 10-membered or 3- to 8-membered, non-aromatic ring radical having one to ten ring carbon atoms (e.g., two to ten) and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is partially or fully saturated and is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic and / or bridged ring systems. Nitrogen, carbon, and sulfur atoms in a heterocyclyl radical are optionally oxidized, and nitrogen atoms may be optionally quaternized. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro- IH-pyrrolizine, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted.Attorney Docket No. 63243-710.601

[0056] “Haloheterocyclylalkyl” refers to a radical group of the formula -RaRb where Ra is an alkyl group and Rb is a haloheterocyclyl group as defined herein. Unless otherwise stated specifically in the specification, a haloheterocyclylalkyl group is optionally substituted.

[0057] “Heterocyclyl alkyl” refers to a radical group of the formula -RaRb where Ra is an alkyl group and Rb is a heterocyclyl group as defined herein. Unless otherwise stated specifically in the specification, a heterocyclylalkyl group is optionally substituted.

[0058] “Heteroaryl” refers to a 5- to 18-membered, for example 5- to 6-membered, ring system radical comprising one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. Heteroaryl radicals may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- l / 7-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl ( / .<., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.

[0059] Oxazolyl, isoxazolyl, 1, 2, 3 -oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5 -oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5 -thiadiazolyl and 1, 3, 4-thiadiazolyl refer to the following structures, respectively:Attorney Docket No. 63243-710.601N-SN x-Nand S—IJ

[0061] wherein the oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, and 1, 3, 4-thiadiazolyl are attached to the remainder of the molecule by a covalent bond to one of the carbon atoms in the ring of the oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, and 1, 3, 4-thiadiazolyl.

[0062] In some embodiments, a heteroaryl group has one of the following structures:

[0063] The term "substituted" as used herein means any of the above groups (e.g, alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxylalkyl) wherein at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of nonhydrogen substituents include, but are not limited to amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxylalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents.

[0064] In some specific embodiments, the optional substitutions are independently selected from the group consisting of halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, Ce-Cio aryl, 5- or 6-membered heteroaryl, Ci-Ce alkoxy and 3-8 membered heterocyclyl.

[0065] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to affect the intended application including but not limited to treating or preventing the symptom of biological aging, as defined below.

[0066] Treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder or medical condition, including but not limited to, the symptom of biological aging.Attorney Docket No. 63243-710.601

[0067] The term "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0068] “Pharmaceutically acceptable salt” includes both acid and base addition salts.

[0069] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness of the free bases, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, et al., " Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane -1,2-di sulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0070] “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness of the free acids, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, etal., " Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of PharmaceuticalAttorney Docket No. 63243-710.601Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable base addition salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropyl amine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0071] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as NLRP3 inflammasome or NEK7 or the association of NLRP3 inflammasome - NEK7. Accordingly, the terms "antagonist" and "inhibitors" may be defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0072] The term “agonist” as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein. Accordingly, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.Attorney Docket No. 63243-710.601

[0073] " Signal transduction" is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response.

[0074] The term "selective inhibition" or "selectively inhibit" refers to a biologically active agent refers to the agent’s ability to preferentially reduce the target signaling activity as compared to off target signaling activity, via direct or indirect interaction with the target.

[0075] “Subject” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[0076] “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

[0077] The term "in vivo" refers to an event that takes place in a subject’s body.

[0078] Certain embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood, or other biological samples.

[0079] Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0080] Often crystallizations produce a solvate of the compounds disclosed herein. As used herein, the term “solvate” refers to an aggregate that comprises one or more compounds of the disclosure with one or more molecules of solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. In some aspects, the compounds of the disclosure are a true solvate, while in other cases, the compounds of theAttorney Docket No. 63243-710.601disclosure merely retain adventitious water or is a mixture of water plus some adventitious solvent.

[0081] A “stereoisomer’ ’ refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0082] The compounds of the disclosure (compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI)) or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and may thus give rise to stereoisomers such as enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0083] Embodiments of the present disclosure include all manner of rotamers and conformationally restricted states of a compound of the invention. Atropisomers, which are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers, are also included. As an example, certain compounds of the disclosure may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer.

[0084] In some embodiments, the compounds of Formula (I), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) are a mixture of enantiomers or diastereomers. In other embodiments, the compounds of Formula (I), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) are substantially oneAttorney Docket No. 63243-710.601enantiomer or diastereomer.

[0085] A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments thus include tautomers of the disclosed compounds.

[0086] The chemical naming protocol and structure diagrams used herein are a modified form of the I. U. P. A. C. nomenclature system, using the ACD / Name Version 9.07 software program and / or ChemDraw Professional Version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names employed herein, a substituent group is typically named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.

[0087] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0088] The disclosure provides that wherever embodiments are provided herein with the term “comprising,” the analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided, if such analogous embodiments are not explicitly provided. The disclosure further provides that wherever embodiments are described herein with the phrase “consisting essentially of,” the analogous embodiments described in terms of “consisting of’ are also provided. The disclosure also provides that wherever embodiments are described herein with the phrase “consisting of,” the analogous embodiments described in terms of “consisting essentially of’ are also provided.

[0089] The term “and / or” as used in a phrase with a list of members is intended to include all members individually and all combination of full or partial list of members. For example, a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0090] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.Attorney Docket No. 63243-710.601Non-Limiting Compounds Applied in the Method of Treating or Preventing the Symptom of Biological Aging

[0091] Described herein are methods of treating or preventing the symptom of biological aging in a subject, comprising administering to the subject a composition comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome.

[0092] Embodiments described herein provide a compound having Formula (I):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;YisNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl and Ci-Ce alkoxy;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-CeAttorney Docket No. 63243-710.601hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclyl alkyl, 3-to 8-membered alkylheterocyclyl cycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-Cs halocycloalkyl, or combinations thereof;R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR6is, at each occurrence, independently halo, Ci-Ce alkyl, cyano, Ci-Ce hydroxylalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl.

[0093] In some embodiments of the compound of Formula (I):A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;YisNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl and Ci-Ce alkoxy;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl;R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR6is, at each occurrence, independently halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0094] In some embodiments of the compound of Formula (I):Attorney Docket No. 63243-710.601A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;Xis CH orN;YisNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl and Ci-Ce alkoxy;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclyl alkyl, 3-to 8-membered alkylheterocyclyl cycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-Cs halocycloalkyl;R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR6is, at each occurrence, independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0095] In some embodiments, A is any suitable functional group as described herein. In some embodiments, A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6. In some embodiments, A is Ce-Cio aryl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6. In some embodiments, A is Ce-Cio aryl optionally substituted with one or more R6. In some embodiments, A is 5-6 memberedAttorney Docket No. 63243-710.601monocyclic heteroaryl optionally substituted with one or more R6. In some embodiments, A is C3-C10 cycloalkyl. In some embodiments, A is 3-10 membered heterocyclyl optionally substituted with one or more R6.

[0096] In some embodiments, A is a divalent optionally substituted C6-10aryl. In some embodiments, A is a divalent optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, A is a divalent optionally substituted 3-10 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, A is a divalent optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0097] In some embodiments, A is a divalent group selected from phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5-oxadiazolyl, 1.3.4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1.3.4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, and xanthenyl; each of which is optionally substituted.

[0098] In some embodiments, A is a divalent group selected from phenyl, pyridinyl, cyclohexyl, and cyclohexenyl; each of which is optionally substituted. In other embodiments,Attorney Docket No. 63243-710.601A is phenyl. In some embodiments, A is saturated or unsaturated cyclohexyl. In more embodiments, A is pyridinyl.

[0099] In some embodiments, A is pyrimidinyl, which is optionally substituted.

[0100] In some embodiments, X is any suitable atom as described herein. In some embodiments, X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

[0101] In some embodiments, Y is any suitable linker as described herein. In some embodiments, Y is NH.

[0102] In some embodiments, R1is any suitable functional group described herein. In some embodiments, R1is H. In some embodiments, R1is Ci-Ce alkyl. In some embodiments, R1is methyl, ethyl, n-propyl, or isopropyl.

[0103] In some embodiments, R2is any suitable functional group described herein. In some embodiments, R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl. In some embodiments R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is cyclopropyl or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is cyclopropyl. In some embodiments, R2is oxetanyl. In some embodiments, R2is unsubstituted cyclopropyl or oxetanyl. In some embodiments, R2is N-methyl substituted pyrrolidinyl. In some embodiments, R2is unsubstituted cyclobutyl.

[0104] In some embodiments, R2is:Attorney Docket No. 63243-710.601

[0105] In some embodiments, R2is:

[0106] In some embodiments, R3is any suitable functional group described herein. In some embodiments, R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R3is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R3is H. In some embodiments, R3is Ci-Ce alkyl. In some embodiments, R3is methyl, ethyl, n-propyl, or isopropyl.

[0107] In some embodiments, R4is any suitable functional group described herein. In some embodiments, R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof. In some embodiments, R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3-to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-Cs halocycloalkyl, and combinations thereof.Attorney Docket No. 63243-710.601

[0108] In some embodiments, R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. In some embodiments, R4is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl.

[0109] In some embodiments, R4is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0110] In some embodiments, R4is thiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0111] In some embodiments, R4is isothiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0112] In some embodiments, R4is 1,2,4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8Attorney Docket No. 63243-710.601halocycloalkyl, and combinations thereof.

[0113] In some embodiments, R4is 1,3,4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclyl cycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0114] In some embodiments, R4is 1,2,4-triazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0115] In some embodiments, R4is 1, 3, 4-oxadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, 3- to 8-membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0116] In some embodiments, R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0117] In some embodiments, R4is:Attorney Docket No. 63243-710.601Attorney Docket No. 63243-710.601

[0120] In some embodiments, R5is any suitable functional group described herein. In some embodiments, R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R5is H or Ci-Ce alkyl, wherein Ci-Ce alkyl is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R5is H. In some embodiments, R5is C1-C6alkyl. In some embodiments, R5is methyl, ethyl, n-propyl, or isopropyl.

[0121] In some embodiments, each R6is any suitable functional group described herein. In some embodiments, each R6is independently halo, Ci-Ce alkyl, cyano, Ci-Ce hydroxylalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl. In some embodiments, each R6is chloro or fluoro. In some embodiments, each R6is fluoro. In some embodiments, each R6is Ci-Ce hydroxylalkyl. In some embodiments, each R6is Ci-Ce hydroxyl alkyl. In some embodiments, each R6is -CH2CH2OH. In other embodiments, each R6is cyano. In some embodiments, each R6is Ci-Ce alkoxy. In some embodiments, each R6is methoxy.

[0122] In some embodiments, A is:

[0123] In some embodiments, A is:Attorney Docket No. 63243-710.601F

[0124] In some embodiments, the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci-Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl.

[0125] In some embodiments, R2ais a branched Ci-Ce alkyl substituted with hydroxyl. In some embodiments, R2ais C3-C8 cycloalkyl. In some embodiments, R2ais:

[0126] In some embodiments, R4ais isoxazolyl substituted with C3-C8 haloalkylcycloalkyl. In some embodiments, R4ais C3-C8 fluoroalkylcycloalkyl. In some embodiments, R4ais fluoroalkylcyclopropyl or fluoroalkyl cyclobutyl. In some embodiments, R4ais:

[0127] In some embodiments, the compound is a compound of Formula (lb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Attorney Docket No. 63243-710.601(IB)wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;Xis CH orN;YisNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl and Ci-Ce alkoxy;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3 -oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andAttorney Docket No. 63243-710.601R6is, at each occurrence, independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0128] In some embodiments, the compound of Formula (I) is administered to treat or prevent the symptom of biological aging. In some embodiments, the compound of Formula (I) is administered to delay and / or slow the development of the symptom of biological aging.

[0129] 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 the NLRP3 inflammasome. In some embodiments, the compound of Formula (I) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (I) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (I) inhibits the priming step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (I) inhibits signaling downstream of members of the TLR (toll-like receptor) family, IL-1R (interleukin 1 receptor) family, and / or TNFR1 / 2 (tumor necrosis factor receptor 1 / 2). In some embodiments, the compound of Formula (I) prevents the activation of NF-kB (nuclear factor kappa-beta). In some embodiments, the compound of Formula (I) reduces the level of TNF-a, IL-6, or the components of the NLRP3 inflammasome (e.g., NLRP3, pro-IL-1β (pro-interleukin-1beta), pro-IL18 (pro-interleukin- 18)), or a combination thereof, in the subject. In some embodiments, the compound of Formula (I) inhibits the assembly and activation step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (I) inhibits the formation of a NLRP3 (protein)-NEK7 (protein) interaction. In some embodiments, the compound of Formula (I) inhibits the formation of the ASC speck and the NLRP3 inflammasome. In some embodiments, the compound of Formula (I) prevents caspase-1 activation. In some embodiments, the compound of Formula (I) inhibits the production of IL-1β. In some embodiments, the compound of Formula (I) inhibits the production of IL-18. In some embodiments, the compound of Formula (I) inhibits the cleavage of gasdermin D. In some embodiments, the compound of Formula (I) prevents pyroptotic cell death.

[0130] In various different embodiments, the compound has one of the structures set forth in Table 1 A below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0131] Compounds in Table 1 A were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Attorney Docket No. 63243-710.601Table 1A: Representative Compounds of Formula (I)No. Structure Namel-(4-(4-amino-7-0 / "x / = A J / " (oxetan-3 -yl)-7Z7- ) Z Z / — / N-"\, N / / \ i \ ( > M - pyrrolo[2,3- rSH1 d]pyrimidin-5- XXyl)phenyl)-3 -(3 -(tert- I JL / ^0Z Ibutyl)isoxazol-5- yl)urea l-(4-(4-amino-7-0r—y 'A cyclopropyl-77 / -F\ J N--\^Npyrrolo[2,3- ZS2H\ d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3 - I! JL / (te / 7-buty l)i soxazol - 5 -Nyl)ureal-(5-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3- 3 d]pyrimidin-5- yl)pyridin-2-yl)-3 -(3 - (te / 7-buty l)i soxazol - 5 - yl)urea l-(4-(4-amino-7- °cyclopropyl-77 / - HN'A X n'^VA H N pyrrolo[2,3- F 74 d]pyrimidin-5-yl)-2- N'" XrX\ fluorophenyl)-3 -(5- H 1 >(te / 7-butyl)i soxazol-3 - b yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7- cyclopropyl-77 / - \ f= pyrrolo[2,3- zzn —.» d]pyrimidin-5-yl)-2- 5fluorophenyl)-3 -(3 -( 1 - (trifluoromethyl)cyclop A° xropyl)isoxazol-5-ZO / yl)urea \ZZ”'\l-(4-(4-amino-7- o0( CO cyclopropyl-77 / -C\ H / NF N F^..xnOVA H N pyrrolo[2,3- 6 F 7NH2y=^ d]pyrimidin-5-yl)-2- N'"^r N fluorophenyl)-3 -(5- H / L / S^N cy cl opropy li soxazol -3 - b yl)urea0 _ / l-(4-(4-amino-7-CHNX F\ cyclopropyl-77 / -F\ 1N> Y"V" A H °NF 7 pyrrolo[2,3- 7 NH2\=^ d]pyrimidin-5-yl)-2- N'" F-A\fluorophenyl)-3 -(3 - U A / methyli soxazol -5 - b yl)ureal-(4-(4-amino-7-CHNF / F cyclopropyl-77 / -F\ JNAl"0# 7H Npyrrolo[2,3- 8 NH2\F d]pyrimidin-5-yl)-2- N'AFXfluorophenyl)-3 -(5- Li A / methyli soxazol -3 -N" K yl)ureaAttorney Docket No. 63243-710.601No. Structure Name\ Fl-(4-(4-amino-7-0HN-^\ cyclopropyl-77 / -F\ JN^\_. N\ \ H0pyrrolo[2,3- 9 NH2\===^ d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3 -(2- H JL / co fluoropropan-2-No yl)isoxazol-5-yl)urea r o l-(4-(4-amino-7- O zr / ~-CF3cyclopropyl-77 / - HNA-A=;OZ Xpyrrolo[2,3- V-N H NYX^id]pyrimidin-5-yl)-2- 10 ONH2\==^£ fluorophenyl)-3 -(5 -( 1 - z ( z —'A I= / ! JL / (trifluoromethyl)cyclop ropyl)isoxazol-3-Nyl)urea l-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3- d]pyrimidin-5-yl)-3- 11fluorophenyl)-3 -(3 -( 1 - (trifluoromethyl)cyclop ropyl)isoxazol-5- yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7- \ / CF30Z ~ cyclopropyl-77 / - HN-N / ' u\ / N— \. N pyrrolo[2,3-Hd]pyrimidin-5-yl)-2- 12 NH2fluorophenyl)-3 -(3 - NXXI! JL / ( 1,1,1 -trifluoro-2- methylpropan-2-Nyl)isoxazol-5-yl)urea l-(4-(4-amino-7-0-J / 'HNX Ji \, cyclopropyl-77 / - J N^x Npyrrolo[2,3- fAH13 NH2\=^ d]pyrimidin-5- NXX yl)phenyl)-3 -(3 -(tert- I! JL / butyl)isoxazol-5-Nyl)urea1 -(4-(4-amino-7-(2- hydroxy-2- / o / fi-7 XCF3HN-A J W methylpropyl)-7Z7- \ / N" A_, Npyrrolo[2,3-H14 NH2d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3 -( 1 - I! X / (trifluoromethyl)cyclop y~OH ropyl)isoxazol-5- yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7- cyclopropyl-77 / -zz / = / = pyrrolo[2,3- )) Z z Z z / —— / / / / / \ z I \ > ( M - d]pyrimidin-5- 15M— \ T' / -z _ _. yl)cyclohex-3 -en- 1 -yl)- JH V' ' " UXi'3-(3-(tert- ^O IZ butyl)isoxazol-5- oy yl)urea k^ Z,l-(4-(4-amino-7-0-J / 'HN'AJ N^ J / cyclopropyl-77 / - x \ N,r \H 0pyrrolo[2,3- 16 NH2d]pyrimidin-5- yl)cyclohexyl)-3 -(3 - I! JL / (te / 7-buty l)i soxazol - 5 -Nyl)ureal-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3- 17 d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3 -( 1 - methylcyclopropyl)isox azol-5-yl)ureal-(4-(4-amino-7- oHN^ JI\ / / \\ cyclopropyl-77 / -FyJ H'V pyrrolo[2,3- 18 NH2\ F=^ 7 d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(4- H 1 > (7c / 7-butyl)thiazol-2- yl)ureaNAttorney Docket No. 63243-710.601No. Structure Name0 l-(4-(4-amino-7- / / N-NHN"\ J! \\ / cyclopropyl-77 / -FyJ ||V <pyrrolo[2,3- o19 NH2d]pyrimidin-5-yl)-2- 1! JL / fluorophenyl)-3 -(5 - (tert-butyl)- 1,3,4-Nthi adiazol -2-yl)urea l-(4-(4-amino-7- °HNA J / cyclopropyl-77 / -F\ y-4 J N^ \ / NHSpyrrolo[2,3- 20 NH2VA d]pyrimidin-5-yl)-2- NAA fluorophenyl)-3 -(3 - H 1 > (tert-butyl)i sothiazol -5 -Nyl)ureal-(4-(4-amino-7- I oI / NA / ~~~HNA / / cyclopropyl-77 / - V7 tANpyrrolo[2,3- 21 NH2\ F=A 7 d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3 - H 1 > (tert-butyl)-l,2,4- thi adiazol -5 -yl)ureaNo y~- l-(4-(4-amino-7- / / N-NCHNA / / \ cyclopropyl-77 / - F\ / N-A\ — k H N pyrrolo[2,3- rs22 NH2\===^ d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3 - 11 J. / (tert-butyl)-l,2,4-Nthi adiazol -5 -yl)ureaAttorney Docket No. 63243-710.601No. Structure Name0 l-(4-(4-amino-7- / / N-NHN"\ J! \\ / cyclopropyl-77 / - V-A H 0 V"- pyrrolo[2,3- O23 NH2d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(5 - 1! JL / (tert-butyl)- 1,3,4-Noxadiazol-2-yl)urea l-(4-(4-amino-7- 9CF3 (pyri din-3 -yl)-7Z7-cHN^kF / u\ I N^ x / NV^k H o pyrrolo[2,3- r sNH2\=^ d]pyrimidin-5-yl)-2- 24fluorophenyl)-3 -(3 -( 1 - H 1 >(trifluoromethyl)cyclop ropyl)isoxazol-5- b yl)ureal-(4-(4-amino-7- 9 r~ / CF3(pyridin-4-yl)-7Z7- HN^\ jn.F\ / N"\V^k H O pyrrolo[2,3- NH2k 7 d]pyrimidin-5-yl)-2- 25fluorophenyl)-3 -(3 -( 1 - H 1 >(trifluoromethyl)cyclop ropyl)isoxazol-5- 6 yl)ureaAttorney Docket No. 63243-710.601No. Structure Nameo / ~CF31 -(4-(4-amino-7-( 1 -,, HNA A N methylpiperidin-4-yl)- H 0 77 / -pyrrolo[2,3- NH2\ F=AAd]pyrimidin-5-yl)-2- 26H fluorophenyl)-3 -(3 -( 1 - A^ 1 N >(trifluoromethyl)cyclop ropyl)isoxazol-5- 0\ yl)urear- °l-(4-(4-amino-7-0 / HN-A cyclopropyl-77 / - J k,F\ / N^_ / NVA H 0 pyrrolo[2,3- FA27 NH2\=A d]pyrimidin-5-yl)-2- N^A-A fluorophenyl)-3 -(3 -(3 - |l JL / methyloxetan-3- yl)isoxazol-5-yl)ureaNb*o Z^F3 l-(4-(4-amino-7- HNF J / AFcyclopropyl-77 / - \ VA JNH^n o-NF 7 pyrrolo[2,3- 28 NH2\=A d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3- 5 A / (trifluoromethyl)isoxaz [> ol-5-yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7- \ / zOHo > — / cyclopropyl-77 / - \? A Vl pyrrolo[2,3- YShd]pyrimidin-5-yl)-2- 29 NH2\=Vfluorophenyl)-3 -(3 -( 1 - 1! JL / hydroxy-2- methylpropan-2- yl)isoxazol-5-yl)urea l-(4-(4-amino-7- °, / - cyclopropyl-77 / - F. 7 A -VV ri H 0 pyrrolo[2,3- A30 NH2\=V d]pyrimidin-5-yl)-2- N' / VrV\ fluorophenyl)-3 -(3 - H 1 >(sec-butyl)isoxazol-5- yl)ureal-(4-(4-amino-7- o ) — / cyclopropyl-77 / -CHN-AF\ / N-\Vi H 0 pyrrolo[2,3- 31 oNH2\=A d]pyrimidin-5-yl)-2- N^y-'-V fluorophenyl)-3 -(3 - 11 JL / (pentan-3 -y 1 )i soxazol- 5-yl)ureaNVAttorney Docket No. 63243-710.601No. Structure NameO l-(4-(4-amino-7- HN^\ / / cyclopropyl-77 / -F\ V4 JNH^n o-Npyrrolo[2,3- F 732 NH2\=^ d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3 - H 1 >i sopropyli soxazol -5 -Nyl)urea° / - - l-(4-(4-amino-7- HN-'-'N / / '1,F\ JNH^n 0-Ncyclopropyl-77 / - O pyrrolo[2,3- 33 NH2\===^d]pyrimidin-5-yl)-2- [J JL / fluorophenyl)-3 -(3- ethyli soxazol -5 -yl)ureaNFl-(4-(4-amino-7-0 / HN^\ J / \.. cyclopropyl-77 / -F\ JNH^n 0"Npyrrolo[2,3- 34 F 7NH2\==7 d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3 -( 1 - H J / methylcyclobutyl)isoxaNzol-5-yl)ureal-(4-(4-amino-7- ft / — <CN_ HN— N j / 1 cyclopropyl-77 / - F\ / N—\yFhpyrrolo[2,3- 35 NH2\===^ d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3 -(2- 1! JL / cyanopropan-2-Nyl)isoxazol-5-yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7- O / ^OHcyclopropyl-77 / - YAhpyrrolo[2,3- 36 NH2\=^ d]pyrimidin-5-yl)-2- 11 A / fluorophenyl)-3 -(3- (hydroxymethyl)isoxaz bol-5-yl)urea l-(5-(4-amino-7- cyclopropyl-77 / - 0 / ~CF3H / N^\N^ b pyrrolo[2,3- b<k / 4NlNH 0d]pyrimidin-5- / 737 NH2\b yl)pyridin-2-yl)-3 -(3 - N'b-bx (1- H 1 >(trifluoromethyl)cyclopNropyl)isoxazol-5- yl)urea l-(4-(4-amino-7- o b cyclopropyl-77 / - HN-A / A pyrrolo[2,3- \ H 0d]pyrimidin-5-yl)-2- 38 NH2\bmethylphenyl)-3 -(3 -( 1 - U b / (trifluoromethyl)cyclop ropyl)isoxazol-5- yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7-(3-CHN^ / n hydroxycyclobutyl)- F\ / N" \H077 / -pyrrolo[2,3- F 7NH2d]pyrimidin-5-yl)-2- 39fluorophenyl)-3 -(3 -( 1 - 8 / I / (trifluoromethyl)cyclopNropyl)isoxazol-5- OH yl)ureal-(6-(4-amino-7- cyclopropyl-77 / - 0 / CF3HN-A / A pyrrolo[2,3- \ H 0 d]pyrimidin-5-yl)-4- 40 F 7NH2methylpyri din-3 -y 1 ) -3 - N'^T VX (3-(l- H A / (trifluoromethyl)cyclop ropyl)isoxazol-5- yl)urea l-(4-(4-amino-7- cyclopropyl-77 / - 1? / -VHN^kCF / N^ j\ l3,_N pyrrolo[2,3-F / H °d]pyrimidin-5-yl)-2,6- 41 Fv difluorophenyl)-3 -(3 - NH2\=^(1- H 1 >(trifluoromethyl)cyclop ropyl)isoxazol-5- byl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7- cyclopropyl-77 / - o / ~CF3\ / =CHN-A / A pyrrolo[2,3-? -n - V— A H o J]pyrimidin-5-yl)-2,5- 42 rNH27 difluorophenyl)-3 -(3 - 1 / N A A v JkA- F- (1- H 1 > ^07IZ(trifluoromethyl)cyclopN ZO 1J \ A - ropyl)isoxazol-5- f\'Z''y'xyl)urea O GJl-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3- J]pyrimidin-5-yl)-3,5- 43 difluorophenyl)-3 -(3 - (1- (trifluoromethyl)cyclop ropyl)isoxazol-5- yl)urea l-(5-(4-amino-7- cyclopropyl-77 / -PHN-A JM. pyrrolo[2,3- F\ / N-NXN\===\ H 0 d]pyrimidin-5-yl)-3- / N44 NH2fluoropyridin-2-yl)-3- (3-(l- u JL / (trifluoromethyl)cyclopNropyl)isoxazol-5- yl)ureaAttorney Docket No. 63243-710.601No. Structure NameCF3JIJ l-(4-(4-amino-7-0 / cyclopropyl-77 / -F\ / H0pyrrolo[2,3- 45 NH2F / d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3 -( 1 - H J / (trifluoromethyl)cyclob utyl)isoxazol-5-yl)ureaNl-(5-(4-amino-7-(2- hydroxy-2- methylpropyl)-7Z7-?CF3 / N"\H 0 pyrrolo[2,3- d]pyrimidin-5- 46 NH2yl)pyridin-2-yl)-3 -(3 - u / L / (1- (trifluoromethyl)cyclop T^-OHropyl)isoxazol-5- yl)urea 1 -(4-(4-amino-7-(2- hydroxy-2- / ?PHNX methylpropyl)-7Z7- A \H° pyrrolo[2,3- 47 NH2d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(3 -( 1 - H 1 >(trifluoromethyl)cyclop ^V-OH ropyl)isoxazol-5- yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(5-(4-amino-7- cyclopropyl-77 / - / rJHN^k J iCF3pyrrolo[2,3- / N^X / NN^\ H 0 d]pyrimidin-5- / N48 NH2yl)pyrimidin-2-yl)-3 -(3 - (1- 8 J / (trifluoromethyl)cyclopNropyl)isoxazol-5- yl)urea l-(4-(4-amino-7- cyclopropyl-77 / - 0 / ^CF3pH J! n-V / HN^A / / \\ pyrrolo[2,3- \ / N"\A \H° d]pyrimidin-5-yl)-2- 49 NH2J— (hydroxymethyl)phenyl )-3-(3-(l- 5 X / (trifluoromethyl)cyclopNropyl)isoxazol-5- yl)urea l-(4-(4-amino-7- cyclopropyl-77 / - / ? z-vCF3.._ HN^J / »NC / N"\ pyrrolo[2,3- \H°d]pyrimidin-5-yl)-2- 50 NH2cy anophenyl)-3 -(3 -( 1 - 5 X / (trifluoromethyl)cyclop ropyl)isoxazol-5-Nyl)ureaAttorney Docket No. 63243-710.601No. Structure Name1 -(4-(4-amino-7-(2- methoxyethyl)-77 / - _ HNY / / AI ^R / HN — <zIICF3pyrrolo[2,3- YA °^nNH2\===^ d]pyrimidin-5-yl)-2- 51fluorophenyl)-3 -(3 -( 1 - H 1 >(trifluoromethyl)cyclop ropyl)isoxazol-5- Oyl)urea 1 -(4-(4-amino-7-(2- ° V7 hydroxyethyl)-77 / - _ R H / N-Y HN — < ZzTA ITI ^CF3pyrrolo[2,3- °^NNH2\=^ d]pyrimidin-5-yl)-2- 52fluorophenyl)-3 -(3 -( 1 - 1! JL / (trifluoromethyl)cyclop ropyl)isoxazol-5- OHyl)urea l-(4-(4-amino-7- ° S7 cyclobutyl-77 / -FCF* pyrrolo[2,3- y$ °'NH2\=^Nd]pyrimidin-5-yl)-2- 53fluorophenyl)-3 -(3 -( 1 - 1! JL / (trifluoromethyl)cyclopN^7 ropyl)isoxazol-5- yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7- o V7 cyclopropyl-77 / - HN-"^Cl. / HN — ( Zz^I ITI ^CF3pyrrolo[2,3- °"Nd]pyrimidin-5-yl)-2- 54 NH2chlorophenyl)-3 -(3 -( 1 - N 1!' Y JLA / (trifluoromethyl)cyclopNropyl)isoxazol-5- yl)urea l-(4-(4-amino-7- cyclopropyl-77 / - ° Vpyrrolo[2,3- 0 / H / N-"^ HN — ( / z^7 ITI 'CF3°"Nd]pyrimidin-5-yl)-2- 55 NH2\=^ methoxyphenyl)-3 -(3 - N 1!' Y JLA / (1- (trifluoromethyl)cyclopNropyl)isoxazol-5- yl)urea 1 -(4-(4-amino-7-( 1 - ° S7_ HN"^ / Yl ^ methylpyrrolidin-3-yl)- R / HN — (zIICF377 / -pyrrolo[2,3- °^NNH2d]pyrimidin-5-yl)-2- 56fluorophenyl)-3 -(3 -( 1 - 1! JL / (trifluoromethyl)cyclop ropyl)isoxazol-5- V-Nyl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7- 9 " ZCF3cyclopropyl-77 / - _ HN^XV=\ H N pyrrolo[2,3- 57 NH2d]pyrimidin-5-yl)-2- fluorophenyl)-3 -(5 -( 1 - II A / (trifluoromethyl)cyclobNutyl)i soxazol-3 -yl)urea l-(4-(4-amino-7- 9 _ / ^CF3cyclobutyl-77 / - _ HN'A / \pyrrolo[2,3- V=AH Nd]pyrimidin-5-yl)-2- 58 NH2fluorophenyl)-3 -(5 -( 1 - 8 / I / (trifluoromethyl)cyclop ropyl)isoxazol-3-Nyl)urea l-(6-(4-amino-7- cyclopropyl-77 / - 0 __Z^CF3HN-'N J / pyrrolo[2,3-. — J XNH W 0 d]pyrimidin-5- 59 nNH2\=N yl)pyri din-3 -y l)-3 -(3 - (1- I! JL / (trifluoromethyl)cyclopNropyl)isoxazol-5- yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7- cyclopropyl-77 / -cHN-A jC n pyrrolo[2,3-F\ \— \ / N H' N NI-'0d]pyrimidin-5-yl)-2,6- 60 rvNH2Fdifluorophenyl)-3 -(5- N J > (1- (trifluoromethyl)cyclopN”K ropyl)isoxazol-3- yl)urea 1 -(4-(4-amino-7-(2- O CFghydroxyethyl)-77 / - C \ H IN'A N'^ jf.|xnO\ < H N pyrrolo[2,3- d]pyrimidin-5-yl)-2- 61 NH2O \==7fluorophenyl)-3 -(5 -( 1 - NXX.I! JL / (trifluoromethyl)cyclop ropyl)isoxazol-3- OH yl)ureal-(4-(4-amino-l-0 / -CF3cyclopropyl-1H- \ pyrrolo[3,2-c]pyridin- N — 7 X X H-Q0 1n 3 -yl)-2-fluorophenyl)- 62 NH23-(3-(l- 1 JL / (trifluoromethyl)cyclop ropyl)isoxazol-5- yl)ureaAttorney Docket No. 63243-710.601No. Structure Name1 -(4-(4-amino-7-( 1 - o / / r - ( CF3cHN^ \ / I methylazeti din-3 -yl)-F\ / N^X / NH 0 77 / -pyrrolo[2,3- F 7NH2\=^ d]pyrimidin-5-yl)-2- 63fluorophenyl)-3 -(3 -( 1 - 8 b / (trifluoromethyl)cyclop ropyl)isoxazol-5- \ yl)ureal-(4-(4-amino-7- cyclopropyl-77 / - 0 / CF3pyrrolo[2,3- J HN'b bFuF-\ / V^X H O d]pyrimidin-5-yl)-2- 64 F 7NH2(difluoromethyl)phenyl )-3-(3-(l- H b / (trifluoromethyl)cyclopNropyl)isoxazol-5- yl)urea l-(4-(4-amino-7- 0 / b / N\ cyclopropyl-77 / -CHN^\ jr~\\ pyrrolo[2,3- V4Hd]pyrimidin-5-yl)-2- 65 NH2fluorophenyl)-3 -(3 -( 1 - 5 1 / ((dimethyl amino)methy 1 )cy cl opropyl)i soxazol - b5-yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7- cyclopropyl-77 / - HN^\ J / ~~^ 'V' / Fpyrrolo[2,3- y-A H 0F 7 J]pyrimidin-5-yl)-2- 66 NH2fluorophenyl)-3 -(3 - II A / ((3,3 -difluoroazeti din- b l-yl)methyl)isoxazol-5- yl)urea

[0132] Embodiments described herein provide a compound having Formula (II):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:X is N or CH;A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;R1is H, halo, Ci-Ce alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R3is aminylalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N-heterocyclyloxy, or 5-6 membered heteroaryl; orR3 joins with an occurrence of R4 attached to a carbon adjacent to a carbon to which R3 is attached to form a C3-C8 cycloalkyl;R4is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 halocycloalkyl, or C3-C8 cycloalkyl; andAttorney Docket No. 63243-710.601n is 0, 1, 2, 3, or 4.

[0133] In some embodiments, A is Ce-Cio arylene. In certain embodiments, A is phenylene. In some specific embodiments, A is 5-6 membered heteroarylene. In certain specific embodiments, A is pyridinylene. In some more specific embodiments, A is C3-C10 cycloalkylene or 3-10 membered heterocyclylene.

[0134] In certain embodiments, A is substituted with one or more substituents selected from halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl. In some embodiments, A is substituted with one or more halo substituents. In some specific embodiments, A is unsubstituted.

[0135] In some embodiments, R1is H. In certain embodiments, R1is Ci-Ce alkyl. In some specific embodiments, R1is methyl. In certain embodiments, R1is C3-C10 cycloalkyl, or 3-10 membered heterocyclyl. In some embodiments, R1is halo (e.g., fluoro, chloro, bromo, etc.).

[0136] In certain embodiments, R2is H. In some more specific embodiments, R2is halo. In more specific embodiments, R2is chloro or fluoro. In some other embodiments, R2is C3-C10 cycloalkyl (e.g., cyclopropyl). In some embodiments, R2is Ci-Ce alkyl, Ci-Ce haloalkyl, or 3-10 membered heterocyclyl. In some embodiments, R2is Ci-Ce alkyl (e.g., methyl).

[0137] In some embodiments, X is CH or CR3. In some specific embodiments, the compound has the following structure (Ila):(Ila)or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0138] In some embodiments, the compound has the following structure (IIb):(IIb)Attorney Docket No. 63243-710.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0139] In certain embodiments, X is N. In certain more specific embodiments, the compound has the following structure (IIc):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0140] In some embodiments, the compound has the following structure (IId):(IId)or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, whereinR3ais, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, aminylalkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N-heterocyclyloxy, or 5-6 membered heteroaryl; andm is 0, 1, 2, 3, or 4.

[0141] In some embodiments, R3ais, at each occurrence, independently halo or 3-10 membered heterocyclyl. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0. In certain embodiments, m is 1. In some embodiments, m is 1. In some embodiments, m is 2. In certain embodiments, m is 3.

[0142] In some embodiments, the compound has the following structure (IId1):Attorney Docket No. 63243-710.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0143] In some embodiments, R3is substituted. In some embodiments, R3is unsubstituted. In some embodiments, R3is substituted with alkyl (e.g., Ci-Ce alkyl), heterocyclyl, halo, haloalkyl (e.g., Ci-Ce haloalkyl), alkylcarbonyl (e.g., -C(=O)CH3), hydroxyalkyl, alkoxyalkyl, cycloalkyl (e.g., C3-C8 cycloalkyl), alkylamino, or combinations thereof.

[0144] In some of the above embodiments, R3is aminylalkyl. In certain embodiments, R3has the following structure:

[0145] In some embodiments, R3is a 3-10 membered heterocyclyl. In some embodiments, R3is morpholino. In certain embodiments, R3is piperazinyl. In some specific embodiments, R3has one of the following structures:

[0146] In certain embodiments, R3is a 3-10 membered heterocyclylalkyl. In certain more specific embodiments, R3has one of the following structures:Attorney Docket No. 63243-710.601

[0147] In some embodiments, R3has one of the following structures:

[0148] In some embodiments, R3is 3-10 membered heterocyclylcarbonyl. In a more specific embodiment, R3has the following structure:

[0149] In some embodiments, R3is a 5-6 membered heteroaryl. For example, in some embodiments, R3has the following structure:

[0150] In some embodiments, R3is a 3-10 membered heterocyclylalkenyl. In more specific embodiments, R3has the following structure:Attorney Docket No. 63243-710.601

[0151] In some embodiments, R3is a 3-10 membered N-heterocyclyloxy. In more specific embodiments, R3has one of the following structures:In some embodiments, R3has one of the following structures:

[0152] 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, R4is, at each occurrence, independently chloro, fluoro, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C8halocycloalkyl, or C3-C8cycloalkyl. In certain embodiments, R4is, at each occurrence, independently methyl, chloro, fluoro, cyano, trifluoromethyl, methoxy, trifluoromethoxy, 2,2-difluorocyclopropyl, or cyclopropyl. In certain embodiments, R4is, at each occurrence, independently methyl, chloro, fluoro, cyano, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, 2,2-difluorocyclopropyl, or cyclopropyl.

[0153] 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.

[0154] 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.Attorney Docket No. 63243-710.601In some embodiments, the compound of Formula (II) is administered to treat or prevent the symptom of biological aging. In some embodiments, the compound of Formula (II) is administered to delay and / or slow the development of the symptom of biological aging.

[0155] 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 the NLRP3 inflammasome. In some embodiments, the compound of Formula (II) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (II) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (II) inhibits the priming step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (II) inhibits signaling downstream of members of the TLR (toll-like receptor) family, IL-1R (interleukin 1 receptor) family, and / or TNFR1 / 2 (tumor necrosis factor receptor 1 / 2). In some embodiments, the compound of Formula (II) prevents the activation of NF-kB (nuclear factor kappa-beta). In some embodiments, the compound of Formula (II) reduces the level of TNF-a, IL-6, or the components of the NLRP3 inflammasome (e.g., NLRP3, pro-IL-1β (pro-interleukin-1beta), pro-IL18 (pro-interleukin- 18)), or a combination thereof, in the subject. In some embodiments, the compound of Formula (II) inhibits the assembly and activation step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (II) inhibits the formation of a NLRP3 (protein)-NEK7 (protein) interaction. In some embodiments, the compound of Formula (II) inhibits the formation of the ASC speck and the NLRP3 inflammasome. In some embodiments, the compound of Formula (II) prevents caspase- 1 activation. In some embodiments, the compound of Formula (II) inhibits the production of IL-1β. In some embodiments, the compound of Formula (II) inhibits the production of IL-18. In some embodiments, the compound of Formula (II) inhibits the cleavage of gasdermin D. In some embodiments, the compound of Formula (II) prevents pyroptotic cell death.

[0156] In various different embodiments, the compound has one of the structures set forth in Table IB below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0157] Compounds in Table IB were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Attorney Docket No. 63243-710.601Table IB: Representative Compounds of Formula (II)Compound Structure NameH H1 -(4-((3 -chloro- 1 H- CY Y YY pyrrolo[2,3-^]pyridin-4- A< Yx o \Ayl)oxy)-2-fluorophenyl)-3 -(4- II- 1 Cl((4-methylpiperazin- 1 - yl)methyl)-3- •P 0Sr (trifluoromethyl)phenyl)ureaHI H HvNppF 1 -(4-((3 -chloro- 1 H- pyrrolo[2,3-^]pyridin-4- A i A Y A o i LA Yci yl)oxy)-2-fluorophenyl)-3 -(3 - II-2fluoro-4- (morpholinomethyl)phenyl)ur P 0 eanr^NH H 1 \ _ 1 -(4-((3 -chloro- 1 H- | Y n YY pyrrolo[2,3-^]pyridin-4- A o il A yl)oxy)-2-fluorophenyl)-3 -(3 - II-3 Cl (4-m ethyl- UY-imidazol- 1 -yl)- YYxCF3 5- N^S< (trifluoromethyl)phenyl)urea HHH H N N ^^ / CF3if 7 Y YY 1 -(4-((3 -chloro- 1 H- pyrrolo[2,3-^]pyridin-4- c AA oII-4 i T ^F A A\yl)oxy)-2-fluorophenyl)-3 -(4- (morpholinomethyl)-3- Y 5 o (trifluoromethyl)phenyl)urea SrnH H[ Y Y Y Y 1 -(4-((3 -chloro- 1 H- AA o L A pyrrolo[2,3-^]pyridin-4- ci O^^FII-5 yl)oxy)-2-fluorophenyl)-3 -(3 - fluoro-4-((4-methylpiperazin- P Y 1 -yl)methyl)phenyl)urea N^A SrHiAttorney Docket No. 63243-710.601Compound Structure NameH H1 -(4-((3 -chloro- \H- ii 7 T pyrrolo[2,3-7>]pyridin-4- II-6 yl)oxy)-2-fluorophenyl)-3 -(3 - ClCF3(4-methylpiperazin- 1 -yl)-5 - CL 1 (trifluoromethyl)phenyl)urea HINH H \ / O CN _ N ^_\\C O Z z. LL? / oz.—- — / F31 -(4-((3 -cyclopropyl -1H- _ (1 1 n Y Y _ \ / \ pyrrolo[2,3-7>]pyridin-4- <7 o AX / O F — y yl)oxy)-2-fluorophenyl)-3 -(4- II-7((4-methylpiperazin- 1 - Z TZ I yl)methyl)-3- C o Y° N^r (trifluoromethyl)phenyl)urea Y° IZ U. IZ U.Hi1 -(4-((3 -chloro- 1H- A t pyrrolo[2,3-7>]pyridin-4- YII-8 yl)oxy)-2-fluorophenyl)-3 -(4- H °Z((dimethylamino)methyl)-3-ZI(trifluoromethyl)phenyl)urea OH H1 -(4-(azetidin- 1 -ylmethyl)-3 - ry Y ry(trifluoromethyl)phenyl)-3 - W oCl O^^F (4-((3-chloro-l / / -pyrrolo[2,3- II-9k AZ»]pyridin-4-yl)oxy)-2- fluoropheny 1 )urea NAV HINH H / Y / N N^^CF31 -(4-((3 -chloro- 1H- Il 7 A Y Y pyrrolo[2,3-7>]pyridin-4- A A\ o < Ayl)oxy)-2-fluorophenyl)-3 -(4- ci O'^-^FII- 10((3-(dimethylamino)azetidin- l-yl)methyl)-3- V (trifluoromethyl)phenyl)ureaH / N\l-(4-((3-chloro-2-methyl-l / 7- pyrrolo[2,3-7>]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(4- II- 11((4-methylpiperazin- 1 - yl)methyl)-3- (trifluoromethyl)phenyl)ureaAttorney Docket No. 63243-710.601Compound Structure Name1 -(4-((3 -chloro- 1 H- pyrrolo[2,3P]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(4- 11-12((3,3 -difluoroazeti din- 1 - yl)methyl)-3- (trifluoromethyl)phenyl)urea Xx A H / HNk xx / CF CF3” 1 -(4-((3 -chloro- A pArYo YA O 1 H- TA pyrrolo[2,3P]pyridin-4- Cl yl)oxy)-2-fluorophenyl)-3 -(4- 11-13((4-cyclopropylpiperazin- 1 - A IZ 0 yl)methyl)-3- N^V > P(trifluoromethyl)phenyl)urea IZ U.A H H 1 -(4-((3 -chloro- 1 H- z\ z N., N. xx, CF3pyrrolo[2,3P]pyridin-4- A PXTY0 Y LAA yl)oxy)-2-fluorophenyl)-3 -(4- 11-14 ClZI ° (((1R,5S)-3-methyl-3,8- _x Ao A d diazabicyclo[3.2.1 ]octan-8- yl)methyl)-3- K^PkrPH1 (trifluoromethyl)phenyl)urea H HNxxNx¥xCF3 1 -(4-((3 -chloro- 1 H- fT A Y 7AA o L A pyrrolo[2,3P]pyridin-4- Cl 0-^^F yl)oxy)-2-fluorophenyl)-3 -(4- 11-15 AA A (((3aR,6aS)-5- methylhexahydropyrrolo[3,4- UJ H^ Hc]pyrrol -2( 1 J7)-yl)methyl)-3 - (trifluoromethyl)phenyl)urea 1H H1 -(4-((3 -chloro- 1 H- XX,NxxNXPXCF3 |I P ¥ YY pyrrolo[2,3P]pyridin-4- kA o k A / Cl O^^F yl)oxy)-2-fluorophenyl)-3 -(4- 11-16( 1 -(4-methylpiperazin- 1 - yl)ethyl)-3- A d (trifluoromethyl)phenyl)urea NAN^ SPH1Attorney Docket No. 63243-710.601Compound Structure NameH HN^^ / CF31 -(4-((3 -chloro- 1H- A Il 7 A O Y Y AY\ pyrrolo[2,3-Z>]pyridin-4- Cl O'^^'F yl)oxy)-2-fluorophenyl)-3 -(4- 11-17((l-methylpiperidin-4- yl)methyl)-3- N^hT (trifluoromethyl)phenyl)ureaH1H H / ^ / CF31 -(4-((3 -chloro- 1H- A ITATYo Y < AA pyrrolo[2,3-^]pyridin-4- ci yl)oxy)-2-fluorophenyl)-3 -(4- 11-18 ((6-methyl-2,6- Yr, diazaspiro[3.3]heptan-2- YA / z\ yl)methyl)-3-HV (trifluoromethyl)phenyl)urea iH H / Y / N\ / N-YY^CF3 1 -(4-((3 -chloro- 1H- f T fl M pyrrolo[2,3-^]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(4- 11-19 ci 9F(4-m ethylpiperazine- 1- carbonyl)-3- A oA / Sr (trifluoromethyl)phenyl)ureaH1H H / YA N^^ / CF 1 -(4-((3 -chloro- 1H- II Y3Y YY pyrrolo[2,3-^]pyridin-4- A A o A yl)oxy)-2-fluorophenyl)-3 -(4- Cl O F11-20 ^ 4((7-methyl-4,7- diazaspiro[2.5]octan-4- Y N^YA Y yl)methyl)-3-kN^:H1 (trifluoromethyl)phenyl)urea H H. N. ^ / CF31 -(4-((3 -chloro- 1H- pyrrolo[2,3-^]pyridin-4- AYwA A o il A yl)oxy)-2-fluorophenyl)-3 -(4- Cl O^^F11-21 ((5 -methyl -2,5 - AY,XNdiazabicyclo[2.2.2]octan-2- n j H yl)methyl)-3- N N NH1 (trifluoromethyl)phenyl)ureaAttorney Docket No. 63243-710.601Compound Structure NameH H1 -(4-((3 -chloro- 1H- Il 7 Y Y ifkk 0 k>kk pyrrolo[2,3-^]pyridin-4- Cl CT11-22 T l yl)oxy)-2-fluorophenyl)-3 -(3 - fluoro-4-((4-methylpiperazin- 7: Y l-yl)methyl)-5- NY (trifluoromethyl)phenyl)ureaH1H H1 -(4-((3 -chloro- 1H- ^k fks Ykf Y O T k^Y i pyrrolo[2,3-^]pyridin-4- yl)oxy)-2-methylphenyl)-3 - 11-23 ci 9 |(4-((4-methylpiperazin- 1 - YY Y yl)methyl)-3- (trifluoromethyl)phenyl)ureaH1H H N N N ^^, CF3l-(5-((3-chloro-l / 7- |l Y Y YY^kkk o LA pyrrolo[2,3-^]pyridin-4- yl)oxy)pyri din-2 -yl)-3-(4-((4- 11-24 ci 9 |methylpiperazin- 1 - < Y5 yl)methyl)-3- oN'Yr SA (trifluoromethyl)phenyl)ureaH1H H1 -(4-((3 -chloro- 1H- k fkA Yf\ Y 0 1 kA1\ pyrrolo[2,3-^]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(3 - 11-25 Cl ^ Ymethyl -4-((4- Y N^S5 methylpiperazin- 1 - A oyl)methyl)phenyl)ureaHI H H A1 -(4-((3 -chloro- 1H- k fk^Al Y o Y kYA\ pyrrolo[2,3-^]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(3 - 11-26 Cl ^Ycyclopropyl -4-((4- methylpiperazin- 1 - k NSA S YA yl)methyl)phenyl)ureaHiH H1 -(4-((3 -chloro- 1H- f l Y Y Yf pyrrolo[2,3-^]pyridin-4- Cl O A^A^F o kA\ yl)oxy)-2-fluorophenyl)-3 -(3 - 11-27methoxy-4-((4- k methylpiperazin- 1 - N-YT 0yl)methyl)phenyl)ureaHiAttorney Docket No. 63243-710.601Compound Structure Nameo / ■v 1 -(4-((3 -chloro- 1H- IZ izpyrrolo[2,3-^]pyridin-4- o y— yl)oxy)-2-fluorophenyl)-3 -(4- 11-28 ((4-(2- hydroxyethyl)piperazin- 1 - Q o yl)methyl)-3- ZI -n zi -n (trifluoromethyl)phenyl)urea ZI ZI o z d—f1 -(4-((3 -chloro- 1H- pyrrolo[2,3-^]pyridin-4- 0 \ \ )z z }z z / ——,——.IZ yl)oxy)-2-fluorophenyl)-3 -(4- / \ J 21 / II-29 ((4-(2)°= I - IZ U. methoxyethyl)piperazin- 1 - yl)methyl)-3- (trifluoromethyl)phenyl)ureaH H°s _Y - ozt[1 1 n Y Y 1 -(4-((3 -chloro- 1H- >l ^k 0 k <?^k pyrrolo[2,3-^]pyridin-4- 11-30 Cl yl)oxy)-2-fluorophenyl)-3 -(3 - chloro-4-((4-methylpiperazin- kHo l 1 -yl)methyl)phenyl)urea1 -(4-((3 -chloro- 1H- pyrrolo[2,3-^]pyridin-4- 11-31 yl)oxy)-2-fluorophenyl)-3 -(4- (4-methylpiperazin- 1 -y 1 ) -3 - (trifluoromethyl)phenyl)urea H H, CF31 -(4-((3 -chloro- 1H- pyrrolo[2,3-b]pyridin-4- 11-32 Cl ck r^rTYrr yl)oxy)-2-fluorophenyl)-3 -(4- (4-m ethyl- 1 / 7-imidazol- 1 -yl)- td 3- N^kr (trifluoromethyl)phenyl)ureaH|NAttorney Docket No. 63243-710.601Compound Structure NameH HN^^CF31 -(4-((3 -chloro- 1H- I Y fl ¥ ikk Y\ 0 k Yx pyrrolo[2,3-^]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(4- 11-33 Cl((4-methyl- 1,4-diazepan- 1 - yl)methyl)-3- o (trifluoromethyl)phenyl)ureaN\H H^x / N. ^x / CF31 -(4-((3 -chloro- 1H- rrYIY pyrrolo[2,3-^]pyridin-4- YYx o kYCl O^^F yl)oxy)-2-fluorophenyl)-3 -(4- 11-34 ((3- (dimethylamino)pyrrolidin-l- k NY / ) Q \ yl)methyl)-3- HNN— / (trifluoromethyl)phenyl)urea H H^YX / N\ / N\^YXYNH n Y 7 1 -(4-((3 -chloro- 1H- AY 0 \Y pyrrolo[2,3-^]pyridin-4- Cl O^^F11-35 yl)oxy)-2-fluorophenyl)-3 -(3 - cyano-4-((4-methylpiperazin- k i 0 1 -yl)methyl)phenyl)urea Y / \rHiH HNY ^^ / CF3 1 -(2-fluoro-4-((3 -methyl- 1H- n A YY pyrrolo[2,3-^]pyridin-4- YYx o kY(YY yl)oxy)phenyl)-3 -(4-((4- 11-36methylpiperazin- 1 - yl)methyl)-3- k i c YYk Sr (trifluoromethyl)phenyl)ureaHiH H / ^x,NX / NX / YX / CF3 1 -(4-((3 -chloro- 1H- Il 1 fl I IYY o kY pyrrolo[2,3-^]pyridin-4- Cl Y^^Y ^Y yl)oxy)-2-fluorophenyl)-3 -(4- 11-37((4-ethylpiperazin- 1 - Y 5 d yl)methyl)-3- n (trifluoromethyl)phenyl)ureaAttorney Docket No. 63243-710.601Compound Structure NameH H1 -(4-((3 -chloro- 1H- A IC AT¥o T k T pyrrolo[2,3-^]pyridin-4- ci "-^ 7 yl)oxy)-2-fluorophenyl)-3 -(4- 11-38((4-i sopropylpiperazin- 1 - cn c": yl)methyl)-3- N^Y SYn (trifluoromethyl)phenyl)urea H H1 -(4-((3 -chloro- 1H- (l 7 Y IT pyrrolo[2,3-^]pyridin-4- XkxA o kAyl)oxy)-2-fluorophenyl)-3 -(4- 11-39((l-methylpiperidin-4- yl)oxy)-3- NAT (trifluoromethyl)phenyl)ureaH1H H1 -(4-((3 -chloro- 1H- (I 7 Y J 7 pyrrolo[2,3-^]pyridin-4- XkxA o k^ACl 0 F 1 yl)oxy)-2-fluorophenyl)-3 -(4- 11-40((l-methylpiperidin-4- n j C J ylidene)methyl)-3- N N N (trifluoromethyl)phenyl)ureaH1H H1 -(4-((3 -chloro- 1H- [1 7 Y YY pyrrolo[2,3-^]pyridin-4- kk-i^k o kA\yl)oxy)-2-fluorophenyl)-3 -(3 - 11-41(difluoromethyl)-4-((4- methylpiperazin- 1 - k i oYY ^Y yl)methyl)phenyl)ureaH1H H. N.. N., CHF21 -(4-((3 -chloro- 1H- |l 7 Y ) TkkY\ o k pyrrolo[2,3-^]pyridin-4- Cl ^ 7 yl)oxy)-2-fluorophenyl)-3 -(3 - 11-42(difluoromethyl)-4-((4- b5 0 ethylpiperazin-1- N^Y ^Yn yl)methyl)phenyl)urea H H1 -(4-((2, 3 -dichloro- 1H- |l 7 Y 7 7 pyrrolo[2,3-^]pyridin-4- kk Y\ o kY\Cl O^^F yl)oxy)-2-fluorophenyl)-3 -(4- 11-43((4-methylpiperazin- 1 -ciyl)methyl)-3- Y NX'Y J O(trifluoromethyl)phenyl)ureaH1Attorney Docket No. 63243-710.601Compound Structure NameH HZ^ / N^ZN^^^CF3 1 -(4-((2, 3 -dichloro- \H- Q Q ZK ZK IZ iz n n M pyrrolo[2,3-^]pyridin-4- ci 9 | yl)oxy)-2-methylphenyl)-3 - 11-44K \~ A o o ■z (4-((4-methylpiperazin- 1 - A——C|yl)methyl)-3- A\X J OM ir (trifluoromethyl)phenyl)ureaH15 hzi zi m -nH H? / O C 1 - O 1 -(4-((3 -chloro- 1H- ZI ZIn n in pyrrolo[2,3-^]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(2- 11-45 ci 5 z / / methoxy-4-((4- IZ methylpiperazin- 1 - f o 65 0-Z -Z ——..K° AA °°z\ - / v yl)methyl)phenyl)HIZ LLv\ f co w - urea i1 -(4-((3 -chloro- 1H- pyrrolo[2,3-^]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(6- / 1 °11-46 ((4-methylpiperazin- 1 - \ _UZIyl)methyl)-5- O(tri fluoromethyl)pyri din-3 - yl)urea1 -(4-((3 -chloro- 1H- pyrrolo[2,3-^]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(4- 11-47((4,4-difluoropiperidin-l- yl)methyl)-3- (trifluoromethyl)phenyl)urea1 -(4-((3 -chloro- 1H- pyrrolo[2,3-^]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(4- 11-48((l-(oxetan-3-yl)piperidin-4- yl)oxy)-3- (trifluoromethyl)phenyl)ureaAttorney Docket No. 63243-710.601Compound Structure NameH H QA^ / x 1 -(4-((4-acetylpiperazin- 1 - ^ ' IZxZ- Irf l n YYyl)methyl)-3- Cl (trifluoromethyl)phenyl)-3 - 11-49 k C^- A o Z—° / N(4-((3-chloro-l#-pyrrolo[2,3- < x j r j Z»]pyridin-4-yl)oxy)-2- N N Nn I fluoropheny 1 )urea X Qzi -n ZI T1Y ° / NZ < O< O O Z^— LL? \I ZI1 -(4-((3 -chloro- \H- pyrrolo[2,3-^]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(4- 11-50 0IZ ^ Vo o z • Z) — ((4-(2-fluoroethyl)piperazin- \ / wY0' n w - — — l-yl)methyl)-3- iz u.(trifluoromethyl)phenyl)ureaH °Z1 -(4-((3 -chloro- 1H- _k ZI- pyrrolo[2,3-^]pyridin-4- O yl)oxy)-2-fluorophenyl)-3 -(4- 11-51((3 -fluoro- 1 -(oxetan-3 - yl)piperidin-4-yl)oxy)-3- (trifluoromethyl)phenyl)ureaH H1 -(4-((3 -chloro- 1H- n n 1 1 pyrrolo[2,3-^]pyridin-4-Cicr ^ r0yl)oxy)-2-fluorophenyl)-3 -(4- 11-52VI JL,F((3-fluoropiperidin-4-yl)oxy)- 3- (trifluoromethyl)phenyl)urea fl "Nu1 -(4-((3 -chloro- 1H- pyrrolo[2,3-^]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(4- 11-53((4-(oxetan-3 -yl)piperazin- 1 - yl)methyl)-3- (trifluoromethyl)phenyl)ureaAttorney Docket No. 63243-710.601Compound Structure NameH H CY Y YYA ^k o k^^k 1 -(4-((3 -chloro- 1H- Cl pyrrolo[2,3-&]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(4- 11-54^Y ii rNrF((2-fluoro-4-(oxetan-3 - yl)piperazin- 1 -yl)methyl)-3 - (trifluoromethyl)phenyl)ureaH H £II 1 -(4-((3 -chloro- 1H- i O fi I kT¥\ pyrrolo[2,3-&]pyridin-4- 11-55 Cl yl)oxy)-2-fluorophenyl)-3 -(4- (piperazin- 1 -ylmethyl)-3 - X (trifluoromethyl)phenyl)urea N'6YT 0HH F F H H X 1 -(4-((3 -chloro- 1H- H T ¥ 1 | pyrrolo[2,3-&]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(3 - 11-56 A A o k A\Cl (2,2-difluorocyclopropyl)-4- ((4-methylpiperazin- 1 - Y J 0 yl)methyl)phenyl)ureaHiH H^^ x N N ^x xCF31 -(4-((3 -chloro- 1H- pyrrolo[2,3-&]pyridin-4- A li i ¥ 0 I kTxACl O^^F yl)oxy)-2-fluorophenyl)-3 -(4- 11-57 ((4- (dimethylamino)piperidin-l- yl)methyl)-3- ¥ Q (trifluoromethyl)phenyl)urea / N\H H^^N.. N. / x YF31 -(4-((3 -chloro- 1H- pyrrolo[2,3-&]pyridin-4- k [kfxY^k¥0 T k Y -APl 0 F N O yl)oxy)-2-fluorophenyl)-3 -(6- 11-58 ((l-methylpiperidin-4- V X Xyl)oxy)-5- NHA< (tri fluoromethyl)pyri din-3 -1 yl)ureaAttorney Docket No. 63243-710.601Compound Structure NameH H1 -(4-((l -acetylpiperidin-4-CA^^ zzI [PTY 0TY yl)oxy)-3- (trifluoromethyl)phenyl)-3 - 11-59 ^y o z—(4-((3-chloro-IT / -pyrrolo[2,3- Z»]pyridin-4-yl)oxy)-2- n | fluoropheny 1 )urea Qzi -nH H 1 -(4-((3 -chloro- \H- ZI pyrrolo[2,3-^]pyridin-4- A nA O fl Y k xA iyl)oxy)-2-fluorophenyl)-3 -(4- 11-60 Cl ((4-methyl-4,7- Vo o z — diazaspiro[2.5]octan-7- p c"x \ f W - yl)methyl)-3-HI (trifluoromethyl)phenyl)urea H H1 -(2-fluoro-4-((3 -methyl- 1H- Y f Al o A | kl A 1 pyrrolo[2,3-^]pyridin-4- 0 F N O yl)oxy)phenyl)-3 -(6-(( 1 - 11-61methylpiperidin-4-yl)oxy)-5- (tri fluoromethyl)pyri din-3 - 0 yl)ureaH1H H 1 -(4-((3 -chloro- 1H- Z^ / N\ZN^^ / OCF3pyrrolo[2,3-^]pyridin-4- A (i Ai O fl T \A i yl)oxy)-2-fluorophenyl)-3 -(4- Cl O^^F11-62 ((4-methylpiperazin- 1 - yl)methyl)-3- P i 0 (tri fluoromethoxy )phenyl)ureHI a1 -(2-fluoro-4-((3 -methyl- 1H- pyrrolo[2,3-^]pyridin-4- 11-63 yl)oxy)phenyl)-3 -(4-(( 1 - methylpiperidin-4-yl)oxy)-3- (trifluoromethyl)phenyl)ureaAttorney Docket No. 63243-710.601Compound Structure NameH H1 -(4-((3 -chloro- 1H- n n T Y pyrrolo[2,3-Z>]pyridin-4- Pl 0 F — O yl)oxy)-2-fluorophenyl)-3 -(4- 11-64((l-ethylpiperidin-4-yl)oxy)- 3- N n'AT (trifluoromethyl)phenyl)urea Z / co —1 -(4-((3 -chloro- 1H- ^0 pyrrolo[2,3-Z>]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(3 - 11-65((4-methylpiperazin- 1 - Z I yl)methyl)-5- )o=(trifluoromethyl)phenyl)urea IZ LL H H1 -(4-((3 -chloro- 1H- n n Y y pyrrolo[2,3-Z>]pyridin-4- yl)oxy)-2-fluorophenyl)-3 -(4- 11-66A X A,F((3 -fluoro- 1 -methylpiperidin- °zi4-yl)oxy)-3- u NAV (trifluoromethyl)phenyl)ureaH1H H f F1 -(4-((3 -chloro- 1H- X 1X Y1k Y o Y XJ 1A) pyrrolo[2,3-Z>]pyridin-4- yl)oxy)-2-fluorophenyl)-3 - 11-67 ri AF(3, 3 -difluoro- 1 -(4- t Ao O methylpiperazin- 1 -yl)-2,3 - dihydro-1H-inden-5-yl)urea

[0158] Embodiments described herein provide a compound having Formula (III):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:Attorney Docket No. 63243-710.601A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;Xis N or CR4;Y is N or CH;R1is Ci-Ce alkyl, Ci-Ce hydroxylalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl; orR2joins with an occurrence of R3attached to a carbon adjacent to a carbon to which R2is attached to form a C3-C8 cycloalkyl;R3is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl;R4is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4.

[0159] In some embodiments, A is Ce-Cio arylene. In some specific embodiments, A is phenylene. In certain embodiments, A is 5-6 membered heteroarylene. In certain specific embodiments, A is pyridinylene. In some embodiments, A is C3-C10 cycloalkylene or 3-10 membered heterocyclylene. In more specific embodiments, A is substituted with one or more substituents selected from halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl. In certain more specific embodiments, A is substituted with one or more halo substituents. In other embodiments, A is unsubstituted.

[0160] In certain embodiments, X is CR4. In more specific embodiments, R4is H or Ci-Ce alkyl. In some embodiments, R4is H. In certain specific embodiments, X is N.

[0161] In some embodiments, R1is Ci-Ce alkyl. In some more specific embodiments, R1is methyl or iso-propyl. In certain embodiments, R1is Ci-Ce hydroxylalkyl. In certain more specific embodiments, R1has one of the following structures:OHor

[0162] In some embodiments, R1has one of the following structures:Attorney Docket No. 63243-710.601OH

[0163] In certain embodiments, R1is Ci-Ce carboxyalkyl. In more specific embodiments, R1has one of the following structures:OH or O

[0164] In some embodiments, R1is Ci-Ce alkoxyalkyl. In some embodiments, R1has the following structure:

[0165] In some embodiments, R1is C3-C10 cycloalkyl. In more specific embodiments, R1is cyclopropyl or cyclobutyl. In certain embodiments, R1is 3-10 membered heterocyclyl. In certain embodiments, R1is oxetanyl, pyrrolidinyl, or piperidinyl. In certain embodiments, R1is oxetanyl, pyrrolidinyl, azetidinyl, or piperidinyl.

[0166] In some embodiments, R1is Ci-Ce alkynyl. In certain embodiments, R1has one of the following structures:

[0167] In some embodiments, R1is substituted with one or more substituents selected from halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-Cs cycloalkyl. In some embodiments, R1is substituted with one or more substituents selected from halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -S(O)2CH3, -S(O)2cyclopropyl, or C3-Cs cycloalkyl. In more specific embodiments, R1is substituted with one or more Ci-Ce alkyl substituents. In other embodiments, R1is unsubstituted.

[0168] In certain specific embodiments, R1has one of the following structures:0H; -CH3;Attorney Docket No. 63243-710.601

[0169] In some embodiments, R1has one of the following structures:

[0170] In some specific embodiments, the compound has the following Structure (Illa):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0171] In some embodiments, Y is N. In other embodiments, Y is CH.

[0172] In certain specific embodiments, the compound has the following Structure (Illb):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0173] In some embodiments, R2is a 3-10 membered heterocyclyl. In some specific embodiments, R2is morpholino. In other specific embodiments, R2is piperazinyl. InAttorney Docket No. 63243-710.601some more specific embodiments, R2has one of the following structures:

[0174] In some embodiments, R2is a 3-10 membered heterocyclylalkyl. In certain more specific embodiments, R2has one of the following structures:

[0175] In some more specific embodiments, R2has one of the following structures:Attorney Docket No. 63243-710.601

[0176] In some embodiments, R2is 3-10 membered heterocyclylcarbonyl. In certain more specific embodiments, R2has the following structure:

[0177] In some embodiments, R2is a 5-6 membered heteroaryl. In some more specific embodiments, R2has the following structure:

[0178] In some embodiments, R2is 3-10 membered heterocyclyloxy. In certain more specific embodiments, R2has the following structure:

[0179] In some embodiments, R2has one of the following structures:Attorney Docket No. 63243-710.601

[0180] In some more specific embodiments, R2has the following structure:

[0181] In some embodiments, n is 0. In some embodiments, n is 1 or 2. In certain embodiments, n is 1. In some embodiments, R3is halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C8 cycloalkyl. In certain specific embodiments, R3is methyl, chloro, fluoro, cyano, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyclopropyl. In some specific embodiments, n is 1 or 2 and R3is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C8 cycloalkyl. In some embodiments, n is 1 and R3is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C8 cycloalkyl. In some embodiments, n is 1 and R3is methyl, chloro, fluoro, trifluoromethyl, methoxy, trifluoromethoxy, or cyclopropyl.

[0182] In some embodiments, the compound has the following Structure (IIIc):(IIIc)or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: R3ais halo or 3-10 membered heterocyclyl; andnl is 1, 2, or 3.

[0183] In some embodiments, R3ais fluoro or piperazinyl. In more specific embodiments, the compound has the following Structure (IIIcl):Attorney Docket No. 63243-710.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0184] In some embodiments, the compound of Formula (III) is administered to treat or prevent the symptom of biological aging. In some embodiments, the compound of Formula (III) is administered to delay and / or slow the development of the symptom of biological aging.

[0185] In some embodiments, the compound of Formula (III) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (III) is an inhibitor of the NLRP3 inflammasome. In some embodiments, the compound of Formula (III) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (III) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (III) inhibits the priming step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (III) inhibits signaling downstream of members of the TLR (toll-like receptor) family, IL-1R (interleukin 1 receptor) family, and / or TNFR1 / 2 (tumor necrosis factor receptor 1 / 2). In some embodiments, the compound of Formula (III) prevents the activation of NF-kB (nuclear factor kappa-beta). In some embodiments, the compound of Formula (III) reduces the level of TNF-a, IL-6, or the components of the NLRP3 inflammasome (e.g., NLRP3, pro-IL-1β (pro-interleukin-1beta), pro-IL18 (pro-interleukin- 18)), or a combination thereof, in the subject. In some embodiments, the compound of Formula (III) inhibits the assembly and activation step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (III) inhibits the formation of a NLRP3 (protein)-NEK7 (protein) interaction. In some embodiments, the compound of Formula (III) inhibits the formation of the ASC speck and the NLRP3 inflammasome. In some embodiments, the compound of Formula (III) prevents caspase- 1 activation. In some embodiments, the compound of Formula (III) inhibits the production of IL-1β. In some embodiments, the compound of Formula (III) inhibits the production of IL-18.Attorney Docket No. 63243-710.601In some embodiments, the compound of Formula (III) inhibits the cleavage of gasdermin D. In some embodiments, the compound of Formula (III) prevents pyroptotic cell death.

[0186] In various different embodiments, the compound has one of the structures set forth in Table 1C below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0187] Compounds in Table 1C were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Table 1C: Representative compounds of Structure (III)Cmp Structure Name0V\HNA l-(4-(4-amino-7- cyclopropyl-7 / 7-H( / / / \-0 pyrrolo[2,3-d]pyrimidin-5- III-l NH2y-77yl)-2-fluorophenyl)-3 -(2- fluoro-4- H 1 > (morpholinomethyl)pheny l)ureabF0_ Hblb / l-(4-(4-amino-7- F. / J / N" N cyclopropyl-7 / 7-H( / <\ / / V-0 pyrrolo[2,3-d]pyrimidin-5- III-2 NH2y-77yl)-2-fluorophenyl)-3 -(3 - fluoro-4- I I A / (morpholinomethyl)pheny l)ureaNCF3l-(4-(4-amino-7- R 7 NA / cyclopropyl-7 / 7- / \H— pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-3 NH2yb(4-methylpiperazin- 1 -yl)- NAA 3- l! JL / (trifluoromethyl)phenyl)ur eaN)yAttorney Docket No. 63243-710.601Cmp Structure NameCF30 _ / l-(4-(4-amino-7- HN-A cyclopropyl-77 / - R / N'-'kx II N'AKH 0 pyrrolo[2,3-d]pyrimidin-5- / / 7 \— -N yl)-2-fluorophenyl)-3 -(4- III-4 NH2x((3-methyl-3,8- diazabicyclo[3.2.1 ]octan- I! JL / 8-yl)methyl)-3- (trifluoromethyl)phenyl)ur eaNCF3l-(4-(4-amino-7-0cyclopropyl-77 / - F pyrrolo[2,3-d]pyrimidin-5- r \Hyl)-2-fluorophenyl)-3 -(4- (((3aR,6aS)-5- III-5 NH2yJ HA_NXmethylhexahydropyrrolo[3,4-c]pyrrol-2(lH)- I I A / yl)methyl)-3-N(trifluoromethyl)phenyl)ur ea0l-(4-(4-amino-7- R cyclopropyl-77 / -H / / pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-6 NH2\ / / X( 1 -(4-methylpiperazin- 1 - yl)ethyl)-3- Li A / (trifluoromethyl)phenyl)urNeaCF3l-(4-(4-amino-7- c cyclopropyl-77 / - Rh / n^ N" J\A\ H / i — N—Y=\ H I _ | pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-7 NH2y— ((6-methyl-2,6- diazaspiro[3.3 ]heptan-2- u A / yl)methyl)-3- (trifluoromethyl)phenyl)ur eaNAttorney Docket No. 63243-710.601Cmp Structure NameCF3l-(4-(4-amino-7- HN^\ / cyclopropyl-77 / - Fxj J / N'AH( / pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-8 NH2x((7-methyl-4,7- diazaspiro[2.5]octan-4- I I A / yl)methyl)-3- (trifluoromethyl)phenyl)ur b ea1-(4-(4-amino-7-0b3cyclopropyl-77 / - y=\ pyrrolo[2,3-d]pyrimidin-5- HL / ) \S-N yl)-2-fluorophenyl)-3 -(4- III-9 NH2y-77\ ((5-methyl-2,5- diazabicyclo[2.2.2]octan- I! JL / 2-yl)methyl)-3- (trifluoromethyl)phenyl)ur eaNCF3l-(4-(4-amino-7- HN^0 / / °F\ / cyclopropyl-77 / - yA N^y. / / N^\H 1 / pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III- 10 NH2\ yJ / 7 / x(4-methylpiperazine- 1 - carbonyl)-3- u A / (trifluoromethyl)phenyl)ur eab0A3l-(4-(4-amino-7- cyclopropyl-77 / - \ y= T\A H-C / V / X / Z. / / \— N pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III- 11 NH2y-7'x((1 -methylpiperidin-4- yl)methyl)-3- 1 JL / (trifluoromethyl)phenyl)urNeaAttorney Docket No. 63243-710.601Cmp Structure Namel-(4-(4-amino-7-z / =\0A *A zz cyclopropyl-77 / - 7\ i \ > ( IK> - H r ) pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(3 - < z\r_ / / III- 12 NH2y27 xfluoro-4-((4- methylpiperazin- 1 - N' AXI I A / ^°Z I yl)methyl)-5- (trifluoromethyl)phenyl)ur l f eaCF \3w0l-(4-(4-amino-l- r- HN^\R. / NA J7 N^\ cyclopropyl-lH- V\H( / pyrrolo[3,2-c]pyridin-3- / / yl)-2-fluorophenyl)-3 -(4- III- 13 NH2y \((4-methylpiperazin- 1 - yl)methyl)-3- (trifluoromethyl)phenyl)ur eal-(5-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- yl)pyridin-2-yl)-3 -(4-((4- III- 14methylpiperazin- 1 - yl)methyl)-3- (trifluoromethyl)phenyl)ur eal-(4-(4-amino-7-(2-0x3hydroxy-2-methylpropyl)- F. TA-O X-.y=\ H / / 7Z / -pyrrolo[2,3- / / N d]pyrimidin-5-yl)-2- III- 15 NH2yx \ fluorophenyl)-3 -(4-((4- methylpiperazin- 1 - l! JL / yl)methyl)-3- (trifluoromethyl)phenyl)urN Nvyon eaAttorney Docket No. 63243-710.601Cmp Structure Name0l-(4-(4-amino-7- HN^A / TVA,-.F\ J N^\ A N^N cyclopropyl-77 / - y=\H( / pyrrolo[2,3-d]pyrimidin-5- (. / / CF3V-Nyl)-2-fluorophenyl)-3 -(4- III- 16 NH2y^ \((4-methylpiperazin- 1 - yl)methyl)-2- Li JL / (trifluoromethyl)phenyl)ur eaNol-(4-(4-amino-7- HN-A J / ^ 7'F\ J N-\ N" N cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- / / OCF3\— Nyl)-2-fluorophenyl)-3 -(4- III- 17 NH2yJ'3\((4-methylpiperazin- 1 - yl)methyl)-2- I! JL / (tri fluoromethoxy )phenyl) ureaNl-(4-(4-amino-7-m ethyl -0A37Z / -pyrrolo[2,3- d]pyrimidin-5-yl)-2- y=\ H / / fluorophenyl)-3 -(4-((4- III- 18 <\ / / NH2y^ \ methylpiperazin- 1 - yl)methyl)-3- Li A / (trifluoromethyl)phenyl)ur eaCF30l-(4-(4-amino-7-._ HN^\F\ J N^N\ J / N^\ cyclobutyl-77 / - pyrrolo[2,3-d]pyrimidin-5- (\ / / yl)-2-fluorophenyl)-3 -(4- III- 19 NH2yj / \((4-methylpiperazin- 1 - N'X^V A yl)methyl)-3- LI A / (trifluoromethyl)phenyl)ur eaAttorney Docket No. 63243-710.601Cmp Structure Name1 -(4-(4-amino-7-(l -Z / =\0A3> z z / — / / i methylpyrrolidin-3-yl)- (M— / H / / 7Z / -pyrrolo[2,3- 4 / / d]pyrimidin-5-yl)-2- NH III-202^ VCzk'z*Xfluorophenyl)-3 -(4-((4- methylpiperazin- 1 - 11 A / ^°-IZyl)methyl)-3- (trifluoromethyl)phenyl)ur eaV-Nx0J*3CHNX / / ) — 0F. / N^\x U N^\ 1 -(4-(4-amino-7-(l - Hx— / / methylpiperidin-4-yl)-7J7- / / N— N pyrrolo[2,3-d]pyrimidin-5- NH2y-^xyl)-2-fluorophenyl)-3 -(4- III-21((4-methylpiperazin- 1 - u A / yl)methyl)-3-N N\ (trifluoromethyl)phenyl)ur ea'"" N\l-(4-(4-amino-l- isopropyl-lH- III-22 pyrazolo[3,4-d]pyrimidin- 3 -yl)phenyl)-3 -(3 -methyl- 4-morpholinophenyl)ureaJ / =CrC°HN-A A V'N\_-VJ N-"\ J1 -(4-(4-amino- 1 -(oxetan- rSH3-yl)-lH-pyrazolo[3,4- NH2\=^III-23 d]pyrimidin-3-yl)phenyl)- 3 -(3 -methyl -4- 11 J 'Nmorpholinophenyl)ureaN N%zAttorney Docket No. 63243-710.601Cmp Structure Namez / =xl-(4-(4-amino-l- \ f=) z z / — / / X S '. isopropyl-lH- / / \M\ I - 1 \ ) ( M - pyrazolo[3,4-d]pyrimidin- 3 -yl)phenyl)-3 -(4-((4- III-24z / ^zoJ l-z methylpiperazin- 1 - yl)methyl)-3- ^° TZ^° IZ (trifluoromethyl)phenyl)ur ea\05pz1 -(4-(4-amino- 1 -(oxetan- 3-yl)-lH-pyrazolo[3,4- d]pyrimidin-3-yl)phenyl)- III-25 3-(3-(4-methyl-lH- imidazol-l-yl)-5- (trifluoromethyl)phenyl)ur ea,_ HN^0CFV\ l-(4-(4-amino-l- \ J] N'Ncyclopropyl-lH- yAH< / pyrazolo[3,4-d]pyrimidin- III-26 NH2V-73 -yl)-2-fluorophenyl)-3 - (2-fluoro-4-NLL A 'N(morpholinomethyl)pheny l)ureaNF0._ HN^ l-(4-(4-amino-l- Fxj N^N J / N^\ cyclopropyl-lH- WH( / pyrazolo[3,4-d]pyrimidin- III-27 NH2y^ / 7 / x3 -yl)-2-fluorophenyl)-3 - (3-fluoro-4-((4- H J N methylpiperazin- 1 - yl)methyl)phenyl)ureaAttorney Docket No. 63243-710.601Cmp Structure Name0l-(4-(4-amino-l- \ j ArCpN-x cyclopropyl-lH- y=\ H / / pyrazolo[3,4-d]pyrimidin- 4 / ) \-N 3 -yl)-2-fluorophenyl)-3 - III-28 NH2y-77 x(4-((4-methylpiperazin- 1 -Nyl)methyl)-3- 11 J,N(trifluoromethyl)phenyl)ur eaNCF301 -(4-(4-amino- 1 -(2- _ HN^\ hydroxy-2-methylpropyl)-F\ J N^ / \ J^7 A Nl-^XxV\ lH-pyrazolo[3,4- H? )(\ / / d]pyrimidin-3-yl)-2- III-29 NH2y^7 xfluorophenyl)-3 -(4-((4- methylpiperazin- 1 -NTAU H ANyl)methyl)-3- (trifluoromethyl)phenyl)ur y-OH ea0X l-(5-(4-amino-l- cyclopropyl-lH- N H '■—“ l ) pyrazolo[3,4-d]pyrimidin- 3 -yl)pyri din-2 -yl)-3 -(4- III-30 NH2y=^ \((4-methylpiperazin- 1 - yl)methyl)-3- u. AN(trifluoromethyl)phenyl)ur eaN)>CF3l-(4-(4-amino-l-cFx H / N^\ N^ / kx / / / TA Nu^^xX cyclopropyl-lH- Wx H 7 ) pyrazolo[4,3 -c]pyri din-3 - (\ / / yl)-2-fluorophenyl)-3 -(4- III-31 NH2VA7 X((4-methylpiperazin- 1 - yl)methyl)-3- tjCN(trifluoromethyl)phenyl)ur eaAttorney Docket No. 63243-710.601Cmp Structure Name0A3l-(4-(4-amino-7-H— ( / cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- III-32 NH2L iX-° yl)-2-fluorophenyl)-3 -(4- (morpholinomethyl)-3 - N / V4H A / (trifluoromethyl)phenyl)ur eaNEJ / 4jA>F. l-(4-(4-amino-7- / XH— cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- III-33 NH2y-Ayl)-2-fluorophenyl)-3 -(3 - methyl -4- U J. / morpholinophenyl)ureaNCF3l-(4-(4-amino-7- HN-AF\ / N-" f\. H / ) - N — \ cyclopropyl-77 / - V=\ H / / pyrrolo[2,3-d]pyrimidin-5- / / N-N yl)-2-fluorophenyl)-3 -(4- III-34 NH2yJ / \((4-methylpiperazin- 1 - yl)methyl)-3- I! JL / (trifluoromethyl)phenyl)ur eaNCF307^=( l-(4-(4-amino-7- HN-XCL / N'AX H N'N. cyclopropyl-77 / - r^ xH— ( / pyrrolo[2,3-d]pyrimidin-5- / / \-Nyl)-2-chlorophenyl)-3-(4- III-35 NH2yJ7\((4-methylpiperazin- 1 - N NA yl)methyl)-3- 1 / L / (trifluoromethyl)phenyl)ur eaNAttorney Docket No. 63243-710.601Cmp Structure NameFz / =\04HNX / / ) — l-(4-(4-amino-7- / / I > < w F -p. / N'"<\ J I N — \ cyclopropyl-77 / - V=\ H / / 4 / / N pyrrolo[2,3-d]pyrimidin-5- III-36 NH2y-J xyl)-2-fluorophenyl)-3 -(3 - fluoro-4-((4- N vA1! JL / ^° zz methylpiperazin- 1 - yl)methyl)phenyl)ureaNClc l-(4-(4-amino-7- F.H / N^ N^\x H ^z N r^N cyclopropyl-77 / - V=\H( / pyrrolo[2,3-d]pyrimidin-5- / / III-37 NH2y-7 xyl)-2-fluorophenyl)-3 -(3 - chloro-4-((4- N' NAI! A / methylpiperazin- 1 - yl)methyl)phenyl)ureaNxo0 / l-(4-(4-amino-7- cyclopropyl-77 / - NA H r > pyrrolo[2,3-d]pyrimidin-5- III-38 / / X"NNH2y-yxyl)-2-fluorophenyl)-3 -(3 - methoxy -4-((4- methylpiperazin- 1 - I! / yl)methyl)phenyl)ureaNl-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- III-39 yl)-2-fluorophenyl)-3 -(3 - methyl-4-((4- methylpiperazin- 1 - yl)methyl)phenyl)ureaAttorney Docket No. 63243-710.601Cmp Structure Name0l-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- III-40 (\ / / NH2y-7 xyl)-2-fluorophenyl)-3 -(3 - cyclopropyl-4-((4- I! A / methylpiperazin- 1 - yl)methyl)phenyl)ureaN0X3l-(4-(4-amino-7- cyclopropyl-77 / - V=\ H / / pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-41 NH24K / / X—((4-ethylpiperazin-l- yl)methyl)-3- 11 A / (trifluoromethyl)phenyl)ur eaN0A3l-(4-(4-amino-7- cyclopropyl-77 / - V=\ Hx— / / pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-42 N 4K / NH2((4-(2- hy droxy ethyl)piperazin- 1 - I! JL / yl)methyl)-3- (trifluoromethyl)phenyl)ur eaN0A3l-(4-(4-amino-7- cyclopropyl-77 / - y=\ HX— / / pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-43 N 4K / NH2— \ ((4-(2- methoxyethyl)piperazin- 1 - N YAL / L / yl)methyl)-3- (trifluoromethyl)phenyl)ur eaNAttorney Docket No. 63243-710.601Cmp Structure Name0A3l-(4-(4-amino-7- cyclopropyl-77 / - A SH— ( J pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-44 NH2((4-m ethyl- 1,4-diazepan- l-yl)methyl)-3- 1! JL / (trifluoromethyl)phenyl)ur eaN0A3l-(4-(4-amino-7- cyclopropyl-77 / - z pyrrolo[2,3-d]pyrimidin-5- > AH'JV yl)-2-fluorophenyl)-3 -(4- III-45 NH2WV((3- (dimethylamino)pyrrolidin 11 A / -l-yl)methyl)-3- (trifluoromethyl)phenyl)ur eaNCF3p / =Nl-(4-(4-amino-7- _F HN"\ cyclopropyl-77 / - \ J Jr \Hpyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-46 NH2S— (4-methyl- IH-imidazol- 1 - yl)-3- LI A / (trifluoromethyl)phenyl)ur eaN0 Al-(4-(4-amino-7- _ HNAFir0'^- \ J JJ ) — \ cyclopropyl-77 / - V=\ H / / pyrrolo[2,3-d]pyrimidin-5- / / yl)-2-fluorophenyl)-3 -(4- III-47 NH2yA7 x((1 -methylpiperidin-4- yl)oxy)-3- 1! JL / (trifluoromethyl)phenyl)ur eaNAttorney Docket No. 63243-710.601Cmp Structure NameF0XHNX l-(4-(4-amino-l-F\ J J7 N^\ cyclopropyl-lH-H( / pyrazolo[3,4-d]pyrimidin- III-48 NH2y^73 -yl)-2-fluorophenyl)-3 - (3-fluoro-4- N '\4|[i X 'N(morpholinomethyl)pheny l)urea b0A3° l-(4-(4-amino-l- c HNXF. / N^ / \\ # / X\ Ni^\ cyclopropyl-lH- y=\ H / / pyrazolo[3,4-d]pyrimidin- 4 / / III-49 NH2y-77 x3 -yl)-2-fluorophenyl)-3 - (4-(4-methylpiperazine- 1 - N 11 Y J A carbonyl)-3-,N(trifluoromethyl)phenyl)ur eaN0X3l-(4-(4-amino-l- cyclopropyl-lH- \ y= J\AX YH / / pyrazolo[3,4-d]pyrimidin- 3 -yl)-2-fluorophenyl)-3 - III-50 NH24 yK - / 7 / x— (4-((4-ethylpiperazin- 1 - N' NXK, yl)methyl)-3- H J,N(trifluoromethyl)phenyl)ur eaNCF30 / X l-(5-(4-amino-l- H / NX / Z / 7> —N"\ cyclopropyl-lH- pyrazolo[4,3-c]pyridin-3- / / / X NH( VN / yl)pyridin-2-yl)-3 -(4-((4- III-51 NH2y=^ \ methylpiperazin- 1 - yl)methyl)-3-NUUN(trifluoromethyl)phenyl)ur eaAttorney Docket No. 63243-710.601Cmp Structure Name0A3l-(4-(4-amino-7- cyclopropyl-77 / - y=\ HX— / / pyrrolo[2,3-d]pyrimidin-5- / / N yl)-2-fluorophenyl)-3 -(4- III-52 NH2x((1 -methylpiperidin-4- ylidene)methyl)-3- I! J / (trifluoromethyl)phenyl)ur eaN0HN-A jfA - l-(4-(4-amino-7-F\ J N-A _ / N—\Y=\H / — ( / cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- III-53 NH2V7\xyl)-2-fluorophenyl)-3 -(2- NAX methoxy-4-((4- I! JL / methylpiperazin- 1 - yl)methyl)phenyl)ureaNCN HN'A / l-(4-(4-amino-7-F\ / N^N\ II N^N cyclopropyl-77 / - X=\ H 1 / / / N— N pyrrolo[2,3-d]pyrimidin-5- III-54 NH2yA7 xyl)-2-fluorophenyl)-3 -(3 - cyano-4-((4- N xALI A / methylpiperazin- 1 - yl)methyl)phenyl)ureaNCF30l-(4-(4-amino-7- HN^x / / ) —CL / N^ \\ H N^\ cyclopropyl-77 / - y=\ H / / pyrrolo[2,3-d]pyrimidin-5- yl)-2-chlorophenyl)-3-(4- III-55 NH2X yJ / 7 / ' —((4-ethylpiperazin-l- yl)methyl)-3- U A / (trifluoromethyl)phenyl)ur eaNAttorney Docket No. 63243-710.601Cmp Structure Namez / =\) Z z / — F. HNANl-(4-(4-amino-l- H?- z cyclopropyl-lH- pyrazolo[4,3 -c]pyri din-3 - III-56 NH2t^ / z^ yl)-2-fluorophenyl)-3 -(3 - methyl -4- ^° IZ morpholinophenyl)ureaoHN-AFJ / ' T' \,--X\ J N-\_yX^Z N / ^-"\ l-(4-(4-amino-7- Hx— / / cyclopropyl-77 / - 4 / / Npyrrolo[2,3-d]pyrimidin-5- NH2xIII-57yl)-2-fluorophenyl)-3 -(4- ((4-methylpiperazin- 1 - u JL / yl)methyl)phenyl)ureaNl-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- III-58yl)-2-fluorophenyl)-3 -(4- ((4-ethylpiperazin-l- yl)methyl)phenyl)ureaCHF20l-(4-(4-amino-7- cHN^ -F\ / N^ \x H N \ cyclopropyl-77 / - y=\ H / / pyrrolo[2,3-d]pyrimidin-5- / / NH2yJ7\ yl)-2-fluorophenyl)-3 -(3 - III-59(difluoromethyl)-4-((4- methylpiperazin- 1 - I! A / yl)methyl)phenyl)ureaNAttorney Docket No. 63243-710.601Cmp Structure NameCHF20HNX / / ) — l-(4-(4-amino-7-F\ / N"\x II N — \ cyclopropyl-77 / - V=\ Hx— / / pyrrolo[2,3-d]pyrimidin-5- 4 / / III-60 NH2X— yl)-2-fluorophenyl)-3 -(3 - (difluoromethyl)-4-((4- N'X\-'AI! JL / ethylpiperazin-1- yl)methyl)phenyl)ureaN0l-(4-(4-amino-7- _ HNA / F\ cyclopropyl-77 / - Y= J\NH \^N / / A / pyrrolo[2,3-d]pyrimidin-5- (\ / ) yl)-2-fluorophenyl)-3 -(6- III-61 NH2X((1 -methylpiperidin-4- yl)oxy)-5- LI A / (trifluoromethyl)pyridin- 3-yl)ureaNCF3l-(4-(4-amino-7- CF\H / N^ N"^ j\jx H / l - N \ cyclopropyl-77 / - y=\ H / / pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-62 NH2y- / 7 / ((4-cyclopropylpiperazin- l-yl)methyl)-3- U A / (trifluoromethyl)phenyl)ur eaN0A3l-(4-(4-amino-7- \ j AThn cyclopropyl-77 / - VA HX— / / pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-63 NH2y-7 / 7 / y^- ((4-i sopropylpiperazin- 1 - yl)methyl)-3- I! JL / (trifluoromethyl)phenyl)ur eaNAttorney Docket No. 63243-710.601Cmp Structure Name1-(4-(4-amino-7-0A3cyclopropyl-77 / - H t > pyrrolo[2,3-d]pyrimidin-5- U / V^N yl)-2-fluorophenyl)-3-(4- III-64 NH2\=^X((5-methyl-2,5- diazabicyclo[2.2. l]heptan- 1! JL / 2-yl)methyl)-3- (trifluoromethyl)phenyl)ur eaN0F\ _CHN-A 7 / ) — \i_-x l-(4-(4-amino-7- F. / N-"\\ II N — \H / / cyclopropyl-77 / - / / N pyrrolo[2,3-d]pyrimidin-5- III-65 NH2Xyl)-2-fluorophenyl)-3 -(2- fluoro-4-((4- I! JL / methylpiperazin- 1 - yl)methyl)phenyl)ureaNCF3l-(4-((4,7- diazaspiro[2.5]octan-4- yl)methyl)-3- / V \—NH (trifluoromethyl)phenyl)- III-66 NH23-(4-(4-amino-7- cyclopropyl-77 / - I! JL / pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)ureaNCF30l-(5-(4-amino-7- CF\H / N^ yN^\ cyclopropyl-77 / -H( / pyrrolo[2,3-d]pyrimidin-5- / / N \_^Nyl)-3-fluoropyri din-2 -yl)- III-67 NH2\=^X3 -(4-((4-methylpiperazin- l-yl)methyl)-3- LI 1 / (trifluoromethyl)phenyl)ur eaNAttorney Docket No. 63243-710.601Cmp Structure Name0A3l-(4-(4-amino-7- cyclopropyl-77 / - yA HX-"N / / pyrrolo[2,3-d]pyrimidin-5- (\ / / N yl)-2-fluorophenyl)-3 -(6- III-68 NH2X((4-methylpiperazin- 1 - NAA yl)methyl)-5- I! JL / (trifluoromethyl)pyridin- 3-yl)ureaN NKl-(4-(4-amino-7-0A3HN^\ jf / )" A cyclopropyl-77 / -F\ / N"\\ II N'A pyrrolo[2,3-d]pyrimidin-5- / \H4 / yl)-2-fluorophenyl)-3 -(4- III-69 NH2NA ((4- T J / (dimethylamino)piperidin- N TA U A / l-yl)methyl)-3- (trifluoromethyl)phenyl)ur eaNCF30^=A l-(4-(4-amino-7- cFUN -A JJ / I - \ / N'-'X u N-A. cyclopropyl-77 / - YAH< / pyrrolo[2,3-d]pyrimidin-5- II ] \— N yl)-2-fluorophenyl)-3 -(4- III-70 NH2N=A \((2,4-dimethylpiperazin- 1 - yl)methyl)-3- U A / (trifluoromethyl)phenyl)ur eaNCF30cl-(4-(4-amino-7-(2- HN^\ / / XAF\ J J? N^\ hydroxyethyl)-77 / - yxH( / pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-71 NH2yAx((4-methylpiperazin- 1 - yl)methyl)-3- u A / (trifluoromethyl)phenyl)ur eaOHAttorney Docket No. 63243-710.601Cmp Structure NameCHF,0r- HNX f / ) - l-(4-(4-amino-7- F. / J N — \ cyclopropyl-77 / - VA Hx— / / pyrrolo[2,3-d]pyrimidin-5- 4 / / III-72 yl)-2-fluorophenyl)-3 -(3 - T j OH (difluoromethyl)-4-((4-(2- N'MXU 1 / hy droxy ethyl)piperazin- 1 - yl)methyl)phenyl)ureaNCF3l-(4-(4-amino-7-0 / ^Ncyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- nHIII-73 NH2((4-methyl-4,7- diazaspiro[2.5 ] octan-7 - yl)methyl)-3- U A / (trifluoromethyl)phenyl)ur eaNl-(4-(4-amino-7-0A3cyclopropyl-77 / - \ j A-v V pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- OHM III-74 NH2\==^ NH ((4- I 7 / (methylamino)piperidin- 1 - N ^T ALI A / yl)methyl)-3- (trifluoromethyl)phenyl)ur eaNE CF30l-(4-(4-amino-7- CF HN^ - \ / H N^\ cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- OHM yl)-2-fluorophenyl)-3 -(4- III-75 NH2\==^ NH2((4-aminopiperidin-l- yl)methyl)-3- U A / (trifluoromethyl)phenyl)ur eaNAttorney Docket No. 63243-710.601Cmp Structure NameCF3> Z z— / 0r===^ 1 -(4-(4-amino- 1 -(2- / / \ i \M- / \ Tl \H / NAXFn hy droxy ethyl)- 1H- pyrazolo[3,4-d]pyrimidin- 3 -yl)-2-fluorophenyl)-3 - III-76 NH2lA / (4-((4-methylpiperazin- 1 - N yl)methyl)-3- 11 y JA N, ^1°Z X(trifluoromethyl)phenyl)ur eaOH \03 / "" Z1 -(4-(4-amino- 1 -(2- Z / ^ / methoxy ethyl)- 1H- pyrazolo[3,4-d]pyrimidin- 3 -yl)-2-fluorophenyl)-3 - III-77(4-((4-methylpiperazin- 1 - yl)methyl)-3- (trifluoromethyl)phenyl)ur eal-(4-(4-amino-7-0ACFScyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- ysho yl)-2-fluorophenyl)-3 -(4- NH2y^7 xIII-78((4-methylpiperazin- 1 - yl)methyl)-3- Li A / (tri fluoromethoxy )phenyl) ureab0A3l-(4-(4-amino-7- 1- HNX / / ) —F. / N'Nk J I N-^\ cyclopropyl-77 / - YAH< / pyrrolo[2,3-d]pyrimidin-5- U 1 \— NHNH2III-79 yl)-2-fluorophenyl)-3 -(4- (piperazin- 1 -ylmethyl)-3 - (trifluoromethyl)phenyl)ur 1 JL / eaNAttorney Docket No. 63243-710.601Cmp Structure NameCF31 -(4-((4-acetylpiperazin- 1 - yl)methyl)-3- (trifluoromethyl)phenyl)- RT III-80 NH2HU 3-(4-(4-amino-7- 1 / 0 cyclopropyl-77 / - N' VApyrrolo[2,3-d]pyrimidin-5- I! A / yl)-2-fluorophenyl)ureaNCF3° r^\ l-(4-(4-amino-7-(2- F. methoxyethyl)-77 / - pyrrolo[2,3-d]pyrimidin-5- HHQyl)-2-fluorophenyl)-3 -(4- III-81 NH2((4-methylpiperazin- 1 - yl)methyl)-3- I! A / (trifluoromethyl)phenyl)ur ea0^CF30 _ / JI \" OX1 -(4-(( 1 -acetylpiperi din-4- \ JNN A7 yl)oxy)-3- V-N H < '[T J (trifluoromethyl)phenyl)- III-82 NH27 3-(4-(4-amino-7- 1 / 0 cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- u y / yl)-2-fluorophenyl)ureaNb>CF30 _ IJI l-(4-(4-amino-7- cyclopropyl-77 / - \ Z N AZpyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-83 NH2O nT JLo (( 1 -(oxetan-3 -yl)piperidin- 4-yl)oxy)-3- I! A / (trifluoromethyl)phenyl)ur eaNAttorney Docket No. 63243-710.601Cmp Structure Namel-(4-(4-amino-7-z / = \) Z z / — / \ / z \ cyclopropyl-77 / -M\ — / T' pyrrolo[2,3-d]pyrimidin-5- Z r^^ yl)-2-fluorophenyl)-3 -(4- III-84 ZzVi- ((4-(2- bo fluoroethyl)piperazin- 1 - TZ yl)methyl)-3- (trifluoromethyl)phenyl)ur V vYO' / j eaCFw3\ / ^ z- o c \ l-(4-(4-amino-7- 0 cyclopropyl-77 / - F.HYNYJYNZ\ pyrrolo[2,3-d]pyrimidin-5- yshM-F yl)-2-fluorophenyl)-3 -(4- III-85 NH2\=Z ZX F((4,4-difluoropiperidin- 1 - N VA (^Oyl)methyl)-3- I! JL / (trifluoromethyl)phenyl)ur Z4^ ea) CM / - L*- (NZ z—'z= / CF3l-(4-(4-amino-7- cyclopropyl-77 / -FxHA X n A pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-86 NH2rt N^7 h vbn ((4-(oxetan-3- 1 / L0 yl)piperazin- 1 -yl)methyl)- N' YYII A / 3- (trifluoromethyl)phenyl)ur eabl-(4-(4-amino-l- cyclopropyl-lH- pyrazolo[3,4-d]pyrimidin- 3 -yl)-2-fluorophenyl)-3 - III-87(3 -((4-methylpiperazin- 1 - yl)methyl)-5- (trifluoromethyl)phenyl)ur eaAttorney Docket No. 63243-710.601Cmp Structure NameCF03l-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-88 NH2A \^S / H / ((l-ethylpiperidin-4- yl)oxy)-3- I! JL / (trifluoromethyl)phenyl)ur eaNCF3l-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-89 NH2y^ ((3 -fluoro- 1- N YY methylpiperidin-4- I! JL / yl)oxy)-3- (trifluoromethyl)phenyl)urNea (diastereomer #1) CF3l-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-90 NH2\=Y ((3 -fluoro- 1- N YY methylpiperidin-4- I! JL / yl)oxy)-3- (trifluoromethyl)phenyl)urNea (diastereomer #2) CF3l-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-91 NH2((3 -fluoro- 1 -(oxetan-3 - N u T JLA yl)piperidin-4-yl)oxy)-3- / (trifluoromethyl)phenyl)ur ea (diastereomer #1)NEAttorney Docket No. 63243-710.601Cmp Structure NameCF3l-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-92 NH2Y“|T r *-o ((3 -fluoro- 1 -(oxetan-3 - N AA yl)piperidin-4-yl)oxy)-3- u JL / (trifluoromethyl)phenyl)ur ea (diastereomer #2)NCF30^-4 l-(4-(4-amino-7-CHN-A jf y _ cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5-Hyl)-2-fluorophenyl)-3 -(3 - III-93 NH2\===^((4-methylpiperazin- 1 - yl)methyl)-5- LI JL / (trifluoromethyl)phenyl)ur eaNE7^^l-(4-(4-amino-l- 0cyclopropyl-lH- AYAn pyrazolo[3,4-d]pyrimidin- 3 -yl)-2-fluorophenyl)-3 - III-94 oH>rNH2\=7F F(3, 3 -difluoro- 1 -(4- methylpiperazin- 1 -yl)-2,3 - 11 J,Ndihydro- 1 H-inden-5 - yl)ureaNCF30l-(4-(4-amino-7- fx TAAJ N'A cyclopropyl-77 / - YAHO pyrrolo[2,3-d]pyrimidin-5- III-95 NH2yl)-2-fluorophenyl)-3 -(4- (piperidin- 1 -ylmethyl)-3 - u A / (trifluoromethyl)phenyl)ur eabAttorney Docket No. 63243-710.601Cmp Structure NameCF3z / =\'Z> n— Z z / / - / — l-(4-(4-amino-7- / / z0\ z \W- / \ TlM— 7 \ / cyclopropyl-77 / - Zz__. _ _ pyrrolo[2,3-d]pyrimidin-5- yyhyy yl)-2-fluorophenyl)-3 -(4- III-96 NH2OH((4-hydroxypiperidin- 1 - ^^°° TZ zz yl)methyl)-3- I I A / (trifluoromethyl)phenyl)ur eab (ob \00\w^" Z l-(4-(4-amino-7- o r-THN^ j S - \ ^X Z cyclopropyl-77 / - R. N \y °- / fK -J ^ ° -~x.~ - / x pyrrolo[2,3-d]pyrimidin-5-z'o yl)-2-fluorophenyl)-3 -(4- V)NHO III- 7 H Xz07 so92((4- 1 / Oz(cyclopropylsulfonyl)piper N VA \ZL A / azin- 1 -yl)methyl)-3 - (trifluoromethyl)phenyl)ur eabl-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-98 ((4- (methylsulfonyl)piperazin- l-yl)methyl)-3- (trifluoromethyl)phenyl)ur eal-(4-(4-amino-7- cyclopropyl-77 / - pyrrolo[2,3-d]pyrimidin-5- yl)-2-fluorophenyl)-3 -(4- III-99 ((4-(2- (methylsulfonyl)ethyl)pipe razin- 1 -yl)methyl)-3 - (trifluoromethyl)phenyl)ur eaAttorney Docket No. 63243-710.601Cmp Structure Namez / =x) Z z / — / / \ I \M2-(4-(4-(3 -(4-(4-amino-7- - I \ T| cyclopropyl-7 / 7- pyrrolo[2,3-d]pyrimidin-5- III- yi)-2- 100 fluorophenyl)ureido)-2- ^°Z T(trifluoromethyl)benzyl)pi perazin- 1 -yl)ethane- 1 - sulfonic acid ° X3 / ■" Z1 -(4-(4-amino-7-(l - F\ TXNXJ''A' C\-\y\ho 'to' (methylsulfonyl)piperidin-z' oo4-yl)-7Z7-pyrrolo[2,3- NH2\=^XId]pyrimidin-5-yl)-2- III- fluorophenyl)-3 -(4-((4- 101 11 A / methylpiperazin- 1 - yl)methyl)-3- (trifluoromethyl)phenyl)ur 0 easo°'s\0X31 -(4-(4-amino-7-(l - (cyclopropylsulfonyl)piper NH2y\hoXidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(4-((4- u A / methylpiperazin- 1 - yl)methyl)-3- Q (trifluoromethyl)phenyl)ur eaAAttorney Docket No. 63243-710.601Cmp Structure Name1 -(4-(4-amino- 1 -(5-zZ / = / =\\) Z z> z z / — / — hydroxypentyl)- 1H- / / / / \ I \ IM M / - Tl \ pyrazolo[3,4-d]pyrimidin- — T' / \HI- 3 -yl)-2-fluorophenyl)-3 - 103 (4-((4-methylpiperazin- 1 - yl)methyl)-3- ^°Z I (trifluoromethyl)phenyl)ur ea ^ / Z^ZkA1o\ \0305K^ Zo c \z1 -(4-(4-amino-7-(l - / ^z ^methylazetidin-3-yl)-7H- y AZ / pyrrolo[2,3-d]pyrimidin-5- HI- yl)-2-fluorophenyl)-3 -(4- 104 ^ °ZI((4-methylpiperazin- 1 - yl)methyl)-3- / (trifluoromethyl)phenyl)ur ea) I CM — u-. SXT I'z e z—z= / l-(4-(4-amino-7- isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2- HI- fluorophenyl)-3 -(4-((4- 105 methylpiperazin- 1 - yl)methyl)-3- (trifluoromethyl)phenyl)ur eaCF3° r=KRH,NAAJ^^ 3 -(4-amino-5 -(3 -fluoro-4- (3 -(4-((4-methylpiperazin- >shQ l-yl)methyl)-3- HI- NH2(trifluoromethyl)phenyl)ur 106eido)phenyl)-7Z7- U JL / pyrrolo[2,3-d]pyrimidin-7- yl)propanoic acid / Z ~OH0Attorney Docket No. 63243-710.601Cmp Structure Name) Z z— / 4-(4-amino-5-(3-fluoro-4- / / iM— T1\ / (3 -(4-((4-methylpiperazin- l-yl)methyl)-3- HI- (trifluoromethyl)phenyl)ur 107eido)phenyl)-7Z7- pyrrolo[2,3-d]pyrimidin-7- A O yl)butanoic acid O'?C \F0530 / "" Z 1 -(4-(4-amino- 1 -(1 - r- HNO / / ) -F\ JNmethylpyrrolidin-3-yl)- J Z / ^ / lH-pyrazolo[3,4- ysHd]pyrimidin-3-yl)-2- HI- NH2Xfluorophenyl)-3 -(4-((4- 108methylpiperazin- 1 - [1 J,Nyl)methyl)-3- (trifluoromethyl)phenyl)ur eaO-NxCF30O\ l-(4-(4-amino-l- (piperi din-3 -yl)- 1 H- pyrazolo[3,4-d]pyrimidin- HHQ HI- NH2\=^ 3 -yl)-2-fluorophenyl)-3 - 109 (4-((4-methylpiperazin- 1 -NH J N yl)methyl)-3- (trifluoromethyl)phenyl)ur ea V zNHCF30r^\ 1 -(4-(4-amino- 1 -(1 - \ TAAO methylpiperidin-3-yl)-lH- pyrazolo[3,4-d]pyrimidin- HHHI- NH2\=7 3 -yl)-2-fluorophenyl)-3 - 110 (4-((4-methylpiperazin- 1 -NN J,Nyl)methyl)-3- (trifluoromethyl)phenyl)urN0 ea( N—Attorney Docket No. 63243-710.601Cmp Structure NameCF3\ f= °> -z z / — / / . y z. HNX / / ) -F\ / N"\\ II N^\ 1 -(4-(4-amino- 1 -(1 -M— \ 71 / Y U A / h< V-N / methylpiperidin-4-yl)-lH- pyrazolo[3,4-d]pyrimidin- NHHi2YZL-ZX3 -yl)-2-fluorophenyl)-3 - ll 1 N T A (4-((4-methylpiperazin- 1 - IL J N YZ Iyl)methyl)-3-N N\ (trifluoromethyl)phenyl)ur X eaV~~N / \ wo\1 -(4-(4-amino- 1 -(azetidin- 3-yl)-lH-pyrazolo[3,4- d]pyrimidin-3-yl)-2- HI- fluorophenyl)-3 -(4-(( 1 - 112 methylpiperidin-4- yl)oxy)-3- (trifluoromethyl)phenyl)ur eao / CF’CHNA / y°^ 1 -(4-(4-amino- 1 -(1 - Y methylazetidin-3-yl)-lH- IIA / H( V^N / pyrazolo[3,4-d]pyrimidin- HI- NH2X3 -yl)-2-fluorophenyl)-3 - 113 (4-((l-methylpiperidin-4- H XNyl)oxy)-3- (trifluoromethyl)phenyl)ur ea\Attorney Docket No. 63243-710.601Cmp Structure Name*\ / = f=) Z z) ~Zz— / / / / — / / .\ i \ I 1 -(4-(4-amino- 1 -(1 -M\ / T1 methylazetidin-3-yl)-lH- pyrazolo[3,4-d]pyrimidin- HI- 3 -yl)-2-fluorophenyl)-3 - ^^ rzi'114 (4-((4-methylpiperazin- 1 - ^>°oIZ zz yl)methyl)-3- (trifluoromethyl)phenyl)ur l fQO' V / -o===ea\wo\o c 0 Z~z~XZZZ-^ / / 1 -(4-(4-amino- 1 -(prop-2- yn-l-yl)-lH-pyrazolo[3,4- d]pyrimidin-3-yl)-2- HI- x °ZIfluorophenyl)-3 -(4-((4- 115 methylpiperazin- 1 -z' yl)methyl)-3- CM \ / - L*- (trifluoromethyl)phenyl)ur Iz < z—zeaz= / 1 -(4-(4-amino- 1 -(prop-2- yn-l-yl)-lH-pyrazolo[3,4- d]pyrimidin-3-yl)-2- HI- fluorophenyl)-3 -(4-(( 1 - 116 methylpiperidin-4- yl)oxy)-3- (trifluoromethyl)phenyl)ur eaCF30r-\1 -(4-(4-amino- 1 -(but-3 - yn-l-yl)-lH-pyrazolo[3,4- HHQ d]pyrimidin-3-yl)-2- HI- NH2fluorophenyl)-3 -(4-((4- 117Nmethylpiperazin- 1 - NX.[I A N yl)methyl)-3- (trifluoromethyl)phenyl)ur ea1\Attorney Docket No. 63243-710.601Cmp Structure NameZ / =\) Z z / — / / \ \ x 1 -(4-(4-amino- 1 -(but-3 - < > M -pjyn-l-yl)-lH-pyrazolo[3,4- d]pyrimidin-3-yl)-2- HI- fluorophenyl)-3 -(4-(( 1 - 118 ^O z ethylpiperidin-4-yl)oxy)- TZ3- (trifluoromethyl)phenyl)ur ea\ co0^Zz / ^ ^

[0188] Embodiments described herein provide a compound having Formula (IV):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;Xis N or CR1C;Y is N or CRld;Z is C(R6)(R7) or NR6;R1a, R1b, R1c, and R1dare each independently H, halo, Ci-Ce alkyl, or C3-C8 cycloalkyl;R2aand R2bare each independently H, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl, provided that R2aand R2bare not both H;R3is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or moreAttorney Docket No. 63243-710.601substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R5is, at each occurrence, independently halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;R6is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl; and R7is H, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl.

[0189] In some embodiments, A is Ce-Cio aryl. In certain embodiments, A is C3-C10 cycloalkyl. In some specific embodiments, A is 3-10 membered heterocyclyl. In certain specific embodiments, A is 5-6 membered monocyclic heteroaryl. In some more specific embodiments, A is substituted with one or more occurrences of R5. In certain more specific embodiments, A is substituted with one or two occurrences of R5. In some embodiments, A is substituted with substituents selected from the group consisting of halo, Ci-Ce haloalkyl, and combinations thereof. In certain embodiments, A is substituted with substituents selected from the group consisting of fluoro, trifluoromethyl, and combinations thereof. In more specific embodiments, A is unsubstituted.

[0190] In some embodiments, X is N. In certain embodiments, X is CRlc. In some specific embodiments, Rlcis H. In certain more specific embodiments, Rlcis halo (e.g., Rlcis chloro). In some other embodiments, Rlcis Ci-Ce alkyl (e.g., Rlcis methyl). In certain embodiments, Rlcis C3-C8 cycloalkyl (e.g., Rlcis cyclopropyl).

[0191] In some embodiments, Y is N. In other embodiments, Y is CRld. In some embodiments, Rldis H. In certain specific embodiments, Rldis halo, Ci-Ce alkyl, or C3-C8 cycloalkyl.

[0192] In some embodiments, Z is C(R6)(R7). In more specific embodiments, R6is H. In some embodiments, R7is -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl. In certain specific embodiments, R6and R7are both H.

[0193] In some other embodiments, Z is NR6. In certain embodiments, R6is H. In certain other embodiments, R6is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl.

[0194] In certain embodiments, Rlais H. In some embodiments, Rlais Ci-Ce alkyl (e.g., Rlais methyl). In some embodiments, Rlais halo or C3-C8 cycloalkyl.Attorney Docket No. 63243-710.601

[0195] In some embodiments, Rlbis H. In certain embodiments, Rlbis halo, Ci-Ce alkyl, or C3-C8 cycloalkyl.

[0196] In certain embodiments, R2ais Ci-Ce alkyl (e.g., R2ais tert-butyl or methyl). In some embodiments, R2ais C3-C8 cycloalkyl. In more specific embodiments, R2ais cyclopropyl. In some embodiments, the cyclopropyl is unsubstituted. In some embodiments, the cyclopropyl is substituted with at least one haloalkyl (e.g., trifluoromethyl). In certain more specific embodiments, R2ahas the following structure:•s'”

[0197] In some embodiments, R2bis H. In certain embodiments, R2bis halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl.

[0198] In certain specific embodiments, R3is Ci-Ce alkyl (e.g., R3is methyl).

[0199] In some embodiments, R3is aryl. For example, in some embodiments, R3is phenyl. In certain embodiments, the phenyl is substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy. In certain other embodiments, the phenyl is unsubstituted.

[0200] In some other embodiments, R3is 3-10 membered heterocyclyl. In more specific embodiments, R3is piperidinyl. In certain specific embodiments, the piperidinyl is substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy. In certain embodiments, R3has the following structure:

[0201] In some embodiments, R4is H. In more specific embodiments, R4is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl.

[0202] In some embodiments, the compound of Formula (IV) is administered to treat or prevent the symptom of biological aging. In some embodiments, the compound of Formula (IV) is administered to delay and / or slow the development of the symptom of biological aging.

[0203] In some embodiments, the compound of Formula (IV) is a modulator of theAttorney Docket No. 63243-710.601NLRP3 inflammasome. In some embodiments, the compound of Formula (IV) is an inhibitor of the NLRP3 inflammasome. In some embodiments, the compound of Formula (IV) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (IV) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (IV) inhibits the priming step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (IV) inhibits signaling downstream of members of the TLR (toll-like receptor) family, IL-1R (interleukin 1 receptor) family, and / or TNFR1 / 2 (tumor necrosis factor receptor 1 / 2). In some embodiments, the compound of Formula (IV) prevents the activation of NF-kB (nuclear factor kappa-beta). In some embodiments, the compound of Formula (IV) reduces the level of TNF-a, IL-6, or the components of the NLRP3 inflammasome (e.g., NLRP3, pro-IL-1β (pro-interleukin-1beta), pro-IL18 (pro-interleukin- 18)), or a combination thereof, in the subject. In some embodiments, the compound of Formula (IV) inhibits the assembly and activation step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (IV) inhibits the formation of a NLRP3 (protein)-NEK7 (protein) interaction. In some embodiments, the compound of Formula (IV) inhibits the formation of the ASC speck and the NLRP3 inflammasome. In some embodiments, the compound of Formula (IV) prevents caspase- 1 activation. In some embodiments, the compound of Formula (IV) inhibits the production of IL-1β. In some embodiments, the compound of Formula (IV) inhibits the production of IL-18. In some embodiments, the compound of Formula (IV) inhibits the cleavage of gasdermin D. In some embodiments, the compound of Formula (IV) prevents pyroptotic cell death.

[0204] In various different embodiments, the compound has one of the structures set forth in Table ID below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0205] Compounds in Table ID were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Attorney Docket No. 63243-710.601Table 1D: Representative compounds of Structure (IV)Compound Structure NameH Hl-(4-((lH-pyrrolo[2,3- Il 7 A Y 'N b]pyridin-4-yl)oxy)-2- IV- 1cy ^ r fluorophenyl)-3 -(3 -(tert-butyl)- 1 -phenyl - 1 H-pyrazol -5 -yl)urea Xx lHINH H ^Y^ l-(4-((lH-pyrrolo[2,3- N N| || I 1 b]pyridin-4-yl)oxy)-3- 'NIV-2 A I o (trifluoromethyl)phenyl)-3 -(3 - (tert-butyl)- 1 -phenyl- 1 H-CF3 / \ pyrazol-5-yl)urea € X 1H "H H / ^ / N N Nl-(4-((7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)-2- IV-3 0 U I Yfluorophenyl)-3 -(3 -(tert-butyl)- / V N / ' 1 -phenyl - 1 H-pyrazol -5 -yl)urea \ I JHHH H ^Y^ / ^. N N N1 -(3 -(tert-butyl)- 1 -phenyl- 1H- pyrazol-5-yl)-3-(2-fluoro-4-((3- IV-4 0 XI F I x?methyl-lH-pyrrolo[2,3- b]pyridin-4-yl)oxy)phenyl)urea iXlHINAttorney Docket No. 63243-710.601Compound Structure NameH H N N 1 -(3 -(tert-butyl)- 1 -phenyl- 1H- pyrazol-5-yl)-3-(2-fluoro-4-((2- IV-5 XI I XNmethyl-lH-pyrrolo[2,3- b]pyridin-4-yl)oxy)phenyl)ureaH "H H / ^ / N N N 1 -(3 -(tert-butyl)- 1 -phenyl- 1H- pyrazol-5-yl)-3-(4-((3-chloro- IV-6 O YClNlH-pyrrolo[2,3-b]pyridin-4- yl)oxy)-2-fluorophenyl)urea H "H H / / ^ / N N N| Y Y Y > 1 -(3 -(tert-butyl)- 1 -methyl - 1H- pyrazol-5-yl)-3-(4-((3-chloro- IV-7 ci A- lH-pyrrolo[2,3-b]pyridin-4- yl)oxy)-2-fluorophenyl)urea XXH’r H HA, N N N 1 -(3 -(tert-butyl)- 1 -phenyl- 1H- pyrazol-5-yl)-3-(4-((3-chloro- IV-8 JCX MNlH-pyrrolo[2,3-b]pyridin-4-CIA- yl)oxy)-2,6-difluorophenyl)urea XXN^|<HAttorney Docket No. 63243-710.601Compound Structure NameCNH H1 -(4-((3 -chloro- lH-pyrrolo[2, 3 - b]pyridin-4-yl)oxy)-2- IV-9 CI? ^F fluorophenyl)-3 -( 1 -(4- X cyanophenyl)-3-methyl-lH- pyrazol-5-yl)ureaHINiH H1 -(4-((3 -chloro- lH-pyrrolo[2, 3 - ( T n ¥ > b]pyridin-4-yl)oxy)-2- IV- 10fluorophenyl)-3 -(3 -methyl- 1 - Clphenyl - 1 H-py razol - 5 -y l)ureaHH H1 -(4-((3 -chloro- lH-pyrrolo[2, 3 - n n Y 'N b]pyridin-4-yl)oxy)-2- IV- 11Cl O^^F fluorophenyl)-3 -(3 -cyclopropyl - 1 -phenyl - 1 H-pyrazol -5 -yl)urea > N^AN> ■'HH H ^7^1 -(3 -(tert-butyl)- 1 -phenyl- 1H- pyrazol-5-yl)-3-(4-((3-chloro- IV- 12 Yj x?lH-pyrrolo[2,3-b]pyridin-4- Cl? \—k j\ F / \~ yl)oxy)-3-fluorophenyl)urea ( X 11HNAttorney Docket No. 63243-710.601Compound Structure NameH H N N 1 -(3 -(tert-butyl)- 1 -phenyl- 1 H- H T n 1. N pyrazol-5-yl)-3-(4-((5-chloro- IV- 137H-pyrrolo[2,3-d]pyrimidin-4- ci A~ yl)oxy)-2-fluorophenyl)urea \ L IJH "= / / =kZ X' AIZ 1 -(3 -(tert-butyl)- 1 -phenyl- 1H- pyrazol-5-yl)-3-(4-((3-chloro-2- IV- 14 IZ U. Y°methyl-lH-pyrrolo[2,3- b]pyridin-4-yl)oxy)-2- fluorophenyl)urea v tH HFx ^N^N^N 1 -(3 -(tert-butyl)- 1 -phenyl- 1H- pyrazol-5-yl)-3-(4-((3-chloro- IV- 15 U l ^NlH-pyrrolo[2,3-b]pyridin-4- ci A- yl)oxy)-2, 5 -difluorophenyl )urea CoHINoH H N N l-(4-((lH-pyrrolo[2,3- 1 1 Y Y > b]pyridin-4-yl)oxy)cyclohexyl)- IV- 163 -(3 -(tert-butyl)- 1 -phenyl- 1 H- pyrazol-5-yl)ureaCoHINAttorney Docket No. 63243-710.601Compound Structure NameoH H 1 -(4-((3 -chloro- lH-pyrrolo[2, 3 - N Nb]pyridin-4-yl)oxy)-2- IV- 17 \\ T n T > fluorophenyl)-3 -(1 -phenyl-3 -( 1 - ci 9F)<CF3(trifluoromethyl)cyclopropyl)- lH-pyrazol-5-yl)urea HHoH H 1 -(3 -(tert-butyl)- 1 -phenyl- 1 H- N Npyrazol-5-yl)-3-(4-((3- IV- 18 fl T v > cy cl opropyl - 1 H-pyrrolo[2, 3 - N / F Yb]pyridin-4-yl)oxy)-2- fluorophenyl)urea H "H H N N 1 -(3 -(tert-butyl)- 1 -phenyl- 1 H- \\ 7 Y Y. N pyrazol-5-yl)-3-(2-fluoro-4-((2- IV- 19O JJ. 0F methyl-3H-imidazo[4,5- N-x / V / \ b ] py ri di n-7 -y l)oxy )phenyl)urea Z1 JHNH H / \. N N N 1 -(3 -(tert-butyl)- 1 -phenyl- 1H- pyrazol-5-yl)-3-(4-((3-chloro- IV-20 XJ YNlH-pyrrolo[2,3-b]pyridin-4-Cl1 / r~ yl)oxy)cyclohexyl)urea YllHINAttorney Docket No. 63243-710.601Compound Structure NameH H 0 / 1 -(3 -(tert-butyl)- 1 -( 1 - / ^. N N N methylpiperidin-4-yl)-lH- IV-21 M > pyrazol-5-yl)-3-(4-((3-chloro- lH-pyrrolo[2,3-b]pyridin-4- ci A- yl)oxy)-2-fluorophenyl)urea XXH "H N-(3 -(tert-butyl)- 1 -phenyl- 1 H- pyrazol-5-yl)-2-(4-((3-chloro- IV-22 XX I XNlH-pyrrolo[2,3-b]pyridin-4- ci 1 ^FA- yl)oxy)-2- fluorophenyl)acetamide XXHN

[0206] Embodiments described herein provide a compound having Formula (V):A A N NH2R<N IIR2(V)or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Yis CHOH orNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with oneAttorney Docket No. 63243-710.601more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0207] In some embodiments of structure (V), A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Yis CHOH orNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected fromAttorney Docket No. 63243-710.601halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, Ci-Ce alkyl, Ci-Ce alkyl or Ci-Ce haloalkyl.

[0208] One embodiment provides a compound of structure (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Yis CHOH orNH;R1is H or Ci-Ce alkyl;R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionallyAttorney Docket No. 63243-710.601substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl.

[0209] In certain embodiment, R1is H. In other embodiments, R1is Ci-Ce alkyl, such as methyl.

[0210] In one embodiment, compounds of Structure (I) are provided, where R2is branched C4-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0211] In another embodiment, compounds of Structure (I) are provided, where R2is branched C4-C6 alkyl, C3-C4 cycloalkyl, or C3-C8 heterocyclyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0212] In specific embodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0213] In different embodiments, R2is methyl, isopropyl, 2-methylpropyl or allyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0214] In different embodiments, R2is methyl, ethyl, isopropyl, 2-methylpropyl or allyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0215] In other embodiments, R2is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or dioxidotetrahydrothiophenyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0216] In other embodiments, R2is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl or dioxidotetrahydrothiophenyl, each of which is optionally substitutedAttorney Docket No. 63243-710.601with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, and 3- to 8-membered heterocyclyl.

[0217] In other embodiments, R2is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl pyrrolidinyl, or dioxidotetrahydrothiophenyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, and 3- to 8-membered heterocyclyl.

[0218] In still more embodiments, R2is pyridinyl optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0219] In any of the foregoing embodiments, R2is unsubstituted. In other of the foregoing embodiments, R2is substituted with one or more of hydroxyl and fluoro.

[0220] In any of the foregoing embodiments, R2is unsubstituted. In other of the foregoing embodiments, R2is substituted with one or more of hydroxyl, methyl, methoxy, and fluoro.

[0221] In more specific embodiments, R2has one of the following structures:

[0222] In further specific embodiments, R2has one of the following structures:

[0223] In further specific embodiments, R2has one of the following structures:Attorney Docket No. 63243-710.601

[0224] In some embodiments, optionally R2is substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, and 3-8 membered heterocyclyl.

[0225] In some embodiments, R2does not have the following structures:+or

[0226] In any of the foregoing embodiments, R3is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl. For example, in certain embodiments, R3is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl. In further specific embodiments, R3is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 halocycloalkyl.

[0227] In further embodiments, R3is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 3, 4-oxadiazolyl, thiazolyl, isothiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl or 1, 2, 4-triazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0228] In certain embodiments, R3is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.Attorney Docket No. 63243-710.601

[0229] In certain embodiments, R3is thiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0230] In certain embodiments, R3is isothiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0231] In certain embodiments, R3is 1,2,4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0232] In certain embodiments, R3is 1,3,4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0233] In certain embodiments, R3is 1,3,4-oxadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0234] In certain embodiments, R3is 1,2,4-triazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0235] In further embodiments, R3is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl or C3-C8 halocycloalkyl, or combinations thereof.

[0236] In various embodiments, R3has one of the following structures:Attorney Docket No. 63243-710.601Attorney Docket No. 63243-710.601

[0239] In other embodiments, R4is H. In other embodiments, R4C1-C6alkyl, such as methyl.

[0240] In certain embodiments, Y is CHOH. In other embodiments, Y is NH.

[0241] In other embodiments, X is N. In more embodiments, X is CH.

[0242] In various embodiments, A is C6-C10aryl, C3-C10cycloalkyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6. It is understood that A is a divalent radical.

[0243] In certain embodiments, A is a divalent optionally substituted C6-10aryl. In certain embodiments, A is a divalent optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring. In certain embodiments, A is a divalent optionally substituted 3-Attorney Docket No. 63243-710.60110 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, A is a divalent optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0244] In certain embodiments, A is a divalent group selected from phenyl, pyridinyl, cyclohexyl, and cyclohexenyl; each of which is optionally substituted.

[0245] In other embodiments, A is phenyl. In different embodiments, A is saturated or unsaturated cyclohexyl. In more embodiments, A is pyridinyl.

[0246] In further embodiments, A is pyrimidinyl, which is optionally substituted.

[0247] In any of the foregoing embodiments, A is unsubstituted. In different of the foregoing embodiments, A is substituted with one or more R5. For example, in some embodiments R5is halo. In other embodiments, R5is fluoro. In other different embodiments, R5is chloro.

[0248] In some embodiments, R5is cyano. In some embodiments, R5is C1-C6alkyl. In certain embodiments, R5is methyl. In some embodiments, R5is C1-C6haloalkyl. In certain embodiments R5is difluoromethyl. In further embodiments, R5is C1-C6hydroxylalkyl. In certain embodiments R5is -CH2OH.

[0249] In certain embodiments, A is a divalent group selected from phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-Attorney Docket No. 63243-710.601quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3 -triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, and xanthenyl; each of which is optionally substituted.

[0250] In specific embodiments, A has one of the following structures:F Cl

[0251] In other specific embodiments, A has one of the following structures:F

[0252] In some embodiments, the compound of Formula (V) is administered to treat or prevent the symptom of biological aging. In some embodiments, the compound of Formula (V) is administered to delay and / or slow the development of the symptom of biological aging.

[0253] In some embodiments, the compound of Formula (V) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (V) is an inhibitor of the NLRP3 inflammasome. In some embodiments, the compound of Formula (V) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (V) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (V) inhibits the priming step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (V) inhibits signaling downstream of members of the TLR (toll-like receptor) family, IL-1R (interleukin 1 receptor) family, and / or TNFR1 / 2 (tumor necrosis factor receptor 1 / 2). In some embodiments, the compound of Formula (V) prevents the activation of NF-kB (nuclear factor kappa-beta). In some embodiments, the compound of Formula (V) reduces the level of TNF-Attorney Docket No. 63243-710.601a, IL-6, or the components of the NLRP3 inflammasome (e.g., NLRP3, pro-IL-1β (pro-interleukin-1beta), pro-IL18 (pro-interleukin- 18)), or a combination thereof, in the subject. In some embodiments, the compound of Formula (V) inhibits the assembly and activation step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (V) inhibits the formation of a NLRP3 (protein)-NEK7 (protein) interaction. In some embodiments, the * / =compound of Formula> z z / — (V) inhibits the formation of the ASC speck and the NLRP3 / / \ i \ < > M -inflammasome. In some embodiments, the compound of Formula (V) prevents caspase- 1 activation. In some embodime / znts, the compound of Formula (V) inhibits the production of IL-1β. In some embodiments, the' c°om xzpound of Formula (V) inhibits the production of IL-18. In some embodiments, the compound of Formula (V) inhibits the cleavage of gasdermin D.f J oIn some embodiments, the compound of Formula (V) prevents pyroptotic cell death.

[0254] In various different embodiments, the compound has one of the structures set forth in Table IE below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0255] Compounds in Table IE were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Table IE. Representative Compounds of Structure (V)No. Structure Name1 -(4-(4-amino- 1 -i sopropyl-17 / - pyrazol o[3,4- J]pyrimi din-3 - V-lyl)phenyl)-3 -(3 -(tert- butyl)isoxazol-5-yl)ureaAttorney Docket No. 63243-710.601No. Structure Name0Z) z / — / / \ \ I J,NXN-QNro- \ / 1 -(4-(4-amino- 1 -(oxetan-3 -yl)- rS U / -pyrazolo[3,4-J]pyrimidin-3- V-2 NH2\=^yl)phenyl)-3 -(3 -(tert-Nbutyl)isoxazol-5-yl)urea 11 A N\" o-^1 -(4-(4-amino- 1 -(oxetan-3 -yl)- U / -pyrazolo[3,4-J]pyrimidin-3- V-3yl)phenyl)-3 -(5 -(tert- butyl)isoxazol-3-yl)urea0r—(rAH1 -(4-(4-amino- 1 -(tetrahydro-27 / - NH2\=^ pyran-4-yl)-l / / -pyrazolo[3,4- V-4d]pyrimidin-3 -yl)phenyl)-3-(3 - |l J N ( / c / 7-butyl)isoxazol-5-yl)urea 0l-(4-(4-amino-l- (tetrahy drofuran-3 -yl)- 1H- V-5 NH2\=^ pyrazol o[3,4- d]pyrimi din-3 - yl)phenyl)-3 -(3 -(tert- 11 J N butyl)isoxazol-5-yl)urea&Attorney Docket No. 63243-710.601No. Structure Name1 -(4-(4-amino- 1 -i sopropyl- 1H- YAhpyrazolo[3,4-J]pyrimidin-3-yl)- V-6 NH22-chl orophenyl)-3 -(3 -(tert- butyl)isoxazol-5-yl)urea H X,NNrSH1 -(4-(4-amino- 1 -cyclobutyl- 1H- pyrazol o[3,4- d]pyrimi din-3 - V-7 NH2yl)phenyl)-3 -(3 -(tert- N" XX butyl)isoxazol-5-yl)urea 11 J,NN0r~(YAh1 -(4-(4-amino- 1 -cyclobutyl- 1H- pyrazolo[3,4-J]pyrimidin-3-yl)- V-8 NH22-fluorophenyl)-3 -(3 -(tert- NXX^ butyl)isoxazol-5-yl)urea H X 'N01 -(4-(4-amino- 1 -(2-hy droxy-2- methylpropyl)-l / / -pyrazolo[3,4- V-9 NH2rSHd]pyrimidin-3 -yl)phenyl)-3-(3 -N( / c / 7-butyl)isoxazol-5-yl)urea IL X >NN Nv X~OHAttorney Docket No. 63243-710.601No. Structure Name01 -(4-(4-amino- 1 -(2-hy droxy-2- YAhmethylpropyl)-177-pyrazolo[3,4- V-10 NH2d]pyrimidin-3-yl)-2- fluorophenyl)-3 -(3 -(tert- N J N butyl)isoxazol-5-yl)ureaN NV^YOH0 / - K A -UYAH1 -(4-(4-amino- 1 -i sopropyl- 1H- pyrazolo[3,4-d]pyrimidin-3-yl)- V-ll NH22-fluorophenyl)-3 -(3 -(tert- butyl)isoxazol-5-yl)urea |l J,NN°1 -(4-(4-amino- 1 -(oxetan-3 -yl)- U / -pyrazolo[3,4-J]pyrimidin-3- V-12 NH2\=^yl)-2-fluorophenyl)-3 -(3 -(tert- NYY, butyl)isoxazol-5-yl)urea Il J 'NoFC / N^NYN1 -(4-(4-amino- 1 -cyclopropyl- U / -pyrazolo[3,4-J]pyrimidin-3- V-13 NH2\^ / yl)-2-fluorophenyl)-3 -(3 -(tert-NNT A, butyl)isoxazol-5-yl)urea H J NNEAttorney Docket No. 63243-710.601No. Structure Name) -z z / —. / / \ \ xM / — 71\1 -(4-(4-amino- 1 -( 1 -(oxetan-3 - yl)piperidin-4-yl)-l / 7- V-14 pyrazolo[3,4-J]pyrimidin-3-yl)-> Oz z 2-fluorophenyl)-3 -(3 -(tert- butyl)isoxazol-5-yl)urea j q0r— / ~HN-A jH,F\ J N--\_Nysh1 -(4-(4-amino- 1 -(4- NH2hydroxy cyclohexyl)- 1H- V-15 pyrazolo[3,4-d]pyrimidin-3-yl)- 11 A N 2-fluorophenyl)-3 -(3 -(tert- butyl)isoxazol-5-yl)ureaNOH° z ~~HN-N JjF\ V-A JNH^n o-N1 -(4-(4-amino- 1 -(3, 3 - oNH2\=^ difluorocyclobutyl)-! / / - V-16 pyrazolo[3,4-d]pyrimidin-3-yl)- 2-fluorophenyl)-3 -(3 -(tert- (I J,Nbutyl)isoxazol-5-yl)ureaAttorney Docket No. 63243-710.601No. Structure Name0ZZ / = / =\\) Z z> z z / — / / — / / / \ z \ iM< > M \ - / TlYAhl-(4-(4-amino-l-(pyridin-4-yl)- NH217 / -pyrazolo[3,4-J]pyrimidin-3- V-17 V 'zcnz— ^ yl)-2-fluorophenyl)-3 -(3 -(tert-N0'1 \1H X,N^O / butyl)isoxazol-5-yl)ureaX°° zz IZ( / J cj of lJs==:\ zz-N<^1 -(4-(4-amino- 1 -(1, 1 - dioxidotetrahydrothiophen-3-yl)- V-18 17 / -pyrazolo[3,4-J]pyrimidin-3- yl)-2-fluorophenyl)-3 -(3 -(tert- butyl)isoxazol-5-yl)urea0r-j / ~._ HN-AF\ 7N'''\-'ZN1 -(4-(4-amino- 1 -(tetrahydro-27 / - y$hpyran-3-yl)-LH-pyrazolo[3,4- NHV-192d]pyrimidin-3-yl)-2-NNXK. fluorophenyl)-3 -(3 -(tert- 11 J 'Nbutyl)isoxazol-5-yl)urea 0— / 1 -(4-(4-amino- 1 -cyclopropyl- 17 / -pyrazolo[3,4-J]pyrimidin-3- V-20yl)phenyl)-3 -(3 -(tert- butyl)isoxazol-5-yl)ureaAttorney Docket No. 63243-710.601No. Structure NameZ / =\) z z / —) / / Z\ i \ / — / / \ I \ > t M -p 1 -(4-(4-amino- 1 -cyclopropyl- - T / \ U / -pyrazolo[3,4-J]pyrimidin-3- V-21 yl)-2-fluorophenyl)-3 -(3 -(1- t f V"* (trifluoromethyl)cyclopropyl)isoAOT2 xazol-5-yl)urea ^° zzf j o\ CF3O / - O„ J WF\ / T," N 1 -(4-(4-amino- 1 -cyclopropyl- YAhU / -pyrazolo[3,4-J]pyrimidin-3- V-22 NH2yl)-2-fluorophenyl)-3 -(3 -(1,1,1- trifluoro-2-methylpropan-2- |l J N y 1 )i soxazol -5 -yl)urea b0r~- / ~1- HN-A / XF\ JNAr°H N1 -(4-(4-amino- 1 -(oxetan-3 -yl)- U / -pyrazolo[3,4-J]pyrimidin-3- V-23 NH2yl)-2-tluorophenyl)-3-(5-( / c / 7- butyl)i soxazol -3 -yl)urea 11 J,Nl-(4-(4-amino-l- (tetrahy drofuran-3 -yl)- 1 / 7- V-24 pyrazolo[3,4-d]pyrimidin-3-yl)- 2-fluorophenyl)-3 -(3 -(tert- butyl)i soxazol -5 -yl)ureaAttorney Docket No. 63243-710.601No. Structure Namez / =xZ / =) z z\ / —) / / z z\ i \ / — / / \ i \ 1 -(4-(4-amino- 1 -cyclopropyl-M\ - Tln / 1H-pyrazolo[3,4-d]pyrimidin-3-V-25 yl)-2-fluorophenyl)-3-(5-(1-z z(trifluoromethyl)cyclopropyl)iso ^O z IZ xazol-3-yl)urea ^° XZo owHN-X / f kF\ JNH N1 -(4-(l -allyl-4-amino- 1H- pyrazolo[3,4-d]pyrimidin-3-yl)-V-26 NH2\=^2-fluorophenyl)-3-(5-( / c / 7-NNT A. butyl)isoxazol-3-yl)urea II J 'N(\ F0F, 7 AX / N 1 -(4-(4-amino- 1 -cyclopropyl- 1H-pyrazolo[3,4-d]pyrimidin-3- V-27NH2\=yHyl)-2-fluorophenyl)-3-(3-(2- fluoropropan-2-yl)i soxazol -5 - N' N A. yl)ureaU A NNE1 -(4-(4-amino- 1 -methyl - 1H- pyrazolo[3,4-J]pyrimidin-3-yl)- V-282-chl orophenyl)-3 -(3 -(tert- butyl)i soxazol -5 -yl)ureaAttorney Docket No. 63243-710.601No. Structure Namezz / = / =v>) z z Z z / — / — / / / / \ i i \ 1 -(4-(4-amino- 1 -methyl -1H-M M— — T' \ / 71\ / pyrazolo[3,4-J]pyrimidin-3-yl)- V-292-fluorophenyl)-3 -(3 -(tert- butyl)isoxazol-5-yl)urea ^° IZJ 'o ^^^^AXX z z z / ^ '’HN" A.F\ J N" \1 -(4-(4-amino- 1 -cyclopropyl- ys 1H-pyrazolo[4,3-c]pyridin-3-yl)- V-30 NH2\==^h2-fluorophenyl)-3 -(3 -(tert- N T A butyl)isoxazol-5-yl)urea 11 J,NOr— / ~HN--A JT ^,J N-'K. N1 -(4-(4-amino- 1 -cyclopropyl- 1H-pyrazolo[4,3-c]pyridin-3- V-312rSNH \=^Hyl)phenyl)-3 -(3 -(tert- butyl)isoxazol-5-yl)urea |l J,N1 -(4-(4-amino- 1 -cyclopropyl- 1H-pyrazolo[3,4-d]pyrimidin-3- V-32 yl)-2-fluorophenyl)-3 -(3 -( 1 - methylcy clopropyl)i soxazol -5 - yl)ureaAttorney Docket No. 63243-710.601No. Structure Name? N-NYAHr 1 -(4-(4-amino- 1 -cyclopropyl- 1H-pyrazolo[3,4-d]pyrimidin-3- V-33 NH2yl)-2-fluorophenyl)-3 -(5 -(tert- 11 J 'Nbutyl)- 1,3,4-thiadiazol-2-yl)ureaNJ1 -(4-(4-amino- 1 -cyclopropyl-H1H-pyrazolo[3,4-d]pyrimidin-3- V-34 NH2yA yl)-2-fluorophenyl)-3-(4-( / c / 7- NH " S XA butyl)thiazol-2-yl)ureaNb0z ~1 -(4-(4-amino- 1 -cyclopropyl- yAh1H-pyrazolo[3,4-d]pyrimidin-3- V-35 NH2y=Y yl)-2-fluorophenyl)-3 -(3 -(tert- butyl)isothiazol-5-yl)urea H XNNJ? N-Nhr 1 -(4-(4-amino- 1 -cyclopropyl- NH 1H-pyrazolo[3,4-d]pyrimidin-3- V-362y=Yyl)-2-fluorophenyl)-3 -(5 -(tert- N yrbll J 'kNlbutyl)- 1, 3,4-oxadiazol-2-yl)ureaNb*Attorney Docket No. 63243-710.601No. Structure NamejF. T N-< X NYYh1 -(4-(4-amino- 1 -cyclopropyl- 1H-pyrazolo[3,4-d]pyrimidin-3- V-37 NH2yl)-2-fluorophenyl)-3 -(3 -(tert- N ILX XI 'N, butyl)-l,2,4-thiadiazol-5-yl)urea boF / / N— N X_. H / N^\ / / A \y4Vh n1 -(4-(4-amino- 1 -cyclopropyl- 1H-pyrazolo[3,4-d]pyrimidin-3- V-38 NH2XAyl)-2-fluorophenyl)-3 -( 1 -(tert- NXXMH XNbutyl)-1H-1,2,4-triazol-3-yl)urea b0 / CF3HNXF. j N-A^N1 -(4-(4-amino- 1 -cyclopropyl- yh1H-pyrazolo[3,4-d]pyrimidin-3- V-39 NH2yl)-2-fluorophenyl)-3 -(3 -N(trifluoromethyl)isoxazol-5- NXM II X 'Nyl)ureaN0 / —\ X X N1 -(4-(4-amino- 1 -cyclopropyl- U / -pyrazolo[3,4-J]pyrimidin-3- V-40NH2b yAAhyl)-2-fluorophenyl)-3 -(3 - (pentan-3-yl)isoxazol-5-yl)urea N H X XX 'MNbAttorney Docket No. 63243-710.601No. Structure NameZ0 / — / =\\ f=> Z z / —) ~Z Z / \ / I \— / . / / \ \ iMFJTA-VN- \ / n 1 -(4-(4-amino- 1 -cyclopropyl-M— T1 / \ YAH1H-pyrazolo[3,4-d]pyrimidin-3- V-41 NH2V^Z^^'7'z!t^ / z^ yl)-2-fluorophenyl)-3 -(3 - ^OZZV''i'isopropylisoxazol-5-yl)urea IL J N ^ X°o IZIZNI \J '1 -(4-(4-amino- 1 -cyclopropyl- U / -pyrazolo[3,4-J]pyrimidin-3- V-42yl)-2-fluorophenyl)-3 -(3 - ethylisoxazol-5-yl)urea1 -(4-(4-amino- 1 -cyclopropyl- U / -pyrazolo[3,4-J]pyrimidin-3- V-43yl)-2-fluorophenyl)-3 -(3 -(sec- butyl)i soxazol -5 -yl)urea0 / —HN^C1 -(4-(4-amino- 1 -cyclopropyl- YAh1H-pyrazolo[3,4-d]pyrimidin-3- V-44 NH2yl)-2-fluorophenyl)-3 -(3 -( 1 - methylcyclobutyl)isoxazol-5- N' N A, yl)urean X 'NbAttorney Docket No. 63243-710.601No. Structure Nameo yCF3zZ / = / =\> z z) z z / — / — HN'A JH, / / / / \X I \ I 'l0> F\ J N" V, N- X / 1 -(4-(4-amino- 1 -cyclopropyl- YAH1H-pyrazolo[4,3-c]pyridin-3-yl)- V-45 NH22-fluorophenyl)-3 -(3-(l-Z^'Z z(trifluoromethyl)cyclopropyl)iso N T A ^^OO z / 11 JL N TZ TZ xazol-5-yl)ureaJ J ' '^\ / Z\o o / ? rACFco3 u1 -(4-(4-amino- 1 -(3 - YYhhydroxycyclobutyl)-1H- NH2\=^ pyrazolo[3,4-d]pyrimidin-3-yl)- V-462-fluorophenyl)-3 -(3-(l- u A N (trifluoromethyl)cyclopropyl)iso xazol-5-yl)ureaNOH1 -(5 -(4-amino- 1 -cy cl opropyl - 1H-pyrazolo[3,4-d]pyrimidin-3- V-47 yl)pyri din-2 -yl)-3 -(3 -(1- (trifluoromethyl)cyclopropyl)iso xazol-5-yl)urea1 -(4-(4-amino- 1 -cyclopropyl- 1H-pyrazolo[3,4-d]pyrimidin-3- V-48 yl)-2-methylphenyl)-3-(3-(l- (trifluoromethyl)cyclopropyl)iso xazol-5-yl)ureaAttorney Docket No. 63243-710.601No. Structure Namez / =\ j? r— ^CF3V zz / / / y IM— T1\ / 1 -(4-(4-amino- 1 -(1 - methylazetidin-3-yl)-1H- NH2ZSHpyrazolo[3,4-d]pyrimidin-3-yl)- V-49 jzki- 2-fluorophenyl)-3 -(3-(l- N XrX,Il J 'N > OIZ(trifluoromethyl)cyclopropyl)iso xazol-5-yl)urea° / A'y z\oz0 y ~~CF31 -(4-(4-amino- 1 -cyclopropyl- 1H-pyrazolo[3,4-d]pyrimidin-3- V-50 NH2y Vbshyl)-2,5-difluorophenyl)-3-(3-(l- 1 J F (trifluoromethyl)cyclopropyl)iso IL XNxazol-5-yl)ureab0 __XCF3HNX X N 1 -(4-(4-amino- 1 -cyclopropyl- HO-N / N^0, N1H-pyrazolo[3,4-d]pyrimidin-3- yl)-2-(hydroxymethyl)phenyl)-3- V-51 NH2O yA (3-(l- (trifluoromethyl)cyclopropyl)iso ll J,Nxazol-5-yl)ureaN1 -(4-(4-amino- 1 -cyclopropyl- 1H-pyrazolo[3,4-d]pyrimidin-3- V-52 yl)-2-fluorophenyl)-3-(3-(2- cyanopropan-2-yl)isoxazol-5- yl)ureaAttorney Docket No. 63243-710.601No. Structure Namez / — / Vz / I \> Z z \ / / — - to / / \ \ i 1 -(4-(4-amino- 1 -cyclopropyl-M— T' / \ 1H-pyrazolo[3,4-d]pyrimidin-3- V-53 yl)-2-fluorophenyl)-3 -(3 - (hydroxymethyl)isoxazol-5- yl)ureaA^°c> zz TZZO / o / x'=:zxoI HN" \ / » o / N-'X u>N-A H 0 1 -(5 -(4-amino- 1 -cy cl opropyl - / / 7 1H-pyrazolo[4,3-c]pyridin-3- V-54 NH2\=^ yl)pyri din-2 -yl)-3 -(3 -(1- (trifluoromethyl)cyclopropyl)iso xazol-5-yl)urea L £ ZNk1-(4-(4-amino-1-(2-hydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- V-55fluorophenyl)-3 -(3-(l- (trifluoromethyl)cyclopropyl)iso xazol-5-yl)ureaAttorney Docket No. 63243-710.601No. Structure NameZ r -Z / V Zz / I \ \ / NJ 4 / =?~CF3\ 7 " V H G N 1 -(4-(4-amino- 1 -(2- hydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- V-56 NH2fluorophenyl)-3 -(5-(l- > '° (trifluoromethyl)cyclopropyl)iso L 1 ZNxazol-3-yl)ureao 11 \ -_ _\ / \^ z- OH ou1 -(4-(4-amino- 1 -(2- methoxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- V-57fluorophenyl)-3 -(3-(l- (trifluoromethyl)cyclopropyl)iso xazol-5-yl)urea0 ^CF.\ j " V GV-N H N 1 -(4-(4-amino- 1 -(2- methoxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- V-58 NH2fluorophenyl)-3 -(5-(l- (trifluoromethyl)cyclopropyl)iso k L,nxazol-3-yl)urea0-_Attorney Docket No. 63243-710.601No. Structure Name1 -(4-(4-amino- 1 -cyclopropyl- 1H-pyrazolo[3,4-d]pyrimidin-3- V-59 yl)-2-methylphenyl)-3-(5-(l- (trifluoromethyl)cyclopropyl)iso xazol-3-yl)urea cooJ \ FZ CF3VA H N 1 -(4-(4-amino- 1 -(3 - F£x °zxhydroxycyclobutyl)-1H- NH2\=^ pyrazolo[3,4-d]pyrimidin-3-yl)- V-60) CM ( 2-fluorophenyl)-3 -(5-(l-N / I \ IT N(trifluoromethyl)cyclopropyl)iso L £ zNz - ' / / \\ZZxazol-3-yl)ureaNN^OHO 5^CF3F, TAXIV--N H N 1 -(4-(4-amino- 1 -cyclopropyl- U / -pyrazolo[4,3-c]pyridin-3-yl)- r?V-61 NH2\=^ 2-fluorophenyl)-3 -(5-(l- (trifluoromethyl)cyclopropyl)iso xazol-3-yl)urea k J£ zNkAttorney Docket No. 63243-710.601No. Structure Name-z r—. / V / I \X / - to1 -(4-(4-amino- 1 -cyclopropyl- U / -pyrazolo[3,4-J]pyrimidin-3- V-62 yl)-2,5-difluorophenyl)-3-(5-(l- (trifluoromethyl)cyclopropyl)iso ^° TZxazol-3-yl)ureacoA O' / X oOo\Z^ o / ZI1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-(hydroxymethyl)phenyl)-3- V-63z- i (5-(l- \ / ~(trifluoromethyl)cyclopropyl)iso ) CM ( / I \ xazol-3-yl)urea / / \\z - 'ZZHN J-A / \ / N-A ^0N-A H N 1-(5-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-2-yl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)ureak 1 / N!>Attorney Docket No. 63243-710.601No. Structure Name1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(tert-butyl)-4-methylisoxazol-5-yl)ureamoz - \ / \—z - oo / 1-(4-(4-amino-1-(2-hydroxy-2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2- V-66T fluorophenyl)-3 -(3-(l- ) \M _ C (trifluoromethyl)cyclopropyl)iso / ( X \ CM ) L*" / X \ xazol-5-yl)urea\\Z / / z \ — '\Z - 'zzJ / =?~CF3\ j " V G 1-(4-(4-amino-1-(2-hydroxy-2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)ureaN N\<Y'OHAttorney Docket No. 63243-710.601No. Structure Name4 / £CFs\ 7 " V GH N 1 -(4-(4-amino- 1 -(1 - methylazetidin-3-yl)-1H- NH2pyrazolo[3,4-J]pyrimidin-3-yl)- V-682-fluorophenyl)-3 -(5-(l- N££ (trifluoromethyl)cyclopropyl)iso k L,nxazol-3-yl)urea\ / CF3CHNA / O\ / N^\ / N 1-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-(trifluoromethyl)cyclopropyl)isoxazol-5-yl)ureaL £ zN< NHj FCFS1-(4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)ureak £ zNNHAttorney Docket No. 63243-710.601No. Structure NameJ"CCF3HNA\ / N^\ / NyA H o1 -(4-(4-amino- 1 -(1 - methylpiperidin-4-yl)- 1 / 7- NH2pyrazolo[3,4-J]pyrimidin-3-yl)- V-712-fluorophenyl)-3 -(3-(l- k L / N(trifluoromethyl)cyclopropyl)iso xazol-5-yl)urea\CHN JA / / =^ \CF3\ / NA / OVA H N 1 -(4-(4-amino- 1 -(1 - F 7 methylpiperidin-4-yl)- 1 / 7- NH2\==^pyrazolo[3,4-J]pyrimidin-3-yl)- V-722-fluorophenyl)-3 -(5-(l- k L / N(trifluoromethyl)cyclopropyl)iso A-^N xazol-3-yl)urea\o y~~~cF3HN-'N II v':.F\ 1N^n"VA H oN1 -(4-(4-amino- 1 -(1 - methylpyrrolidin-3-yl)-l / 7- nNH pyrazolo[3,4-J]pyrimidin-3-yl)- V-7322-fluorophenyl)-3 -(3-(l- (trifluoromethyl)cyclopropyl)iso k JL / Nxazol-5-yl)urea\^NXAttorney Docket No. 63243-710.601No. Structure NameZ / =\> Z z— / Z / = / / \ iM— T' / \ 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-(difluoromethyl)phenyl)-3- V-74(3-(l- (trifluoromethyl)cyclopropyl)iso ^° xzxazol-5-yl)urea^ z\J ''\SZ: ZNo9 wFHN-A fl\ J N-"\_N 1 -(5 -(4-amino- 1 -cy cl opropyl - M H 0 U / -pyrazolo[3,4-J]pyrimidin-3- / Ny 1 ) - 3 -fluoropyridin-2-yl)-3 -(3- V-75 NH2(1-N(trifluoromethyl)cyclopropyl)iso (I A,Nxazol-5-yl)ureaN<1 1HN^\F\ / N J' x^~\. N 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-((dimethylamino)methyl)cyclopropyl)isoxazol-5-yl)urea1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-((3,3-difluoroazetidin-1-yl)methyl)isoxazol-5-yl)ureaAttorney Docket No. 63243-710.601No. Structure Namez / =Z> / =) Z z ~z z / — / —~ / / 7\\ \ i X \> z z / — / / M— I A1 / \ 1 -(4-(4-amino- 1 -cyclopropyl-M— \ T' / z v^^ U / -pyrazolo[3,4-J]pyrimidin-3- yl)-2-fluorophenyl)-3 -(3 -( 1 -(4- V-78z^^OO z z methylpiperazin- 1 - IZ IZ yl)cy clopropyl)i soxazol -5 - yl)ureaJ '?^ J / x z ' / ^\ zO0 0 z / 1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(2-(4-methylpiperazin-1-yl)propan-2-yl)isoxazol-5-yl)urea1-(4-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-3-(3-(1-hydroxy-2-methylpropan-2-yl)isoxazol-5-yl)urea

[0256] Embodiments described herein provide a compound having Formula (VI):Attorney Docket No. 63243-710.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:= represents a double or a single bond such that all valences are satisfied;A is an optionally substituted 5-6-membered heterocyclyl, an optionally substituted 6-membered aryl, or an optionally substituted 5-6-membered heteroaryl;Xis N or CR3;Y is C or N;W is CH or N;Z is CH or N;R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;R2is optionally substituted aryl or optionally substituted heteroaryl; andR3is hydrogen, halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.

[0257] In some embodiments, = represents a double bond. In some other embodiments, = represents a single bond.

[0258] In some embodiments, A is a 5-membered heterocyclyl. In certain embodiments, A is a 6-membered heterocyclyl. In some embodiments, A is a 6-membered heteroaryl. In certain embodiments, A is a 5-membered heteroaryl. In some embodiments, A is a 6-membered aryl.

[0259] In some embodiments, Y is N. In some embodiments, A is unsubstituted. In certain embodiments, A is substituted. In some embodiments, A is substituted with one or more substituents selected from the group consisting of halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.

[0260] In some embodiments, A is substituted with one or more substituents selected from the group consisting of halo, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, and optionally substituted Ci-CeAttorney Docket No. 63243-710.601haloalkoxy.

[0261] In some embodiments, A is substituted with one or more substituents selected from the group consisting of Ci-Ce alkyl, halo, and Ci-Ce haloalkyl. In some embodiments, A is substituted with one or more substituents selected from the group consisting of methyl, fluoro, and trifluoromethyl.

[0262] has the following structure:

[0263] In some embodiments, Z is CH. In certain embodiments, Z is N. In certain embodiments, X is N. In some embodiments, X is CR3. In some embodiments, R3is hydrogen or optionally substituted Ci-Ce alkyl. In certain embodiments, X is CH.

[0264] In some embodiments, R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In certain embodiments, R1is optionally substituted Ci-Ce alkyl. In some embodiments, R1is methyl, ethyl, or -propyl. In certain embodiments, R1is optionally substituted Ci-Ce alkenyl or optionally substituted Ci-Ce alkynyl. In some more specific embodiments, R1has the following structure:Attorney Docket No. 63243-710.601

[0265] In some embodiments, R1is optionally substituted Ci-Ce hydroxyalkyl. In certain embodiments, R1has one of the following structures:

[0266] In some embodiments, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some more specific embodiments, R1has one of the following structures:

[0267] In some embodiments, R1is optionally substituted 3-10 membered heterocyclyl. In certain embodiments, R1has the following structure:

[0268] In some embodiments, R1is optionally substituted 5-10 membered heteroaryl. In certain embodiments, R1is unsubstituted pyridinyl. In some embodiments, R1has one of the following structures:

[0269] In some embodiments, R1is optionally substituted Ci-Ce carboxyalkyl. In certain embodiments, R1has the following structure:Attorney Docket No. 63243-710.601

[0270] In some embodiments, R1is optionally substituted Ci-Ce alkoxyalkyl. In certain embodiments, R1has the following structure:i°\

[0271] In certain embodiments, R2is optionally substituted phenyl or optionally substituted 5-membered heteroaryl. In some embodiments, R2is optionally substituted phenyl. In certain embodiments, R2is optionally substituted 5-membered heteroaryl. In certain embodiments, R2is optionally substituted isoxazolyl or optionally substituted pyrazolyl. In some embodiments, R2is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted 5-10-membered heterocyclylalkyl, optionally substituted 5-10-membered heterocyclyloxy, and optionally substituted C6-C10 aryl.

[0272] In some embodiments, R2is optionally substituted with one or more substituents selected from the following structures:

[0273] In some embodiments, R2has one of the following structures:Attorney Docket No. 63243-710.601

[0274] In some embodiments, R2has one of the following structures:Attorney Docket No. 63243-710.601Attorney Docket No. 63243-710.601

[0275] In some embodiments, the compound of Formula (VI) is administered to treat or prevent the symptom of biological aging. In some embodiments, the compound of Formula (VI) is administered to delay and / or slow the development of the symptom of biological aging.

[0276] In some embodiments, the compound of Formula (VI) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) is an inhibitor of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (VI) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) inhibits the priming step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) inhibits signaling downstream of members of the TLR (toll-like receptor) family, IL-1R (interleukin 1 receptor) family, and / or TNFR1 / 2 (tumor necrosis factor receptor 1 / 2). In some embodiments, the compound of Formula (VI) prevents the activation of NF-kB (nuclear factor kappa-beta). In some embodiments, the compound of Formula (VI) reduces the level of TNF-a, IL-6, or the components of the NLRP3 inflammasome (e.g., NLRP3, pro-IL-1β (pro-interleukin-1beta), pro-IL18 (pro-interleukin- 18)), or a combination thereof, in the subject. In some embodiments, the compound of Formula (VI) inhibits the assembly and activation step of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) inhibits the formation of a NLRP3 (protein)-NEK7 (protein) interaction. In some embodiments, the compound of Formula (VI) inhibits the formation of the ASC speck and the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) prevents caspase- 1 activation. In some embodiments, the compound of Formula (VI) inhibits the production of IL-1β. In some embodiments, the compound of Formula (VI) inhibits the production of IL-18. In some embodiments, the compound of Formula (VI) inhibits the cleavage of gasdermin D. In some embodiments, the compound of Formula (VI) prevents pyroptotic cell death.

[0277] In various different embodiments, the compound has one of the structures set forth in Table IF below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0278] Compounds in Table IF were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Attorney Docket No. 63243-710.601Table IF: Representative compounds of Structure (VI)No. Structure Namel-(4-(4-amino-7-cyclopropyl- 7#-py rrol o [2, 3 -d] py rimi din- 5 - VI- 1 yl)naphthalen- 1 -y 1) - 3 -(3 -( 1 - (trifluoromethyl)cyclopropyl)i soxazol-5-yl)urea0cs o LL LL COoQ O' / N" V^ X / V^ZNr \H> ¥0^^ V X / Aozl-(5-(4-amino-7-cyclopropyl- jo rC / - ° 77 / -pyrrolo[2,3-t / ]pyrimidin-5- VI-2yl)quinolin-8-yl)-3 -(3 -(tert- ^^ ° ozxZIA °ZXbutyl)i soxazol -5 -yl)urea 1! / A^ z / A^N\ \ z \ / z \ / _ _JJ^^zZ W ^zZ£ £ z z= / = / l-(5-(4-amino-7-cyclopropyl- 77 / -pyrrolo[2,3-t / ]pyrimidin-5- VI-3 yl)quinolin-8 -y 1 ) - 3 -(3 -( 1 - (trifluoromethyl)cyclopropyl)i soxazol-5-yl)ureal-(5-(4-amino-7-cyclopropyl- 77 / -pyrrolo[2,3-t / ]pyrimidin-5- VI-4 yl)quinolin-8-yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure Name0r-V "H ° l-(5-(4-amino-7-cyclopropyl- 7#-py rrol o [2, 3 -d] py rimi din- 5 - VI-5 H2N^ yby 1 )i soquinolin-8-yl)-3 -(3 -(tert- N NA butyl)i soxazol -5 -yl)urea II I / L / NV^° TZ0HN'AH lbZ°'Nl-(5-(4-amino-7-cyclopropyl- A °^v 7Z / -pyrrolo[2,3-J]pyrimidin-5- VI-6 H2N o yl)isoquinolin-8-yl)-3-(3-(l- wmethylcy clopropyl)i soxazol -5 - yl)urea0 _ / ^CF3HN^\l-(5-(4-amino-7-cyclopropyl- V>"\ H O'N77 / -pyrrolo[2,3-t / ]pyrimidin-5- VI-7 H2N yl)isoquinolin-8-yl)-3-(3-(l- (trifluoromethyl)cyclopropyl)i 11 / L / soxazol-5-yl)ureakN^Nbl-(5-(4-amino-7-cyclopropyl- 77 / -pyrrolo[2,3-t / ]pyrimidin-5- VI-8 yl)isoquinolin-8-yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure NameO CF3l-(5-(4-amino-7-cyclopropyl- \ J / / 7H-pyrrolo[2,3-d]pyrimidin-5- VI-9 H2N^M yl)isoquinolin-8-yl)-3-(4-((4- methylpiperazin- 1 -yl)methyl)- LkN^ 2 N / 3 -(trifluoromethyl)phenyl)urea bCF03l-(5-(4-amin,N=VX H^7O o-7-cyclopropyl- \ / / ) \^N 77 / -pyrrolo[2,3-t / ]pyrimidin-5- VI- 10 y 1 )i soquinolin-8-yl)-3 -(4-(( 1 - H2NX^M / Xmethylpiperidin-4-yl)oxy)-3- ^XZ r A - —'' (trifluoromethyl)phenyl)urea L / L / p 1 zb - —kN^Nb ^OZIY yz. / ~l-(5-(4-amino-7-cyclopropyl- ( I ) z - / / V 77 / -pyrrolo[2,3-t / ]pyrimidin-5- ze z - yl)imidazo[ 1,2-a]pyridin-8-yl)- VI- 11 Z I= / b r i 3 -(3 -(tert-butyl)- 1 -phenyl- 1H- pyrazol-5-yl)urea 11 b / l-(5-(4-amino-7-cyclopropyl- 7. H-py rrol o [2, 3 -d] py rimi din- 5 - VI- 12 yl)imidazo[ 1,2-a]pyridin-8-yl)- 3 -(3 -(tert-butyl)- 1 -( / ?-tolyl)- UZ-pyrazol -5 -yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(5-(4-amino-7-cyclopropyl- 7#-py rrol o [2, 3 -d] py rimi din- 5 - yl)imidazo[ 1,2-a]pyridin-8-yl)- VI- 133 -(3 -(tert-butyl)- 1 -(4- chlorophenyl)-l / / -pyrazol-5- yl)ureal-(5-(4-amino-7-cyclopropyl- 7. H-py rrol o [2, 3 -d] py rimi din- 5 - VI- 14 yl)imidazo[ 1,2-a]pyridin-8- ^z \b / ^XZ r A- -' —' yl)-3-(3-methylisoxazol-5- yl)urea^ OZI0- bTzA xz^( I ) Z —1 ) ( z —£ l-(5-(4-amino-7-cyclopropyl- zC z-7 / / ^7YY z zh 07. H-py rrol o [2, 3 -d] py rimi din- 5 - H VI 1 z I= / z2T= / N yY- 5 yl)imidazo[ 1,2-a]pyridin-8- yl)-3-(3-ethylisoxazol-5- u A / yl)ureaN0—„NYNXNX? N l-(5-(4-amino-7-cyclopropyl- £YA H07. H-py rrol o [2, 3 -d] py rimi din- 5 - VI- 16 H2NNV=^ yl)imidazo[ 1,2-a]pyridin-8-yl)- 3 -(3 -i sopropyli soxazol -5 - u A / yl)ureabAttorney Docket No. 63243-710.601No. Structure Name0l-(5-(4-amino-7-cyclopropyl-H 07#-py rrol o [2, 3 -d] py rimi din- 5 - VI- 17 H2N yl)imidazo[ 1,2-a]pyridin-8-yl)- 3 -(3 -(tert-butyl)i soxazol-5 - 11 A / yl)ureaN0, N l-(5-(4-amino-7-cyclopropyl-h 077 / -pyrrolo[2,3-t / ]pyrimidin-5- yl)imidazo[ 1,2-a]pyridin-8- VI- 18 H2NNVJyl)-3-(3-(l- N'^T V L b methylcy clopropyl)i soxazol -5 - 11 A / yl)ureaN^ oZI1 ( )Z- — ~0^z. z— ■ HNX l-(5-(4-amino-7-cyclopropyl- N / N^_, Nz i= / 77 / -pyrrolo[2,3-t / ]pyrimidin-5-H 0yl)imidazo[ 1,2-a]pyridin-8- VI- 19 H2NNA yl)-3-(3-(l- N yA methylcyclobutyl)isoxazol-5- 11 A / yl)ureaNl-(5-(4-amino-7-cyclopropyl- 77 / -pyrrolo[2,3-t / ]pyrimidin-5- VI-20 yl)imidazo[ 1,2-a]pyridin-8- y 1 )-3 -(3 -(2-fluoropropan-2- yl)isoxazol-5-yl)ureaAttorney Docket No. 63243-710.601No. Structure Name\, CF3l-(5-(4-amino-7-cyclopropyl-H 07#-py rrol o [2, 3 -d] py rimi din- 5 - N / yl)imidazo[ 1,2-a]pyridin-8- VI-21 H2Ny 1 )- 3 -(3 -( 1, 1, 1 -trifluoro-2- methylpropan-2-yl)isoxazol-5- 11 A / yl)ureal-(5-(4-amino-7-cyclopropyl- co co 77 / -pyrrolo[2,3-t / ]pyrimidin-5- u u yl)imidazo[ 1,2-a]pyridin-8- VI-22 \O^ yl)-3-(3-(l- y^^ \ / kxzz\(trifluoromethyl)cyclopropyl)i L Lbbsoxazol-5-yl)urea ^ oxZI°ZI1 ) ( z -Y ^Z^x °ZI,z ( z —7 zl-(5-(4-amino-7-cyclopropyl- zt z z e z z— — I7 / F= / \F^7H-pyrrolo[2,3-d]pyrimidin-5- z z T I= / = / yl)imidazo[ 1,2-a]pyridin-8-yl)- VI-233-(3-(l- (trifluoromethyl)cyclobutyl)iso xazol-5-yl)ureal-(5-(4-amino-7-cyclopropyl- 77 / -pyrrolo[2,3-t / ]pyrimidin-5- VI-24 yl)imidazo[ 1,2-a]pyridin-8- yl)-3-(5-methylisoxazol-3- yl)ureaAttorney Docket No. 63243-710.601No. Structure Name0—HN^\ / kN JNAr°HNl-(5-(4-amino-7-cyclopropyl- 7Z / -pyrrolo[2,3-J]pyrimidin-5- VI-25 H2NNA yl)imidazo[ 1,2-a]pyridin-8- yl)-3-(5-ethylisoxazol-3- 11 A / yl)ureab0—HNlbl-(5-(4-amino-7-cyclopropyl-H N7Z / -pyrrolo[2,3-J]pyrimidin-5- VI-26 H2NNA yl)imidazo[ 1,2-a]pyridin-8- yl)-3-(5-isopropylisoxazol-3- N'zvrbI I J / yl)ureabo, / b~HN^ / k.XNX / N^\rO l-(5-(4-amino-7-cyclopropyl-H N7Z / -pyrrolo[2,3-J]pyrimidin-5- VI-27 H2NNA yl)imidazo[ 1,2-a]pyridin-8- yl)-3-(5-(tert-butyl)isoxazol-3- N'"'^r vu A / yl)ureab0HNb / kN / N^VO l-(5-(4-amino-7-cyclopropyl- QA HN7Z / -pyrrolo[2,3-J]pyrimidin-5- yl)imidazo[ 1,2-a]pyridin-8- VI-28 H2NnAyl)-3-(5-(l- methylcy clopropyl)i soxazol -3 - Li b / yl)ureaNAttorney Docket No. 63243-710.601No. Structure Name0b / 'HN^\ / k l-(5-(4-amino-7-cyclopropyl- / N^.rO7#-py rrol o [2, 3 -d] py rimi din- 5 -H Nyl)imidazo[ 1,2-a]pyridin-8- VI-29ZHF / =\ r2NNVyl)-3-(5-(l- ) Z Z / — / / methylcyclobutyl)isoxazol-3- II ) ( 1zA — / yl)urea b^° IZ \ F0HN-b / kN J N-'V J. O l-(5-(4-amino-7-cyclopropyl- A ° \yOAh N77 / -pyrrolo[2,3-t / ]pyrimidin-5- oVI-30 H2NN\J yl)imidazo[ 1,2-a]pyridin-8- uy 1 )- 3 -(5 -(2-fluoropropan-2- y 1 )i soxazol-3 -yl)urea u A / Nb\ / CF30HNlb l-(5-(4-amino-7-cyclopropyl- N JNAr°77 / -pyrrolo[2,3-t / ]pyrimidin-5- O" SH Nyl)imidazo[ 1,2-a]pyridin-8- VI-31 H2NNVJy 1 )- 3 -(5 -( 1, 1, 1 -trifluoro-2- methylpropan-2-yl)isoxazol-3- u A / yl)ureabl-(5-(4-amino-7-cyclopropyl- 77 / -pyrrolo[2,3-t / ]pyrimidin-5- yl)imidazo[ 1,2-a]pyridin-8- VI-32yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3 -yl)ureaAttorney Docket No. 63243-710.601No. Structure Name0 J / CF3HN^A / \ l-(5-(4-amino-7-cyclopropyl- H N 7H-pyrrolo[2,3-d]pyrimidin-5-yl)imidazo[1,2-a]pyridin-8-yl)-3-(5-(1-(trifluoromethyl)cyclobutyl)isoxazol-3-yl)ureaNHNEN / 0N'A X / / 3N^\ l-(5-(4-amino-7-cyclopropyl- 7#-py rrol o [2, 3 -d] py rimi din- 5 -HU yl)imidazo[ 1,2-a]pyridin-8- VI-34 H2N \y 1 ) - 3 -(4-((4-methylpiperazin- U A / l-yl)methyl)-3- (trifluoromethyl)phenyl)urea E0Al l-(5-(4-amino-7-cyclopropyl- \ X\ AN / H < \^N ) 7#-py rrol o [2, 3 -d] py rimi din- 5 - yl)imidazo[ 1,2-a]pyridin-8- VI-35 H2N \=X \ y 1 )- 3 -(4-((4-ethylpiperazin- 1 - N U' X A" A / yl)methyl)-3- (trifluoromethyl)phenyl)urea E CF30l-(5-(4-amino-7-cyclopropyl- O-A 7#-py rrol o [2, 3 -d] py rimi din- 5 - VI-36 H2NN\= / Hyl)imidazo[ 1,2-a]pyridin-8- y 1 ) - 3 -(3 -((4-methylpiperazin- N Li Y AA / l-yl)methyl)-5- (trifluoromethyl)phenyl)urea b0XF3HNA _X V0' _ _ l-(5-(4-amino-7-cyclopropyl- < H / ) 7#-py rrol o [2, 3 -d] py rimi din- 5 - ^-N / \--N yl)imidazo[ 1,2-a]pyridin-8- VI-37 H2NXyl)-3 -(4-(( 1 -methylpiperidin-4- N^E'-'A yl)oxy)-3- u JL / (trifluoromethyl)phenyl)ureaNEAttorney Docket No. 63243-710.601No. Structure Namel-(5-(4-amino-7-cyclopropyl- 7Z / -pyrrolo[2,3-J]pyrimidin-5- yl)imidazo[ 1,2-a]pyridin-8- VI-38H? / =\,H) / = Z z— / \ _ / / >\ \ Z z / - _ yl)-3-(4-((l-ethylpiperidin-4- / / \ \ yl)oxy)-3- (trifluoromethyl)phenyl)urea 1 / zA°:zA f l-(5-(4-amino-7-cyclopropyl- L v 7Z / -pyrrolo[2,3-J]pyrimidin-5- \w\ W yl)imidazo[ 1,2-a]pyridin-8- o / ^Z■ ^VI-39 yl)-3-(4-((4-(2- hydroxyethyl)piperazin- 1 - x yl)methyl)-3- (trifluoromethyl)phenyl)urea0O ’ l-(5-(4-amino-7-cyclopropyl- o AkO ' 7Z / -pyrrolo[2,3-J]pyrimidin-5- yl)imidazo[ 1,2-a]pyridin-8- VI-40 H2NVNUVN^ yl)-3-(4-((4-(2- methoxyethyl)piperazin- 1 - yl)methyl)-3-1(trifluoromethyl)phenyl)urea [>0o3l-(5-(4-amino-7-cyclopropyl- 7Z / -pyrrolo[2,3-J]pyrimidin-5- y-t H ) yl)imidazo[ 1,2-a]pyridin-8- VI-41 yl)-3-(4-((4-(2- fluoroethyl)piperazin- 1 - uX >< Fyl)methyl)-3-N N\ (trifluoromethyl)phenyl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(5-(4-amino-7-cyclopropyl- 7#-py rrol o [2, 3 -d] py rimi din- 5 - yl)-2-fluoroimidazo[ 1,2- VI-42 Z T m / a]pyridin-8-yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea0A3l-(5-(4-amino-7-cyclopropyl- F, NA TAh( / 7#-py rrol o [2, 3 -d] py rimi din- 5 - yl)-2-fluoroimidazo[ 1,2- VI-43 H2N y=v OxGJ a]pyridin-8-yl)-3-(4-((4- N' NA methylpiperazin- 1 -yl)methyl)- I! JL / 3 -(trifluoromethyl)phenyl)urea9HN' x / l-(5-(4-amino-7-cyclopropyl- ^"4 rv° 7#-py rrol o [2, 3 -d] py rimi din- 5 - yl)-2-methylimidazo[ 1,2- VI-44 H2NN. Va]pyridin-8-yl)-3-(5-(l- N' A^A (trifluoromethyl)cyclopropyl)i II A / soxazol-3-yl)urea bCF30HN-bN / N-AX Z< N \ l-(5-(4-amino-7-cyclopropyl- --A H I ) 7#-py rrol o [2, 3 -d] py rimi din- 5 - V-N / A-N yl)-2-methylimidazo[ 1,2- VI-45 H2N \^ / \a]pyridin-8-yl)-3-(4-((4- N^rb methylpiperazin- 1 -yl)methyl)- U JL / 3 -(trifluoromethyl)phenyl)ureabAttorney Docket No. 63243-710.601No. Structure Namel-(5-(4-amino-7-cyclopropyl- 7Z / -pyrrolo[2,3-J]pyrimidin-5- yi)-2- VI-46 (trifluoromethyl)imidazo[ 1,2- a]pyridin-8-yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea0 / =< L l-(5-(4-amino-7-cyclopropyl- F, C 7Z / -pyrrolo[2,3-J]pyrimidin-5- °VN,\\ I Nk Fl / m / M / x o— N yi)-2- VI-47 H2NX(trifluoromethyl)imidazo[ 1,2- a]pyridin-8-yl)-3-(4-((4- NbX > (bI! X / methylpiperazin- 1 -yl)methyl)- 3 -(trifluoromethyl)phenyl)urea bJ-CF3o YX Lz° l-(5-(4-amino-7-cyclopropyl- / M \ C / r zj z i — HN N NZ U I= / "7 H 77 / -pyrrolo[2,3-t / ]pyrimidin-5- LL? yl)-3 -methylimidazo[ 1,2- VI-48 < / =NH2N YN'X a]pyridin-8-yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i N'X^V V soxazol-3-yl)ureaU A / kN^NbCF3o riiT^N'^VHN^N-'V Uk l-(5-(4-amino-7-cyclopropyl- ■y H 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylimidazo[1,2- VI-49 ( / =2NH N a]pyridin-8-yl)-3-(4-((4- methylpiperazin- 1 -yl)methyl)- N'" YYU A / 3 -(trifluoromethyl)phenyl)ureabAttorney Docket No. 63243-710.601No. Structure Nameo yCF3HNA / N / NA\ 0 l-(5-(4-amino-7-cyclopropyl- < VAH N7Z / -pyrrolo[2,3-J]pyrimidin-5- V N yl)imidazo[l,2-a]pyrazin-8- VI-50 H2N \Ayl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i L A / soxazol-3-yl)urea0A3N l-(5-(4-amino-7-cyclopropyl- 7Z / -pyrrolo[2,3-J]pyrimidin-5- VNrN VNm2oxyl)imidazo[l,2-a]pyrazin-8- VI-51 H N y=vy 1 ) - 3 -(4-((4-methylpiperazin- yVo l-yl)methyl)-3- I! JL / o (trifluoromethyl)phenyl)urea ^ OZII ) ( o — l-(4-(4-amino-7-cyclopropyl- ( z z—77Z / -pyrrolo[2,3-J]pyrimidin-5- z I=J yl)-2,3-dihydrobenzofuran-7- VI-52yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureaCF3HN'A / (DxJ NA\ IJ N^N l-(4-(4-amino-7-cyclopropyl- 7Z / -pyrrolo[2,3-J]pyrimidin-5- c / AHyl)-2,3-dihydrobenzofuran-7- VI-53 H2N \A \y 1 ) - 3 -(4-((4-methylpiperazin- l-yl)methyl)-3- u A / (trifluoromethyl)phenyl)urea NAttorney Docket No. 63243-710.601No. Structure NameCF3oHlXlbO J JJ N^N l-(4-(4-amino-7-cyclopropyl- 7#-py rrol o [2, 3 -d] py rimi din- 5 - VI-54 H2N c / \=AXHO yl)-2,3-dihydrobenzofuran-7- y 1 )- 3 -(4-((4-ethylpiperazin- 1 - N u' vX yl)methyl)-3- A / (trifluoromethyl)phenyl)urea bl-(4-(4-amino-7-cyclopropyl- 77 / -pyrrolo[2,3-t / ]pyrimidin-5- yl)-2,3-dihydrobenzofuran-7- VI-55o yl)-3 -(4-(( 1 -methylpiperidin-4- yl)oxy)-3- v ox (trifluoromethyl)phenyl)ureaz O210 _bcF3HN^\ / \ l-(4-(4-amino-7-cyclopropyl- / Ck / N^VO 77 / -pyrrolo[2,3-t / ]pyrimidin-5- | ) ( o — bbh Nyl)-2-methyl-2,3- zC z—' ■VI-56 H2N b=^ dihydrobenzofuran-7-yl)-3-(5- z I=J(1- N U'X^V VA / (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea b0xF37X"-W n l-(4-(4-amino-7-cyclopropyl- 77 / -pyrrolo[2,3-t / ]pyrimidin-5- yl)-2-methyl-2,3- VI-57 H2N dihydrobenzofuran-7-yl)-3-(4- ((4-methylpiperazin- 1 - u A / yl)methyl)-3- (trifluoromethyl)phenyl)ureaAttorney Docket No. 63243-710.601No. Structure NameCF3oO H / NY A JJ / T0^ r^\ l-(4-(4-amino-7-cyclopropyl- YA H ) 7H-pyrrolo[2,3-d]pyrimidin-5-2\ — U / H N A yl)-2-methyl-2,3- VI-58 A \dihydrobenzofuran-7-yl)-3-(4- N NA ((l-methylpiperidin-4-yl)oxy)- I I A / 3 -(trifluoromethyl)phenyl)urea A9 JACF3HN"\ / k l-(4-(4-amino-7-cyclopropyl- \ / Oy JNAr° 77 / -pyrrolo[2,3-t / ]pyrimidin-5- Ay YAH Nyl)-2,2-dimethyl-2,3- VI-59 H2N y=A dihydrobenzofuran-7-yl)-3-(5- (1- NYA I I A. / (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea N CF30HNY\ O / NA Y JJ / AA N.^ l-(4-(4-amino-7-cyclopropyl- 'N 77 / -pyrrolo[2,3-t / ]pyrimidin-5- yl)-2,2-dimethyl-2,3- VI-60 H2N yyH\ dihydrobenzofuran-7-yl)-3-(4- ((4-methylpiperazin- 1 - N' / YY\u A / yl)methyl)-3- (trifluoromethyl)phenyl)ureaHNY0 / X3\ Ax J NAX JJ r^\ l-(4-(4-amino-7-cyclopropyl- A Y \ H ^ / ) 77 / -pyrrolo[2,3-t / ]pyrimidin-5- \ — II / yl)-2,2-dimethyl-2,3- VI-61 H2N \A \dihydrobenzofuran-7-yl)-3-(4- N" YY\ ((l-methylpiperidin-4-yl)oxy)- u A ) 3 -(trifluoromethyl)phenyl)ureaAttorney Docket No. 63243-710.601No. Structure Name07^X1 / X— A H N l-(4-(4-amino-7-cyclopropyl- 7#-py rrol o [2, 3 -d] py rimi din- 5 - VI-62 yl)benzofuran-7 -y 1 ) - 3 -(3 -(tert- butyl)- 1 -phenyl- lJ7-pyrazol-5- NAAu JL / yl)ureaN0o 7A- / Il-(4-(4-amino-7-cyclopropyl-h 0coH2N u 77 / -pyrrolo[2,3-t / ]pyrimidin-5- VI-63 y=vyl)benzofuran-7 -y 1 ) - 3 -(3 -(tert- N'^VA ^ \ / z\ butyl)i soxazol -5 -yl)urea II A / LbA °ZI / l-(4-(4-amino-7-cyclopropyl-,\? JA °Z < Z —zz I= / 7Z / -pyrrolo[2,3-J]pyrimidin-5- VI-64 yl)benzofuran-7-yl)-3 -(3 -( 1 - (trifluoromethyl)cyclopropyl)i soxazol-5-yl)ureap yCF3HN'X / k / Ox / N^VO l-(4-(4-amino-7-cyclopropyl- 7Z / -pyrrolo[2,3-J]pyrimidin-5- oAHVI-65 H2N yl)benzofuran-7-yl)-3 -(5 -( 1 - (trifluoromethyl)cyclopropyl)i N'>5VAI! A / soxazol-3-yl)ureaNAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-5-zI / = / \ KJ yl)benzofuran-7-yl)-3-(4-((4- > Z Z— / methylpiperazin- 1 -yl)methyl)- A H 3 -(trifluoromethyl)phenyl)urea ^° zz0xF3HN'A / / 7^°\ _ / NA # ) - \ l-(4-(4-amino-7-cyclopropyl- (\ y\h< / V— / / / \wV-N 7Z / -pyrrolo[2,3-t7]pyrimidin-5- VI-67 H2N N=A \ yl)benzofuran-7-yl)-3-(4-((l- methylpiperidin-4-yl)oxy)-3- N vAu A / (trifluoromethyl)phenyl)ureaN0 YCF3HN-A / \O / NA 0 l-(4-(4-amino-7-cyclopropyl- N VA H N 7Z / -pyrrolo[2,3-t7]pyrimidin-5- WJ / 7 yl)benzo[d]isoxazol-7-yl)-3- VI-68 H2N \=A(5-(l- (trifluoromethyl)cyclopropyl)i U JL / soxazol-3-yl)ureaN0A3.ojA-Cr ^, l-(4-(4-amino-7-cyclopropyl- N YAHI / 7Z / -pyrrolo[2,3-t7]pyrimidin-5- AJ 7 yl)benzo[d]isoxazol-7-yl)-3- VI-69 H2N yA(4-((4-methylpiperazin- 1 - N'^yAx yl)methyl)-3- U A / (trifluoromethyl)phenyl)ureaNAttorney Docket No. 63243-710.601No. Structure Name0X3HNYO / NA Y J / A°\ ) — _ _ \ 1-(4-(4-amino-7-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)benzo[d]isoxazol-7-yl)-3- VI-70 H2N (4-((1-methylpiperidin-4-ll Y / yl)oxy)-3- (trifluoromethyl)phenyl)ureaN NAp ycF3. OxH / NYNA / O k 1-(4-(4-amino-7-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)benzo[d]oxazol-7-yl)-3-(5- VI-71 H2N(1- (trifluoromethyl)cyclopropyl)i I I A / soxazol-3-yl)urea0Y1-(4-(4-amino-7-cyclopropyl-<\ YAh(? 7Z / -pyrrolo[2,3-J]pyrimidin-5- NY / yl)benzo[d]oxazol-7-yl)-3-(4- VI-72 H2NX((4-methylpiperazin- 1 - N'-'Y'A yl)methyl)-3- U / (trifluoromethyl)phenyl)ureaNCF3HNYn j / j r7 °\ r^A 1-(4-(4-amino-7-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-5- VI-73 H2N yl)benzo[d]oxazol-7-yl)-3-(4- ((1-methylpiperidin-4-yl)oxy)- L A / 3 -(trifluoromethyl)phenyl)ureaYAttorney Docket No. 63243-710.601No. Structure Name0o.-uVsV l-(7-(4-amino-7-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-5- N=< / VI-74 H2N yl)benzo[c][l,2,5]oxadiazol-4- yl)-3-(3-( / ert-butyl)isoxazol-5- yl)ureau JL / N01-(7-(4-amino-7-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)benzo[c][1,2,5]oxadiazol-4- VI-75 H2N yl)-3-(3-(1-methylcyclopropyl)isoxazol-5- LikA / yl)urea N^Nb0 / / ~~Cp3XNXH / NA l-(7-(4-amino-7-cyclopropyl- N.^TII0 M\ H ° 77 / -pyrrolo[2,3-t / ]pyrimidin-5- N=Z / yl)benzo[c][l,2,5]oxadiazol-4- VI-76 H2N \=Yyl)-3-(3-(l- N^'b-b. (trifluoromethyl)cyclopropyl)i J b / soxazol-5-yl)urea bO / ^CFal-(7-(4-amino-7-cyclopropyl- O HN77 / -pyrrolo[2,3-t / ]pyrimidin-5- N=Z / yl)benzo[c][l,2,5]oxadiazol-4- VI-77 H2Nyl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i U A / soxazol-3-yl)ureabAttorney Docket No. 63243-710.601No. Structure NameCF3° r=bNl-(7-(4-amino-7-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-5- 7 rshVNyl)benzo[c][l,2,5]oxadiazol-4- VI-78 H2Ny 1 ) - 3 -(4-((4-methylpiperazin- l-yl)methyl)-3- I I A / (trifluoromethyl)phenyl)urea bCF3ojj / HNA / . / / l-(7-(4-amino-7-cyclopropyl- / N^V / )o H ( 77 / -pyrrolo[2,3-t / ]pyrimidin-5- ' / A \ _o c NN=< / o \ yl)benzo[c][l,2,5]oxadiazol-4- VI-79 H2N y=^ yl)-3 -(4-(( 1 -methylpiperidin-4- \ VO- yl)oxy)-3- L A / (trifluoromethyl)phenyl)urea b b °ZIbzx,z^ J Z \ / 1 -(5-(4-amino- 1 -cyclopropyl-z_ / / V 1H-pyrrolo[3,2-c]pyridin-3- yl)imidazo[1,2-a]pyridin-8- VI-80yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea0A ’1 -(5-(4-amino- 1 -cyclopropyl- N. JJ'N4T'N'',U / -pyrrolo[3,2-c]pyridin-3- < yAH< / V-N / X— N yl)imidazo[ 1,2-a]pyridin-8- H2NNY \ VI-81y 1 ) - 3 -(4-((4-methylpiperazin- l-yl)methyl)-3- U JL / (trifluoromethyl)phenyl)ureaAttorney Docket No. 63243-710.601No. Structure Name0A 'HN-X _N / Jj ) - \ 1 -(5-(4-amino- 1 -cyclopropyl- ( YA H ) 1H-pyrrolo[3,2-c]pyridin-3- yl)imidazo[1,2-a]pyridin-8- VI-82 H2Nyl)-3 -(4-(( 1 -methylpiperidin-4- NZV4 yl)oxy)-3- I! JL / (trifluoromethyl)phenyl)urea1-(5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5- OOO C C C yl)imidazo[ 1,2-a]pyridin-8- VI-83 U O O yl)-3-(5-(l- \v\ v V Vooo--- (trifluoromethyl)cyclopropyl)i > r soxazol-3-yl)urea LA^^ o ozxzxV °ZITz x z?) ( 1 ) 1 ) ( ( I Z ZZ- - -y—x ~ x A^' l-(5-(4-amino-7-cyclobutyl- 7H-pyrrolo[2,3-d]pyrimidin-5- / \ CM (z. C z z 6 z Z Z—' — —z / r ■^ yl)imidazo[ 1,2-a]pyridin-8- VI-84 z z z T I I= / = / =J yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea1-(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)isoxazol-3-yl)urea VI-85a]pyridin-8-yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure Name1-(5-(4-amino-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)imidazo[1,2-a]pyridin-8-yl)- VI-86a]pyridin-8-yl)-3-(5-(l- ) Z z / — / / \ \ (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea WZ° x1-(5-(4-amino-7-(3-hydroxycyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5- VI-87 N\ W V V oOo— w- yl)imidazo[ 1,2-a]pyridin-8- Ez yl)-3-(5-(l- \Z(trifluoromethyl)cyclopropyl)i ^ O OZIsoxazol-3-yl)urea \ / v° °zxZ°JYf 11 wz,w-z^) ) ( ( 1 ) ( I I Z z Z - - — / / V vz <sZvz z ( z z ( Z —' —' —zZz z z I I I= / = / = / 3-(4-amino-5-(8-(3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)ureido)imidazo[1,2-a]pyridin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propanoic acid1-(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)isoxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure Name1 -(5 -(4-amino-7 -(oxetan-3 -yl)- 7#-py rrol o [2, 3 -d] py rimi din- 5 - yl)imidazo[ 1,2-a]pyridin-8- VI-90yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureaOooO C c c C 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)isoxazol-3-yl)urea ^Y °zY °i°XXY / r\°"Zs / N ) ( 1 ) ( IZ. Z - -Y / ~ Yz^^ / \ CM7 z z ze z Z ( z Z 6 Z< - —z— - / r^z z z z I I I I= / = / = / =J 1 -(5-(4-amino-7-(pyridin-4- yl)-7Z / -pyrrolo[2,3 - J]pyrimidin-5-yl)imidazo[ 1,2- VI-92a]pyridin-8-yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea1-(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)isoxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure NameHN^\ / \«N1-(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)isoxazol-3-yl)urea VI-94) z z— / - / / ^\\ \ r a]pyridin-8-yl)-3-(5-(l- L A / (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea 0 'z^°- xHZoH ^ / N / / \ yN \x° xCF3kNA\ 0 o 1-(5-(4-amino-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5- VI-95 yl)imidazo[ 1,2-a]pyridin-8- yl)-3-(5-(l- L A / (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea 0 \HN^\ / kNx / NA' 0l-(5-(4-amino-7-(l- mH N(methylsulfonyl)piperidin-4- H2NNVJyl)-7Z / -pyrrolo[2,3 - VI-96 N'^V V d]pyrimidin-5-yl)imidazo[ 1,2- 11 A / a]pyridin-8-yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea Q°^S1-(5-(4-amino-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)imidazo[1,2-a]pyridin-8- VI-97yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure Name0Al 1 -(5-(4-amino- 1 -cyclopropyl-.N..H'J Z N^ VN"\ U / -pyrazolo[3,4-d]pyrimidin-Hu 3-yl)imidazo[l,2-a]pyridin-8- VI-98z\ H??2N / = f=\ r r \A \) Z Z / —_ _ y 1 ) - 3 -(4-((4-methylpiperazin- > z z / -N / / / / \\ N \ \TA, l-yl)methyl)-3- (trifluoromethyl)phenyl)urea b 'Z l / zKiz^O ZEZ1 -(5-(4-amino- 1 -cyclopropyl- kk v v A" / O AT) / "n "n U / -pyrazolo[3,4-d]pyrimidin- \ \ wwO o c 3-yl)imidazo[l,2-a]pyridin-8- VI-99u y 1 )- 3 -(4-((4-ethylpiperazin- 1 - yl)methyl)-3- v Vo- (trifluoromethyl)phenyl)urea \Z^ °ZICF3HNX0X XX\^ 1 -(5-(4-amino- 1 -cyclopropyl-XNX / N\ J V z \ I —X! AzA^A / HA JJ Y^\ / U / -pyrazolo[3,4-d]pyrimidin- VN )3-yl)imidazo[l,2-a]pyridin-8- VI-?_( V _ / - H2N \Ax100 yl)-3 -(4-(( 1 -methylpiperidin-4- z I= / yl)oxy)-3-N{XN(trifluoromethyl)phenyl)urea b1-(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-1011-(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)isoxazol-3-yl)urea VI-102Attorney Docket No. 63243-710.601No. Structure Name1-(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-1030Y3HNYN / N'A J F ^\ 1 -(5-(4-amino- 1 -cyclopropyl- i YAH / ) U / -pyrazolo[4,3-c]pyridin-3- VI- A ) \_N yl)imidazo[ 1,2-a]pyridin-8-yl)- H2N \=^ ^z mo c= ~ / x104 u u 3 -(4-(( 1 -methylpiperidin-4- NAY yl)oxy)-3- H A 'N\vv V V mOo-- (trifluoromethyl)phenyl)urea AZ'YY ° °ZIZIAY AA z-"\ Y VYz^11 -(5-(4-amino- 1 -methyl- 1H- ff Y YA FzYz^ pyrazolo[3,4-d]pyrimidin-3- VI- YZY ) ( z - J Z \ / ^ yl)imidazo[ 1,2-a]pyridin-8- / \ CM ( ( z z z z — —105zz\Yyl)-3-( / M \ C Z z T I v y= / = z — 5-(l- / z Iz(trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureal-(5-(4-amino-l-(3,3- difluorocyclobutyl)- 1H- pyrazolo[3,4-d]pyrimidin-3- VI- yl)imidazo[ 1,2-a]pyridin-8- 106yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure Name1-(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)isoxazol-3-yl)urea VI-107^ %oTZ1 -(5-(4-amino- 1 -(but-3 -yn- 1 - ^A o yl)-l / / -pyrazolo[3,4- o cVI- u o o d]pyrimidin-3 -yl)imidazo[ 1,2- 108 o a]pyridin-8-yl)-3-(5-(l- v\\ V V Voo-^ (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea ^^ oZIY J 1 z^ VzZ — 1 -(5 -(4-amino- 1 -(4- / \ o> zc z ( z z z zi- —77-7hy droxy cyclohexyl)- 1H- z z z=J=J=J pyrazolo[3,4-d]pyrimidin-3- VI- yl)imidazo[ 1,2-a]pyridin-8- 109yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureal-(5-(4-amino-l- (tetrahy drofuran-3 -yl)- 1H- pyrazolo[3,4-d]pyrimidin-3- VI- yl)imidazo[ 1,2-a]pyridin-8- 110yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure Name1 -(5 -(4-amino- 1 -(tetrahy dro- 2Z / -pyran-4-yl)- 1 / 7- pyrazolo[3,4-d]pyrimidin-3- VI- yl)imidazo[ 1,2-a]pyridin-8- 111yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea1 -(5 -(4-amino- 1 -(tetrahy dro- o u u u 2Z / -pyran-3 -yl)- 1 / 7- pyrazolo[3,4-J]pyrimidin-3- VI- vV\ V V VOOo-'- ’yl)imidazo[ 1,2-a]pyridin-8- 112 (T nzo yl)-3-(5-(l- _Z(trifluoromethyl)cyclopropyl)i ^^ o OIoZ=5 °ZIZIO- ' " soxazol-3-yl)urea )fl z n z r g-°) 1 ) ( I ( ZZ- - — ~I ( ( (Z. z z z z z zV z —- —z—zz / r ■^z z z z I I i I= / =J= / =J1 -(5-(4-amino- 1 -(1, 1 - di oxidotetrahydrothi ophen-3 - yl)-l / / -pyrazolo[3,4- VI- J]pyrimidin-3 -yl)imidazo[ 1,2- 113a]pyridin-8-yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea1 -(5 -(4-amino- 1 -(azeti din-3 - yl)-l / / -pyrazolo[3,4- VI- J]pyrimidin-3 -yl)imidazo[ 1,2- 114 a]pyridin-8-yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(5-(4-amino-l-(l- methylazeti din-3 -yl)- 1H- pyrazolo[3,4-J]pyrimidin-3- VI- yl)imidazo[ 1,2-a]pyridin-8- 1ZZ?? / =5 / =\ r1 \ r Z Z>> Z Z / - / — / / / / N^\ y \ r>zyl)-3-(5-(l- 1 / — \ (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea < JzA Vi^O>X^°°z x zzzJ'\\ / ° °y \x o cO o 1 -(5-(4-amino- 1 -(piperi din-3 - o oGJ GJ yl)-l / / -pyrazolo[3,4- VI- W v\oo^ J]pyrimidin-3 -yl)imidazo[ 1,2- 116 O a]pyridin-8-yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i W! soxazol-3-yl)urea X)I / * 'z) ( ) ( I Z Z - - (ZC z z z —z— / / ■^z z I I= / = / l-(5-(4-amino-l-(l- methylpiperi din-3 -yl)- 1H- pyrazolo[3,4-J]pyrimidin-3- VI- yl)imidazo[ 1,2-a]pyridin-8- 117yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)urea1 -(5 -(4-amino- 1 -( 1 -(oxetan-3 - yl)piperidin-4-yl)-l / 7- pyrazolo[3,4-J]pyrimidin-3- VI- yl)imidazo[ 1,2-a]pyridin-8- 118yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure Name0l-(5-(4-amino-7-cyclopropyl-h 07#-py rrol o [2, 3 -d] py rimi din- 5 - VI-z / = / \ 7 z119 > z / — yl)imidazo[ 1,2-a]pyridin-8- / / X"\ > NHI r2oM— / \ yl)-3 -(3 -cyclopropylisoxazol- z. _,r5-yl)ureaI I A / b bo TZ0HNb / \\ co l-(5-(4-amino-7-cyclopropyl- £VVh noN / 7#-py rrol o [2, 3 -d] py rimi din- 5 - VI- NH2y= yl)imidazo[ 1,2-a]pyridin-8- 120 ^^Zzy^ ^ yl)-3-(5-cyclopropylisoxazol- N^Vl11 A / 3-yl)ureaNl-(4-(4-amino-7-cyclopropyl- 7Z / -pyrrolo[2,3-J]pyrimidin-5- VI- yl)-2-methyl-2,3- 121 dihydrobenzofuran-7-yl)-3-(4- (( 1 -ethylpiperi din-4-yl)oxy)-3 - (trifluoromethyl)phenyl)urea0 _^bcF3HN'N / \ l-(4-(4-amino-7-cyclobutyl- \ / O. / N^rO7#-py rrol o [2, 3 -d] py rimi din- 5 - \ yAh Nyl)-2,2-dimethyl-2,3- VI- dihydrobenzofuran-7-yl)-3-(5- 122(1- N'^V Vu A / (trifluoromethyl)cyclopropyl)i soxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure Namel-(4-(4-amino-7-cyclopropyl- 7Z / -pyrrolo[2,3-<7]pyrimidin-5- VI- \z yl)-2,2-dimethyl-2,3- 123 > Z J z z / — / / A\ r T \ dihydrobenzofuran-7-yl)-3-(4- ®M / \ — (( 1 -ethylpiperi din-4-yl)oxy)-3 - A^ / ZZ^ _ _ ^ (trifluoromethyl)phenyl)ureaCF3O zXHNY / C> J AA Jo / )^\i YA H \ 00 l-(4-(4-amino-7-cyclopropyl- )tjJ 7 o V^N 7Z / -pyrrolo[2,3-<7]pyrimidin-5- VI- NH yl 1242)benzofuran-7-yl)-3-(4-((l- zz^^ ^ ethylpiperidin-4-yl)oxy)-3- N NA I I A / (trifluoromethyl)phenyl)ureaCF3o ^7J / / / X-C)OK / / N l-(4-(4-amino-7-cyclopropyl-N_ V / / A NH\ J 7Z / -pyrrolo[2,3-<7]pyrimidin-5- VI- yl)benzo[d]isoxazol-7-yl)-3- 125 (4-((l -ethylpiperi din-4- N' XYS. yl)oxy)-3- L A / (trifluoromethyl)phenyl)urea h0 $-CF3HN^A / \ l-(5-(4-amino-7-methyl-7J7- / Nx / N^\rO pyrrolo[2,3-d]pyrimidin-5- VI- £VA HNyl)imidazo[ 1,2-a]pyridin-8- N / 126 NH2yl)-3-(5-(l- (trifluoromethyl)cyclopropyl)i N" X-YL A / soxazol-3-yl)ureaAttorney Docket No. 63243-710.601No. Structure NameCF30l-(5-(4-amino-7-methyl-7J7- N / N^ pyrrolo[2,3-d]pyrimidin-5- VI- H VN'N yl)imidazo[ 1,2-a]pyridin-8- 7 \127 NH2y 1 ) - 3 -(4-((4-methylpiperazin- l-yl)methyl)-3- (trifluoromethyl)phenyl)urea 11 A / CF30<01 -(5 -(4-amino-7-i sopropyl-777- N jA'CTnpyrrolo[2,3-d]pyrimidin-5- LVAHVN'VI- N / \ yl)imidazo[ 1,2-a]pyridin-8- 128 NH2y 1 ) - 3 -(4-((4-methylpiperazin- l-yl)methyl)-3- co \II A / (trifluoromethyl)phenyl)urea ) kZI^ OzY A71 *" l-(5-(4-amino-7-cyclobutyl- ( )Z. I CM - • 7#-py rrol o [2, 3 -d] py rimi din- 5 - VI- 6 z z— yl)imidazo[ 1,2-a]pyridin-8- 129 Z= / y 1 ) - 3 -(4-((4-methylpiperazin- l-yl)methyl)-3- (trifluoromethyl)phenyl)urea CF30<0l-(5-(4-amino-7-(2- LVA H hydroxyethyl)-77 / -pyrrolo[2,3- ^-N / \VI- NH2J]pyrimidin-5-yl)imidazo[ 1,2- 130 a]pyridin-8-yl)-3-(4-((4- methylpiperazin- 1 -yl)methyl)- U A / 3 -(trifluoromethyl)phenyl)ureaOHAttorney Docket No. 63243-710.601No. Structure NameCF301 -(5 -(4-amino-7-(2-hy droxy-2- methylpropyl)-7Z / -pyrrolo[2,3- VI- N / J]pyrimidin-5-yl)imidazo[ 1,2- NH2y^ \131 a]pyridin-8-yl)-3-(4-((4- methylpiperazin- 1 -yl)methyl)- 11 A / 3 -(trifluoromethyl)phenyl)ureaN Nv ^yoHCF3°. NjAtTn l-(5-(4-amino-7-(3- tVAHVN' hydroxycyclobutyl)-77 / - pyrrolo[2,3-d]pyrimidin-5- VI- NH2y^ \ co yl)imidazo[ 1,2-a]pyridin-8- 132 N^AA y 1 ) - 3 -(4-((4-methylpiperazin- I I A / l-yl)methyl)-3- ZI (trifluoromethyl)phenyl)urea 0 °OHf kz? AA>-' YrCF3ze z A0AA- z= / £AAHVN' l-(5-(4-amino-7-(piperidin-4- yl)-7Z / -pyrrolo[2,3 - VI- NH2y^ d]pyrimidin-5-yl)imidazo[ 1,2- 133 N'^vy a]pyridin-8-yl)-3-(4-((4- II A / methylpiperazin- 1 -yl)methyl)-N N\ 3 -(trifluoromethyl)phenyl)urea Hl-(5-(4-amino-7-(l- methylpiperidin-4-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-5- VI- yl)imidazo[ 1,2-a]pyridin-8- 134y 1 ) - 3 -(4-((4-methylpiperazin- l-yl)methyl)-3- (trifluoromethyl)phenyl)ureaAttorney Docket No. 63243-710.601No. Structure Name1 -(5 -(4-amino-7-i sopropy 1 -7 / 7- pyrrolo[2,3-J]pyrimidin-5- VI- yl)imidazo[ 1,2-a]pyri di n-8- 135 yl)-3 -(4-(( 1 -methylpiperidin-4- 44 44 yl)oxy)-3- (trifluoromethyl)phenyl)urea 4oIZ1 -(5 -(4-amino-7-i sopropy 1 -7 / / - o ^zz~~ pyrrolo[2,3-J]pyrimidin-5- VI- yl)imidazo[ 1,2-a]pyridin-8- 136 yl)-3-(4-((l-ethylpiperidin-4- oco \zyl)oxy)-3- (trifluoromethyl)phenyl)ureaZI CF30 JTX / "N / J \ZVV / A l-(5-(4-amino-7-cyclobutyl- ) ( CM Z I - I 7#-py rrol o [2, 3 -d] py rimi din- 5 - VI- z z— N / yl)imidazo[ 1,2-a]pyridin-8- 137 4= / NH27 yl)-3-(4-((l-ethylpiperidin-4- yl)oxy)-3- u 4 / (trifluoromethyl)phenyl)ureaPharmaceutical Compositions

[0279] In one aspect, compounds provided herein are formulated into pharmaceutical compositions that are useful in a variety of applications including, but not limited to, therapeutic methods, such as the treatment or prevention of the symptom of biological aging.

[0280] In some aspects, treatment of a symptom of biological aging increases the healthspan of a patient. In some aspects, treatment of a symptom of biological aging increases the longevity of a patient. Healthspan is the length of time a patient is healthy. Healthspan may be measured as the length of time a patient is free of a chronic disease. Healthspan may be measured as the length of time a patient is free of a terminal disease. Healthspan may be measured as the length of time a patient is healthy, as measured by survey. The methods of use may be in vitro, ex vivo, or in vivo methods. In various embodiments, the pharmaceuticalAttorney Docket No. 63243-710.601compositions are formulated for delivery via oral administration.

[0281] The pharmaceutical compositions may contain any pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body. For example, the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of the formulation. It must also be suitable for use in contact with any tissues or organs with which it may come in contact, meaning that does not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.

[0282] In some embodiments, pharmaceutical compositions of the compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) are modulators of the NLRP3 inflammasome. In some embodiments, pharmaceutical compositions of the compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) inhibit NEK7 when administered to a patient or a biological sample.Methods of Treatment

[0283] Provided herein are methods of treating or preventing a symptom of biological aging in a subject in need thereof by administering to the subject a composition comprising a therapeutically effective amount of an inflammasome modulator. Provided herein are methods of treating or preventing the symptom of biological aging in a subject in need thereof by administering to the subject a composition comprising a therapeutically effective amount of a NEK7 inhibitor. Provided herein are methods of treating or preventing the symptom of biological aging in a subject in need thereof by administering to the subject a composition comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI).

[0284] A symptom of biological aging includes loss or reduction of immune function, loss or reduction of neurological function, and / or loss or reduction of muscle function.

[0285] A symptom of biological aging includes clonal hematopoiesis (CH), clonal hematopoiesis of indeterminate potential (CHIP), and / or clonal cytopenias of undetermined significance (CCUS). Other symptoms of biological aging include when the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variantAttorney Docket No. 63243-710.601allele fraction (VAF) of 2% or greater, in the absence of cytopenia. Other symptoms of biological aging include when the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 1% or greater, in the absence of cytopenia. Other symptoms of biological aging include when the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 5% or greater, in the absence of cytopenia. Non-limiting example genes are DNMT3A, TET2, ASXL1, TP53. In some aspects, the symptom of biological aging includes the presence of an acquired mutation to the DNMT3 A (DNA methyl transferase 3 alpha) gene. In some aspects, the symptom of biological aging includes the presence of an acquired mutation to the TET2 gene. In some aspects, the symptom of biological aging includes the presence of an acquired mutation to the ASXL1 gene. In some aspects, the symptom of biological aging includes the presence of an acquired mutation to the TP53 gene. In some aspects, the symptom of biological aging includes the presence of novel acquired mutations.

[0286] Another symptom of biological aging includes when the subject has somatic mutations in normal dividing cells. In example methods herein, the subject treated with a compound or composition herein has clonal hematopoiesis (CH). In example methods herein, the subject treated with a compound or composition herein has CH, CHIP, or CCUS. In example methods herein, the subject with CH has CHIP, CCUS, or a combination thereof. In some example methods herein, the subject treated with a compound or composition herein has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 2% or greater, in the absence of cytopenia. In some example methods herein, the subject treated with a compound or composition herein has somatic mutations in normal dividing cells.

[0287] A symptom of biological aging includes the loss or reduction of muscle function. Some example methods involve treating or preventing the symptom of biological aging by restoring muscle function in a subject. The treatment or prevention may include the restoration of glucose tolerance and insulin sensitivity. The treatment or prevention may include the reduction of protein catabolism. The treatment or prevention may include the reduction of muscle atrophy.

[0288] A symptom of biological aging includes the loss or reduction of immune function. Some example methods involve treating or preventing the symptom of biological aging by improving immune function in a subject. The treatment or prevention may include the reduction of SASP biomarkers in humans. The SASP biomarkers that are being reduced as aAttorney Docket No. 63243-710.601result of the treatment or prevention may include ILlb, IL6, and / or IL8. The treatment or prevention may include the reduction of CHIP allele frequency in a subject.

[0289] A symptom of biological aging includes the loss or reduction of neurological and / or cognitive function. Some example methods involve treating or preventing the symptom of biological aging by restoring neurological and / or cognitive function in a subject. The treatment or prevention may include the reduction of obesity-related chronic inflammation. The treatment or prevention may include the protection of the blood-brain barrier (BBB). The treatment or prevention may include the maintenance of a functional blood-brain barrier (BBB). The treatment or prevention may include the prevention of obesity-related cognitive decline. Restoring cognition includes improving cognition, e.g., cognition is improved as compared to prior the administering. The improvement may be to a level prior to aging in the subject. The treatment or prevention may include the reduction in age-related decrease in tissue elasticity.

[0290] The inflammasome modulator may be administered at a dose of about 0.5 mg to about 10 mg. For example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg. The dose may be administered at an interval of every day, 5 days on and 2 days off, three times a week (e.g., Monday, Wednesday, Friday), twice a week (e.g., Monday, Thursday), once a week, once every 2 weeks, or once a month. The inflammasome modulator may be administered at a dose of about 1 mg to about 4 mg daily for 5 days on and 2 days off. The inflammasome modulator may be administered at a dose of about 2 mg daily for 5 days on and 2 days off.

[0291] The NEK7 inhibitor may be administered at a dose of about 0.5 mg to about 10 mg. For example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg. The dose may be administered at an interval of every day, 5 days on and 2 days off, three times a week (e.g., Monday, Wednesday, Friday), twice a week (e.g., Monday, Thursday), once a week, once every 2 weeks, or once a month. The NEK7 inhibitor may be administered at a dose of about 1 mg to about 4 mg daily for 5 days on and 2 days off. The NEK7 inhibitor may be administered at a dose of about 2 mg daily for 5 days on and 2 days off.

[0292] The compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) may be administered at a dose of about 0.5 mg to about 10 mg. For example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg. The dose may be administered at an interval of every day, 5 days on and 2 days off, three times a week (e.g., Monday,Attorney Docket No. 63243-710.601Wednesday, Friday), twice a week (e.g., Monday, Thursday), once a week, once every 2 weeks, or once a month. The compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) may be administered at a dose of about 1 mg to about 4 mg daily for 5 days on and 2 days off. The compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) may be administered at a dose of about 2 mg daily for 5 days on and 2 days off.

[0293] The compound of Formula (I) may be administered at a dose of about 0.5 mg to about 10 mg. For example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg. The dose may be administered at an interval of every day, 5 days on and 2 days off, three times a week (e.g., Monday, Wednesday, Friday), twice a week (e.g., Monday, Thursday), once a week, once every 2 weeks, or once a month. The compound of Formula (I) may be administered at a dose of about 1 mg to about 4 mg daily for 5 days on and 2 days off. The compound of Formula (I) may be administered at a dose of about 2 mg daily for 5 days on and 2 days off.

[0294] Compound 10 may be administered at a dose of about 0.5 mg to about 10 mg. For example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg. The dose may be administered at an interval of every day, 5 days on and 2 days off, three times a week (e.g., Monday, Wednesday, Friday), twice a week (e.g., Monday, Thursday), once a week, once every 2 weeks, or once a month. Compound 10 may be administered at a dose of about 1 mg to about 4 mg daily for 5 days on and 2 days off. Compound 10 may be administered at a dose of about 2 mg daily for 5 days on and 2 days off.EXAMPLES

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

[0296] Examples and procedures for compounds 1 to 66 are herein incorporated by reference from US Patent No. 11,713,321.

[0297] Examples and procedures for compounds II-1 to II-67 are herein incorporated by reference from PCT publication WO2022226182A1.

[0298] Examples and procedures for compounds III- 1 to III- 118 are herein incorporatedAttorney Docket No. 63243-710.601by reference from PCT publication WO2022216680A1.

[0299] Examples and procedures for compounds IV- 1 to IV-22 are herein incorporated by reference from PCT publication WO2022159835A1.

[0300] Examples and procedures for compounds V-1 to V-80 are herein incorporated by reference from US Patent Application Publication US 2023 / 0203045 Al and PCT publication WO2021226547A2.

[0301] Examples and procedures for compounds VI-1 to VI-137 are herein incorporated by reference from PCT publication W02024059200A1.Example 1: Synthesis Scheme

[0302] The following General Reaction Schemes illustrate examples of compounds of Structure (I):or pharmaceutically acceptable salts, stereoisomers or prodrug thereof, wherein each of A, X, Y, R1, R2, R3, R4and R5are as defined herein.General Reaction Scheme 1

[0303] The following General Reaction Scheme, wherein X1and X2are independently halogens, and X, R1, R2, R3and A have the meanings described herein, illustrates examples of methods of making the amine Intermediate D:Attorney Docket No. 63243-710.6011. Cu(II)acetate or Reagent 2. Electrophilic R2or R2boronate Intermediate A Intermediate B1. Carbocyclic or heterocyclic boronic acid or dioxoborolane derivative / Pd; or2a. Carbocyclic or heterocyclicboronic acid derivative / PdIntermediate C 2b. Fe / NH4Cl Intermediate D

[0304] As shown in General Reaction Scheme 1, alkylation of the pyrimidine / pyridine pyrrole (i.e., Intermediate A) with a cycloalkyl boronate or an appropriate electrophile in presence of base affords the Intermediate B. This precursor is treated with ammonium hydroxide to form the pyrolopyrimidine / pyridine-4-amine derivative Intermediate C. The resulting Intermediate C can then be subject to palladium catalyzed arylation to form Intermediate D.General Reaction Scheme 2

[0305] The following General Reaction Scheme illustrates examples of methods of making the carbamate Intermediate E:H2N-R4pyridineIntermediate E

[0306] As shown in General Reaction Scheme 2, Intermediate E can be prepared the in presence of base by reaction of phenyl chloroformates and the indicated heteroaryl amine (an amine-substituted analogue of R4). General Reaction Scheme 2 depicts preparation of compounds wherein R5is H; however, compounds wherein R5is other than H can be prepare by similar methods by instilling R5after preparation of Intermediate E, or by using an appropriately substituted heteroaryl amine.General Reaction Scheme 3

[0307] The following General Reaction Scheme illustrates examples of methods of makingAttorney Docket No. 63243-710.601the compounds of Structure (I):HN'R4Base Compounds of Structure (I)THF Intermediate D Intermediate E

[0308] Intermediate D and Intermediate E are treated with a base (e.g., trimethylamine, DIPEA, DMAP, and the like) in THF to afford the compounds of Structure (I).General Reaction Scheme 4

[0309] The following General Reaction Scheme illustrates examples of methods of making the compounds of Structure (I):Ck pyridineIntermediate DbaseH2N — R4THFCompounds of Structure (I)

[0310] Intermediate D is reacted with the phenyl carb onochlori date shown under appropriate conditions to yield Intermediate E. Intermediate E is then coupled with the amine using a suitable base e.g., trimethylamine, DIPEA, DMAP, and the like) in THF to afford the compounds of Structure (I).

[0311] Any of the above reaction scheme can be modified at any step to add and / or modify a substituent may be added or modified as appropriate during any stage of the overall synthesis of desired compounds.Cl

[0312] An intermediate Al (4-chloro-5-iodo-7h-pyrrolo[2,3-d]pyrimidineHwas prepared as follows: N-iodosuccinimide (1.465 g, 6.51 mmol) was added to a stirredAttorney Docket No. 63243-710.601solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.000 g, 6.51 mmol) in DMF (10 mL) at 0 °C and the resulting mixture was stirred at 25 °C for 12 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was poured into ice cold water (100 mL) and stirred at 25 °C for 15 min. The resulting solid was filtered, washed with water (2 x 25 mL), and dried to afford the title compound as an off-white solid (1.7 g, 93% yield). 1H NMR (400 MHz, DMSO-d6) 6 = 12.96 (bs, 1H), 8.60 (s, 1H), 7.95 (d, J = 2.40 Hz, 1H); LCMS: 279.9 [M+H],

[0313] An intermediate B 1 (4-chloro-7-cyclopropyl-5-iodo-7h-pyrrolo[2,3-d]pyrimidine C! |^) 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 oxygen atmosphere for 12 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of celite which was then rinsed with DCM (2 x 20 mL). The combined filtrates were washed with water (20 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude material which was purified by flash chromatography (silica gel 230-400 mesh, eluting with 15% EtOAc in petroleum ether), affording the title compound as an off-white solid (0.7 g, 61% yield). 1H NMR (400 MHz, DMSO-d6) 8 = 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],

[0314] An intermediate Cl (7-cyclopropyl-5-iodo-7h-pyrrolo[2,3-d]pyrimidin-4-amine NH2|t^) was prepared as follows: A mixture of 4-chloro-7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Bl, 1.00 g, 2.191 mmol) and ammonium hydroxide (25% in water, 5 mL) was subjected to microwave irradiation at 150 °C for 1 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to afford the title compound as an off-white solid (0.75 g, 80% yield). 1H NMR (400 MHz,Attorney Docket No. 63243-710.601DMS0-d6) 6 = 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],An intermediate DI (5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7h-pyrrolo[2,3-d]pyrimidin-4-aminewas prepared as follows: A mixture of 7-cyclopropyl-5-iodo-7H- pyrrolo[2,3-d]pyrimidin-4-amine (Cl, 0.160 g, 0.533 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline (0.190 g, 0.800 mmol), and K2CO3 (0.221 g, 1.599 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was purged with N2 for 10 min. Pd(PPh3)4 (0.062 g, 0.053 mmol) was then added and the reaction mixture was stirred at 100 °C for 12 h.Following completion of the reaction (as indicated by TLC), the mixture was filtered through a pad celite which was then rinsed with EtOAc (2 x 10 mL). The combined filtrates were concentrated under reduced pressure to yield crude material which was purified by flash chromatography (silica gel 230-400 mesh, eluting with 3% MeOH in DCM), affording the title compound as a yellow solid (0.110 g, 73% yield). 1H NMR (400 MHz, DMSO-d6) 6 = 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],was prepared following the general procedure for urea formation starting from 5-(4-amino-3- fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (DI, 0.10 g, 0.35 mmol) and phenyl (5-(l-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (0.11 g, 0.35 mmolAttorney Docket No. 63243-710.601

[0316] Specifically, triethylamine (2.0 eq.) was added to a mixture of DI (1.0 eq.) and El (1.0 eq.) in THF (10 Vol.) and the resulting mixture was stirred at 60 °C for 12 h in a sealed tube. Following completion of the reaction (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to give crude material which was purified by reverse phase preparative HPLC to afford the desired product. Compound 10 was obtained as an off-white solid (0.010 g, 6% yield). 1HNMR (400 MHz, DMSO-d6) 8 = 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: Use of Compound 10 for treatment or prevention of the symptom of biological aging

[0317] An experiment is performed to evaluate the efficacy and safety of Compound 10 in subjects with a symptom of biological aging, such as the reduction or loss of muscle function, the reduction or loss of cognitive and / or neurological function, and / or the reduction or loss of immune function.Table 2a. Synopsis of experiment of Compound 10 in subjects with a symptom of biological aging.OBJECTIVE:To assess:Primary:• The efficacy of Compound 10 in subjects to reduce a symptom of biological aging.Secondary:• Monitor the adverse events and ensure safety of subjects after investigational product administration.SUBJECT TYPE: Patients with a reduction or loss of muscle function, a reduction or loss of cognitive and / or neurological function, a reduction and / or loss of immune function, or another symptom of biological aging; optionally where the patient has: CH, CHIP, or CCUS, or a combination thereof; the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 2% or greater, in the absence of cytopenia; and / or somatic mutations in normal dividing cells.DOSAGE AND DOSEPatients are administered Compound 10 at a dose of about 2 mg daily for PROGRESSION:5 days on and 2 days off.Attorney Docket No. 63243-710.601STUDY Subjects are monitored for drug tolerance, safety and hematological PARAMETERS: response. Specific parameters based on the type of symptom of biological aging is included in Tables 3b-5d. For the reduction or loss of muscle function and the reduction or loss of immune function, the subject will be evaluated based on whether it exceeds a threshold for % improvement in two out of the three subdomains. For the reduction or loss of cognitive and / or neurological function, the subject will be evaluated based on whether it exceeds a threshold for % Fluid Cognition Composite or improvements in >50% of selected cognitive function tests.Table 2b: Synopsis of endpoint assessment measures for the experiment of Compound 10 in subjects with the reduction or loss of muscle function.Subdomain Type Optimal measure Acceptable measure Endurance Function Cardiopulmonary • 6-min walk distance capacity exercise test (peak VO2) • 400m walk time Lower body Function Knee extensor power or • 1 -repetition maximum power rate of torquedevelopment (RTD)Muscle mass Biospecimen Urinary D3 creatine • CT muscle volumeor imaging dilution • MRI muscle volumeTable 2c: Synopsis of endpoint assessment measures for the experiment of Compound 10 in subjects with the reduction or loss of cognitive and / or neurological function.Subdomain Type Optimal measure Acceptable measure Cognitive Function NIH Toolbox Fluid CanTab / Cambridge Cognition summary Composite (executive (executive function, attention score function, attention and and processing speed,processing speed, memory)working memory)Table 2d: Synopsis of endpoint assessment measures for the experiment of Compound 10 in subjects with the reduction or loss of immune function.Subdomain Type Optimal measure Acceptable measure Response to Biospecimen Ex vivo naive immune Cellular mediated antigen-challenge response to a new specific immune response in stimulus (e.g., yellow stimulated PBMCs or fever) response to vaccine Immune cell Biospecimen IMM-AGE score CD4+: CD8+ ratio and composition lymphocyte: neutrophil ratio Inflammatory Biospecimen ‘Multikine’ multiplexedstatus assays (e.g., SASPindex)Attorney Docket No. 63243-710.601Example 3: Use of Compound 10 for treatment or prevention of the symptom of biological aging

[0318] An experiment is performed to evaluate the efficacy and safety of Compound 10 in subjects with a symptom of biological aging, such as a reduction in quality of life. Quality of life may be assessed with the OPQOL survey. Quality of life may be assessed with the WHOQOL-OLD survey. Quality of life may be assessed with the CASP-19 survey. Quality of life may be assessed with the following health -related quality of life survey.Sample health-related quality of life surveyHeath-Related Quality of Life

[0319] This study includes patients and explores their perception of experiences they have had with their heath.Personal Data Protection

[0320] All information that may permit an identification of the participants in this study will be kept strictly confidential, will be used only for the purpose of the study, and will not be disclosed for any reason without previous written consent, unless requested by Law.Instructions:1. Answer the question by selecting one answer.Example: (Mark the appropriate answer jYES NOa. Have you been in a submarine?.2. If you are not sure about the right choice for your answer, mark the closest match and write a comment in the left margin.3. If necessary, you can ask the dedicated Staff for assistance.Thank you for your participation in this studyIntroduction:1. In general, you would say that your health is:Excellent Good Acceptable Poor2. Compared to a month ago, your health is:Improved The same Worse Much WorseAttorney Docket No. 63243-710.601Physical Well-Being:3. In the last week, some daily activities may have been limited by your health, such as:I find it very I find it It is not difficult partially difficult at all difficultA Performing heavyactivities (for example,running, jumping, etc.)B Climbing stairsC Lowering myselfD Taking care of myself(washing, dressing, feedingmyself)Functional Well-Being:4. In the last week, what problems have you had in daily activities because of your health?Yes No A I got very little doneB I had more fatigue doing my work5. During the last week was it difficult for you to stay awake during the daytime? Always For many hours For a few hours NeverSocial or Family Well-Being:6. According to you, are the following statements true or false?True I do not know False A My present conditioninterferes too much withmy lifeB I feel oppressed by mydiseaseC I feel that I am a burdenfor my familyAttorney Docket No. 63243-710.6017. Your health is an impediment for you to keep a paid job (whether you are of retirement age or not).True False8. In the last week, was sexual arousal a problem for you?Never Rarely Sometimes OftenDisturbances, Related to Health:9. In the last week, how much did fatigue get in the way with your daily chores?Not at all A little A lot Extremely10. In the last week, how much fatigue did you have?Not at all A little A lot Extreme11. In the last week, how much did the following problems disturb you?Not at all A little A lot Extremely A HeadacheB Palpitations (i.e. heartpounding)C Difficulty in taking care ofyourselfD Being bedridden12. During the last week, did you get enough sleep?Always Often Rarely Never13. During the last week, did shortness of breath while climbing stairs disturb you? Never Sometimes Often Very often14. What effects of aging disturb your daily life?No, not at all A little bit Yes, extremely A Not being able to do housechoresAttorney Docket No. 63243-710.601B Not being able to travel C Being dependent on the hospital, doctors, and / or nursesD Stress and worry because of the diseaseE The effect on your sex life F Side effects of treatment

Claims

Attorney Docket No. 63243-710.601CLAIMS WHAT IS CLAIMED IS:

1. A method of treating or preventing biological aging or a symptom of biological aging, restoring muscle function, restoring cognition, or improving immune function, or any combination thereof, comprising administering to a subject in need thereof an inflammasome modulator.

2. The method of claim 1, wherein the inflammasome modulator is a modulator of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome.

3. The method of claim 2, wherein the inflammasome modulator inhibits the priming step of the NLRP3 inflammasome.

4. The method of claim 3, wherein the inflammasome modulator inhibits signaling downstream of members of the TLR (toll-like receptor) family, IL-1R (interleukin 1 receptor) family, and / or TNFR1 / 2 (tumor necrosis factor receptor 1 / 2).

5. The method of claim 3 or claim 4, wherein the inflammasome modulator prevents the activation of NF-kB (nuclear factor kappa-beta).

6. The method of any one of claims 2-5, wherein the administering reduces the level of TNF-a, IL-6, or the components of the NLRP3 inflammasome (e.g., NLRP3, pro-IL-1β (pro-interleukin-1beta), pro-IL18 (pro-interleukin- 18)), or a combination thereof, in the subject.

7. The method of claim 2, wherein the inflammasome modulator inhibits the assembly and activation step of the NLRP3 inflammasome.

8. The method of claim 7, wherein the inflammasome modulator inhibits the formation of a NLRP3 (protein)-NEK7 (protein) interaction.

9. The method of claim 8, wherein the inflammasome modulator inhibits the formation of the ASC speck and the NLRP3 inflammasome.

10. The method of any one of claims 7-9, wherein the inflammasome modulator prevents caspase- 1 activation.

11. The method of any one of claims 7-10, wherein the inflammasome modulator inhibits the production of IL-1β.

12. The method of any one of claims 7-11, wherein the inflammasome modulator inhibits the production of IL- 18.

13. The method of any one of claims 7-12, wherein the inflammasome modulator inhibits the cleavage of gasdermin D.

14. The method of any one of claims 7-13, wherein the inflammasome modulator prevents pyroptotic cell death.Attorney Docket No. 63243-710.60115. The method of any one of claims 1-14, wherein the administering comprises administering about 0.5 mg to about 10 mg of the inflammasome modulator to the subject.

16. The method of any one of claims 1-15, wherein the administering comprises administering the inflammasome modulator to the subject every day, every other day, every two days, every three days, every four days, every five days, every six days, once a week, five days on and two days off, once every two weeks, or once a month.

17. The method of any one of claims 1-16, wherein the administering comprises orally administering to the subject the inflammasome modulator.

18. The method of any one of claims 1-17, wherein the inflammasome modulator is in the form of a tablet, capsule or pill.

19. A method of treating or preventing biological aging or a symptom of biological aging, restoring muscle function, restoring cognition, or improving immune function, or any combination thereof, comprising administering to a subject in need thereof a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (I)wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;Xis CH orN;YisNH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl,Attorney Docket No. 63243-710.601isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl;Formula (II) wherein:X is N or CH;A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;R1is H, halo, Ci-Ce alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R3is aminylalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N-heterocyclyloxy, or 5-6 membered heteroaryl; orR3joins with an occurrence of R4attached to a carbon adjacent to a carbon to which R3is attached to form a C3-C8 cycloalkyl;R4is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 halocycloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4;Attorney Docket No. 63243-710.601Formula (III)wherein:A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;Xis N or CR4;Y is N or CH;R1is Ci-Ce alkyl, Ci-Ce hydroxylalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl; orR2joins with an occurrence of R3attached to a carbon adjacent to a carbon to which R2is attached to form a C3-C8 cycloalkyl;R3is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl;R4is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4;R3Formula (IV) wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;Xis N or CR1C;Y is N or CRld;Attorney Docket No. 63243-710.601Z is C(R6)(R7) or NR6;R1a, R1b, R1c, and R1dare each independently H, halo, Ci-Ce alkyl, or C3-C8 cycloalkyl;R2aand R2bare each independently H, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl, provided that R2aand R2bare not both H;R3is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R5is, at each occurrence, independently halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;R6is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl; and R7is H, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl;OR3( A r N-RNH2R4JI 1,Nr2Formula (V)wherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Yis CHOH orNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with oneAttorney Docket No. 63243-710.601more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadiazolyl, 1, 2, 4 -thiadiazolyl, 1, 2, 5 -thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl;O HN^r2x / N^R( * H( A A' wNH2LDzN 1RFormula (VI)wherein:represents a double or a single bond such that all valences are satisfied; A is an optionally substituted 5-6-membered heterocyclyl, an optionally substituted 6-membered aryl, or an optionally substituted 5-6-membered heteroaryl;Xis N or CR3;Y is C or N;W is CH or N;Attorney Docket No. 63243-710.601Z is CH or N;R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;R2is optionally substituted aryl or optionally substituted heteroaryl; andR3is hydrogen, halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.

20. A method of treating or preventing biological aging or a symptom of biological aging, restoring muscle function, restoring cognition, or improving immune function, or any combination thereof, comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:VR4NH2R5Njl y— R3X Nwherein:A is C6-C10aryl, C3-C10cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;Xis CH orN;YisNH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;Attorney Docket No. 63243-710.601R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

21. The method of claim 19 or claim 20, wherein the administering comprises administering about 0.5 mg to about 10 mg of the compound to the subject.

22. The method of any one of claims 19-21, wherein the administering comprises administering the compound to the subject five days on and two days off.

23. The method of any one of claims 19-22, wherein the administering comprises orally administering to the subject the compound.

24. The method of any one of claims 19-23, wherein the compound is in the form of a tablet.

25. The method of claim 20, wherein R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

26. The method of claim 20, wherein R2is:

27. The method of claim 20 or 25-26, wherein R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl,Attorney Docket No. 63243-710.601cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

28. The method of any one of claims 20 or 25-27, wherein R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof.

29. The method of any one of claims 20 or 25-28, wherein R4has one of the following structures:Attorney Docket No. 63243-710.60130. The method of any one of claims 20 or 25-29, wherein A is C6-C10 aryl, C3-C10 cycloalkyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6.

31. The method of any one of claims 20 or 25-30, wherein A is cyclohexyl, cyclohexenyl, phenyl, pyridinyl, or pyrimidinyl.

32. The method of any one of claims 20 or 25-31, wherein A is phenyl.

33. The method of any one of claims 20 or 25-32, wherein A is unsubstituted.

34. The method of any one of claims 20 or 25-32, wherein A is substituted with one or more R6.

35. The method of any one of claims 20 or 25-32, wherein R6is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy.

36. The method of any one of claims 20 or 25-31, or 50-56, wherein A is:\ Cl 0 F37. The method of any one of claims 20 or 25-36, wherein the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:Attorney Docket No. 63243-710.601R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci- Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkyl cycloalkyl.

38. The method of claim 37, wherein R2ais cyclopropyl.

39. The method of claim 37 or 38, wherein R4ais:

40. The method of claim 20, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

41. The method of any one of claims 20-40, wherein the compound of Formula (I) isor a pharmaceutically acceptable salt or solvate thereof.

42. The method of any one of claims 1-41, wherein the method comprises the treating or preventing the symptom of biological aging.

43. The method of claim 42, wherein the symptom of biological aging comprises loss of muscle function, or the method of any one of claims 1-41, wherein the method comprises the restoring muscle function in the subject.

44. The method of claim 43, wherein the method restores glucose tolerance and insulin sensitivity.

45. The method of claim 43, wherein the method reduces protein catabolism.

46. The method of claim 43, wherein the method reduces muscle atrophy.Attorney Docket No. 63243-710.60147. The method of any one of claims 42-46, wherein the symptom of biological aging comprises reduction of immune function, or the method of any one of claims 1-41, wherein the method comprises the improving immune function in the subject.

48. The method of claim 47, wherein the method reduces the amount of SASP biomarkers in the subject.

49. The method of claim 47, wherein the method reduces IL lb in the subject.

50. The method of claim 47, wherein the method reduces IL6 in the subject.

51. The method of claim 47, wherein the method reduces IL8 in the subject.

52. The method of any one of claims 42-51, wherein the symptom of biological aging comprises a reduction of neurological function, or the method of any one of claims 1-41, wherein the method comprises restoring cognition in the subject.

53. The method of claim 52, wherein the method reduces obesity-related chronic inflammation.

54. The method of claim 52, wherein the method protects the blood-brain barrier (BBB).

55. The method of claim 52, wherein the method prevents obesity-related cognitive decline.

56. The method of any one of claims 1-55, wherein the subject has clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP).

57. The method of any one of claims 1-55, wherein the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 2% or greater, in the absence of cytopenia.

58. The method of any one of claims 1-55, wherein the subject has somatic mutations in normal dividing cells.

59. The method of any one of claims 1-55, wherein the subject has clonal cytopenias of undetermined significance (CCUS).

60. The method of any one of claims 1-59, wherein the subject is 30 years old or older.

61. The method of any one of claims 1-59, wherein the subject is 40 years old or older.

62. The method of any one of claims 1-59, wherein the subject is 50 years old or older.

63. The method of any one of claims 1-59, wherein the subject is 60 years old or older.

64. The method of any one of claims 1-59, wherein the subject is 70 years old or older.

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