WSGR Docket No. 63243-701.601 PHARMACEUTICAL COMPOSITIONS FOR INHIBITORS OF NEK7 KINASE CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/512,188 filed July 6, 2023 and U.S. Provisional Patent Application No.63/657,018 filed June 6, 2024, both of which are incorporated by reference herein in their entirety. BACKGROUND [0002] The NLRP3 inflammasome is a multi-protein complex comprising NLRP3, ASC, and caspase-1. NEK7 is a member of the family of NIMA-related kinases (NEKs) and acts as an NLRP3-binding protein to regulate its oligomerization and activation. SUMMARY [0003] Provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: A is C
6-C
10 aryl, C
3-C
10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6; X is CH or N; Y is NH; R
1 is H; R
2 is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl; R
3 is H;
WSGR Docket No. 63243-701.601 R
4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1-C
6 cyanoalkyl, 3- to 8-membered heterocyclyl, C
3-C
8 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; R
5 is H; and each R
6 is independently halo, C
1-C
6 alkyl, C
1-C
6 alkoxy, cyano, C
1-C
6 hydroxylalkyl or C1-C6 haloalkyl; and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition comprises no more than 10 mg of Formula (I). [0004] An aspect of the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6; X is CH or N; Y is NH; R
1 is H; R
2 is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl;
WSGR Docket No. 63243-701.601 R
3 is H; R
4 is 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, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 haloalkyl, C
3-C
8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C
3-C
8 aminylalkylcycloalkyl, C
3-C
8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C
3-C
8 halocycloalkyl; R
5 is H; and each R
6 is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C
1-C
6 haloalkyl; and at least one pharmaceutically acceptable excipient, wherein the amount of a compound of Formula (I) in the pharmaceutical composition is from about 0.5 to about 5 mg. [0005] In some embodiments, the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, or magnesium stearate, or a combination of two or more thereof. [0006] An aspect of the present disclosure provides a method of treating an NLRP3- mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein. [0007] In some embodiments, the NLRP3-mediated disease or disorder is myelodysplastic syndrome. [0008] In some embodiments, the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
WSGR Docket No. 63243-701.601
wherein: R
2a is C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R
4a is isoxazolyl optionally substituted with one more substituents selected from C
1- C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl. [0009] In some embodiments, the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. [0010] In some embodiments, the compound of Formula (I) is selected from:
WSGR Docket No. 63243-701.601
[0011] In some embodiments, the compound of Formula (I) is Compound 10 of Table 1. [0012] In some embodiments the amount of the compound of Formula (I) in the pharmaceutical composition is about 4 mg. [0013] In some embodiments, the amount of the compound of Formula (I) in the pharmaceutical composition is about 5 mg [0014] In some embodiments, the amount of the compound of Formula (I) in the pharmaceutical composition is about 2 mg. [0015] In some embodiments, the amount of the compound of Formula (I) in the pharmaceutical composition is about 0.5 mg [0016] In some embodiments, the pharmaceutical composition is in a tablet. [0017] In some embodiments, the tablet is a film-coated immediate-release tablet.
WSGR Docket No. 63243-701.601 [0018] In some embodiments, the tablet is coated with Opadry II. [0019] In some embodiments, the tablet has a diameter of about 7 mm. [0020] In some embodiments, the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, magnesium stearate, or a combination of two or more thereof. [0021] In some embodiments, the pharmaceutically acceptable excipient comprises at least three ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. [0022] In some embodiments, the pharmaceutically acceptable excipient comprises at least four ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. [0023] In some embodiments, the pharmaceutically acceptable excipient comprises at least five ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. [0024] In some embodiments, the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. [0025] In some embodiments, the sodium lauryl sulfate is in an amount of about 0.01% w/w to about 0.1% w/w. [0026] In some embodiments, the partially pre-gelatinized maize starch is in an amount of about 30% w/w to about 50% w/w. [0027] In some embodiments, the microcrystalline cellulose is in an amount of about 30% w/w to about 50% w/w. [0028] In some embodiments, the sodium starch glycolate is in an amount of about 1% w/w to about 5% w/w. [0029] In some embodiments, the hydroxypropyl cellulose LF is in an amount of about 1% w/w to about 5% w/w. [0030] In some embodiments, the colloidal silicon dioxide is in an amount of about 0.5% w/w to about 5% w/w.
WSGR Docket No. 63243-701.601 [0031] In some embodiments, the magnesium stearate is in an amount of about 0.5% w/w to about 5% w/w. [0032] In some embodiments, the sodium lauryl sulfate is in the amount of about 0.01% w/w to about 0.1% w/w, the partially pre-gelatinized maize starch is in the amount of about 43% w/w to about 44% w/w, the microcrystalline cellulose is in the amount of about 44% w/w to about 48% w/w, the sodium starch glycolate is in the amount of about 3% w/w to about 4% w/w, the hydroxypropyl cellulose LF is in the amount of about 2% w/w to about 3% w/w, the colloidal silicon dioxide is in the amount of about 1% w/w to about 1.5% w/w, and the magnesium stearate is in the amount of about 1% w/w to about 1.5% w/w. [0033] In some embodiments, the sodium lauryl sulfate is Kolliphore SLS fine, the partially pre-gelatinized maize starch is Starch 1500, the microcrystalline cellulose is Avicel PH 101, the sodium starch glycolate is type A, the hydroxypropyl cellulose LF is Klucel HPC LF, and the colloidal silicon dioxide is Aerosil Pharma 200. [0034] In an aspect, the present disclosure provides a method of treating an NLRP3- mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein. [0035] In some embodiments, the NLRP3-mediated disease or disorder is a myelodysplastic syndrome, an inflammatory disease or disorder, an auto-immune disease or disorder, a cardiovascular disease, a neurodegenerative disease or disorder, a bacterial and/or viral infection, an allergy, asthma, pancreatitis, multi-organ failure, a kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, a lung injury, a respiratory disease, an ischemic condition, or a combination thereof. [0036] In some embodiments, the NLRP3-mediated disease or disorder is myelodysplastic syndrome or inflammatory disease or disorder. [0037] In some embodiments, the NLRP3-mediated disease or disorder is myelodysplastic syndrome. [0038] In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome with multilineage dysplasia, myelodysplastic syndrome with single lineage dysplasia, myelodysplastic syndrome with ring sideroblasts, myelodysplastic syndrome with excess blasts, myelodysplastic syndrome with isolated del, or myelodysplastic syndrome unclassifiable. [0039] In some embodiments, the NLRP3-mediated disease or disorder is an inflammatory disease or disorder.
WSGR Docket No. 63243-701.601 [0040] In some embodiments, the inflammatory disease or disorder is acute inflammatory pain. [0041] In some embodiments, the pharmaceutical composition is administered daily. [0042] In some embodiments, the pharmaceutical composition is administered daily for about 1 week to about 12 weeks. [0043] In some embodiments, the pharmaceutical composition is administered daily for about 12 or more weeks. [0044] In an aspect, the present disclosure provides a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: A is C
6-C
10 aryl, C
3-C
10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6; X is CH or N; Y is NH; R
1 is H; R
2 is C
1-C
6 alkyl, C
3-C
4 cycloalkyl, C
3-C
8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl; R
3 is H; R
4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4- triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5- thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-
WSGR Docket No. 63243-701.601 C
6 haloalkyl, C
3-C
8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1-C
6 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; R
5 is H; and each R
6 is independently halo, C
1-C
6 alkyl, C
1-C
6 alkoxy, cyano, C
1-C
6 hydroxylalkyl or C1-C6 haloalkyl; wherein: (i) the subject has symptomatic anemia; (ii) the subject is refractory, intolerant of or ineligible for treatment with an erythroid stimulating agent (ESA), optionally wherein the subject has discontinued prior ESA at least two weeks prior to the administering; (iii) the subject has very low-risk MDS, low-risk MDS, or intermediate-risk MDS; (iv) administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, orally to the subject; (v) administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject daily; or (vi) a combination of two or more of (i) to (v). [0045] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily. [0046] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily for about 1 week to about 12 weeks. [0047] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily for 12 or more weeks. [0048] In some embodiments, administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, orally to the subject.
WSGR Docket No. 63243-701.601 [0049] In some embodiments, each dose of the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is about 0.5 mg to about 5 mg. [0050] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: R
2a is C
3-C
4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R
4a is isoxazolyl optionally substituted with one more substituents selected from C
1-C
6 haloalkyl, C
3-C
8 cycloalkyl or C
3-C
8 haloalkylcycloalkyl. [0051] In some embodiments, the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. [0052] In some embodiments, the compound of Formula (I) is Compound 10 of Table 1, or a pharmaceutically acceptable salt or solvate thereof. [0053] In some embodiments, the compound of Formula (I) is selected from:
WSGR Docket No. 63243-701.601
[0054] Provided herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein.
WSGR Docket No. 63243-701.601 BRIEF DESCRIPTION OF THE DRAWINGS [0055] FIG.1 illustrates the plasma concentration-time profiles resulting from dosing 1 mg to 4 mg of Compound 10 for 2 cycles of 5 days on and 2 days off. DETAILED DESCRIPTION [0056] Embodiments described herein are generally directed to pharmaceutical compositions and methods for use as therapeutic or prophylactic agents, for example for treatment of inflammation and/or cancer. Definitions [0057] 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 defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. [0058] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. [0059] As used in the specification and claims, 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. [0060] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. As used herein, the terms “about” and “approximately” mean ± 5% or ± 1% of the indicated range, value, or structure, unless otherwise indicated.
WSGR Docket No. 63243-701.601 [0061] 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, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor. [0062] “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. [0063] “Amino” refers to the ˗NH2 radical. [0064] “Carboxy” or "carboxyl" refers to the ˗CO2H radical. [0065] “Cyano” refers to the ˗CN radical. [0066] “Hydroxy” or “hydroxyl” refers to the ˗OH radical.
[0067] “Nitro” refers to the ˗
NO2 radical. [0068] “Oxo” refers to the =O substituent.
[0069] “Thiol” refers to the ˗
SH substituent. [0070] “Thioxo” refers to the =S substituent. [0071] “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 (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl), or any value within these ranges, such as C4-C6 alkyl and the like, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted. [0072] “Alkenyl” refers to an unsaturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds, having from two to twelve carbon atoms (C2-C12 alkenyl), two to eight 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,
WSGR Docket No. 63243-701.601 prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted. [0073] “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 (C
2-C
6 alkynyl), or any value within these ranges, and having at least one carbon- carbon triple bond. Examples of alkynyl groups may be selected from the group consisting of ethynyl, propargyl, but-1-ynyl, but-2-ynyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted.
[0074] “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 (C
1-C
8 alkoxy) or one to six carbon atoms (C
1-C
6 alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.
[0075] “Aminyl” refers to a radical of the formula ˗
NRa
Rb
, where Ra
and Rb
are each independently H or C
1-C
6 alkyl as defined above. When both of R
a and R
b are H, an "aminyl" group is the same as an "amino" group as defined above. The C
1-C
6 alkyl portion of an aminyl group is optionally substituted unless stated otherwise. [0076] “Aminylalkylcycloalkyl” refers to a radical of the formula –RaRbNRcRd where Ra is cycloalkyl as defined herein, R
b is C
1-C
6 alkyl, R
c is H or C
1-C
6 alkyl and R
d is C
1-C
6 alkyl as defined above. The cycloalkyl and each C1-C6 alkyl portion of an aminylalkylcycloalkyl group are optionally substituted unless stated otherwise. [0077] “Aromatic ring” refers to a cyclic planar molecule or portion of a molecule (i.e., 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 π-electrons (for example, alternating double and single bonds) that is even but not a multiple of 4 (i.e., 4n + 2 π- electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl,
WSGR Docket No. 63243-701.601 pyrimidonyl. Unless stated otherwise specifically in the specification, an "aromatic ring" includes all radicals that are optionally substituted. [0078] “Aryl” refers to a carbocyclic ring system radical comprising 6 to 18 carbon atoms, for example 6 to 10 carbon atoms (C
6-C
10 aryl) and at least one carbocyclic aromatic ring. For purposes of embodiments of this invention, the aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group is optionally substituted. [0079] “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. [0080] "Carbocyclic" or "carbocycle" refers to a ring system, wherein each of the ring atoms are carbon. [0081] “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 (C
3-C
10 cycloalkyl), or from three to eight ring carbon atoms (C
3-C
8 cycloalkyl), or any value within these ranges such as three to four carbon atoms (C
3-C
4 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. [0082] “Alkylcycloalkyl” refers to a radical group of the formula –R
aR
b where R
a 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. [0083] “Fused” refers to any ring structure described herein which is fused to another ring structure. [0084] "Halo" refers to bromo, chloro, fluoro, or iodo.
WSGR Docket No. 63243-701.601 [0085] “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, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted. [0086] “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, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a halocycloalkyl group is optionally substituted. [0087] “Haloalkylcycloalkyl” refers to a radical group of the formula –R
aR
b where R
a 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. [0088] “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. [0089] “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[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrrolizine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted.
WSGR Docket No. 63243-701.601 [0090] “Haloheterocyclylalkyl” refers to a radical group of the formula –R
aR
b where R
a 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. [0091] “Heterocyclylalkyl” refers to a radical group of the formula –R
aR
b where R
a 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. [0092] “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, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted. [0093] 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:
WSGR Docket No. 63243-701.601
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. [0094] The term "substituted" as used herein means any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl and/or hydroxylalkyl) wherein at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of non- hydrogen substituents include, but are not limited to amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and/or hydroxylalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents. [0095] In some specific embodiments, the optional substitutions are independently selected from the group consisting of halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 5- or 6-membered heteroaryl, C
1-C
6 alkoxy and 3-8 membered heterocyclyl. [0096] “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 disease treatment, as defined below. [0097] As used herein, “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 a therapeutic effect and/or a prophylactic effect. Therapeutic benefit includes eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the
WSGR Docket No. 63243-701.601 physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. [0098] 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. [0099] “Pharmaceutically acceptable salt” includes both acid and base addition salts. [0100] “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-disulfonic 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
WSGR Docket No. 63243-701.601 acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2- sulfonic acid, 1-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. [0101] “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, 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 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, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. [0102] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts such as quaternary amine alkyl halide salts (e.g., methyl bromide). [0103] 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" are defined in the context of the biological role of the target protein. While
WSGR Docket No. 63243-701.601 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. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor. [0104] The term “agonist” as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the 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. [0105] “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. [0106] “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. [0107] 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. [0108] 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
WSGR Docket No. 63243-701.601 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 the disclosure merely retain adventitious water or is a mixture of water plus some adventitious solvent. [0109] 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. [0110] The compounds of the disclosure (i.e., compounds of Formula (I)) or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and may thus give rise to stereoisomers such as enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. [0111] 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.
WSGR Docket No. 63243-701.601 [0112] In some embodiments, the compounds of Formula (I) are a mixture of enantiomers or diastereomers. In other embodiments, the compounds of Formula (I) are substantially one enantiomer or diastereomer. [0113] 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. [0114] 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. [0115] “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. [0116] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Inflammasomes [0117] Inflammasomes are multi-protein complexes whose activation plays a central role in innate immunity and inflammation. To date, four inflammasomes have been described: NLRP1, NLRC4, NLRP3, and AIM2. The NLRP3 inflammasome is composed of NLRP3, ASC, and caspase-1. Its activation results in the activation of caspase-1 which promotes the secretion of IL-1 ^ and IL-18, cytokines that mediate inflammation in animal models of several autoimmune diseases, myocardial infarction, metabolic syndromes, inflammatory bowel disease, and macrophage activation syndrome. [0118] NEK7 is a serine/threonine kinase essential for mitotic entry, cell cycle progression, cell division, and mitotic progression. It is expressed in a variety of tissues such as the brain, heart, lung, liver, and spleen. Overexpression of NEK7 induces the production of
WSGR Docket No. 63243-701.601 abnormal cells, which has an intimate connection to tumors, such as retinoblastoma, gallbladder cancer, and carcinoma of the head and neck. [0119] A great number of inhibitors have been widely used to disturb effector signaling pathways involving IL-1 ^ or IL-18 without abolishing the inflammation response. Inhibitors of NLRP3 inflammasome activation that block the NLRP3-NEK7 interaction can have therapeutic or prophylactic activity in several human diseases, such as type 2 diabetes (T2D), atherosclerosis, gout, and neurodegenerative diseases. However, the exact mechanism of the NLRP3-NEK7 interaction is not well understood. [0120] Accordingly, there is a need to develop inhibitors that will directly target NEK7 to affect the inflammatory response modulated by the NLRP3 inflammasome in several pathological diseases, such as gout, atherosclerosis, Type 2 diabetes, metabolic syndrome, macular degeneration, Alzheimer’s disease, multiple sclerosis, and inflammatory bowel disease. Embodiments of the present disclosure fulfill this need and provide further related advantages. Compounds in the Pharmaceutical Composition [0121] Described herein are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which are capable of inhibiting NEK7 and/or modulating the activity of NLRP3 inflammasome. [0122] Embodiments described herein provide a compound having Formula (I):
or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: A is C
6-C
10 aryl, C
3-C
10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6; Y is NH; R
1 is H or C
1-C
6 alkyl; R
2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 alkoxy and 3-8 membered heterocyclyl;
WSGR Docket No. 63243-701.601 R
3 is H, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2- C
6 alkenyl, C
2-C
6 alkynyl and C
1-C
6 alkoxy; R
4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, , cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1-C
6 cyanoalkyl, 3- to 8-membered heterocyclyl, C
3-C
8 haloalkylcycloalkyl, C
3-C
8 aminylalkylcycloalkyl, C
3-C
8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof; R
5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C
1- C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl and C
1-C
6 alkoxy; and R
6 is, at each occurrence, independently halo, C1-C6 alkyl, cyano, C1-C6 hydroxylalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkyl. [0123] In some embodiments of the compound of Formula (I): A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6; Y is NH; R
1 is H or C1-C6 alkyl; R
2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; R
3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy;
WSGR Docket No. 63243-701.601 R
4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl; R
5 is H, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1- C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl and C
1-C
6 alkoxy; and R
6 is, at each occurrence, independently halo, C
1-C
6 alkyl, or C
1-C
6 haloalkyl. [0124] In some embodiments of the compound of Formula (I): A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6; X is CH or N; Y is NH; R
1 is H or C1-C6 alkyl; R
2 is C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
8 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, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2- C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; R
3 is H, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
8 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, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2- C6 alkynyl and C1-C6 alkoxy; R
4 is 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, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 haloalkyl, C
3-C
8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C
3-C
8 aminylalkylcycloalkyl, C
3-C
8 alkylcycloalkyl, 3- to 8-membered
WSGR Docket No. 63243-701.601 heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C
3-C
8 halocycloalkyl; R
5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C
6-C
10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl and C
1-C
6 alkoxy; and R
6 is, at each occurrence, independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C
1-C
6 haloalkyl. [0125] In some embodiments, A is any suitable functional group as described herein. In some embodiments, A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6. In some embodiments, A is C
6-C
10 aryl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6. In some embodiments, A is C6-C10 aryl optionally substituted with one or more R
6. In some embodiments, A is 5-6 membered monocyclic heteroaryl optionally substituted with one or more R
6. In some embodiments, A is C
3-C
10 cycloalkyl. In some embodiments, A is 3-10 membered heterocyclyl optionally substituted with one or more R
6. [0126] In some embodiments, A is a divalent optionally substituted C6-10 aryl. 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. [0127] In some embodiments, A is a divalent group selected from phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl,
WSGR Docket No. 63243-701.601 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, tetrahydro furanyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4- triazolyl, oxetanyl, azetidinyl, and xanthenyl; each of which is optionally substituted. [0128] In some embodiments, A is a divalent group selected from phenyl, pyridinyl, cyclohexyl, and cyclohexenyl; each of which is optionally substituted. In other embodiments, A is phenyl. In some embodiments, A is saturated or unsaturated cyclohexyl. In more embodiments, A is pyridinyl. [0129] In some embodiments, A is pyrimidinyl, which is optionally substituted. [0130] 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. [0131] In some embodiments, Y is any suitable linker as described herein. In some embodiments, Y is NH. [0132] In some embodiments, R
1 is any suitable functional group described herein. In some embodiments, R
1 is H. In some embodiments, R
1 is C
1-C
6 alkyl. In some embodiments, R
1 is methyl, ethyl, n-propyl, or isopropyl. [0133] In some embodiments, R
2 is any suitable functional group described herein. In some embodiments, R
2 is C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl. In some embodiments R
2 is C
1-C
6 alkyl, C
3-C
4 cycloalkyl, C
3-C
8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R
2 is butyl, cyclopropyl, cyclobutyl,
WSGR Docket No. 63243-701.601 pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R
2 is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8- membered heterocyclyl. In some embodiments, R
2 is cyclopropyl or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R
2 is cyclopropyl. In some embodiments, R
2 is oxetanyl. In some embodiments, R
2 is unsubstituted cyclopropyl or oxetanyl. In some embodiments, R
2 is N-methyl substituted pyrrolidinyl. In some embodiments, R
2 is unsubstituted cyclobutyl. [0134] In some embodiments, R
2 is:
[0135] In some embodiments, R
2 is:
[0136] In some embodiments, R
3 is any suitable functional group described herein. In some embodiments, R
3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy. In some embodiments, R
3 is H or C1- C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl and C1-C6 alkoxy. In some embodiments, R
3 is H. In some embodiments, R
3 is C1-C6 alkyl. In some embodiments, R
3 is methyl, ethyl, n-propyl, or isopropyl. [0137] In some embodiments, R
4 is any suitable functional group described herein. In some embodiments, R
4 is 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
WSGR Docket No. 63243-701.601 halo, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 haloalkyl, C
3-C
8 cycloalkyl, , cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof. In some embodiments, R
4 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C
1-C
6 cyanoalkyl, 3- to 8-membered heterocyclyl, C
3-C
8 haloalkylcycloalkyl, C
3-C
8 aminylalkylcycloalkyl, C
3-C
8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3- C8 halocycloalkyl, and combinations thereof. [0138] In some embodiments, R
4 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl or 1, 3, 4- oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1-C
6 cyanoalkyl, 3- to 8-membered heterocyclyl, C
3-C
8 haloalkylcycloalkyl, C
3-C
8 aminylalkylcycloalkyl, C
3-C
8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C
3-C
8 halocycloalkyl, and combinations thereof. In some embodiments, R
4 is isoxazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl. [0139] In some embodiments, R
4 is isoxazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C
3-C
8 haloalkylcycloalkyl, C
3-C
8 aminylalkylcycloalkyl, C
3-C
8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. [0140] In some embodiments, R
4 is thiazolyl optionally substituted with one more substituents selected from halo, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl,
WSGR Docket No. 63243-701.601 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. [0141] In some embodiments, R
4 is isothiazolyl optionally substituted with one more substituents selected from halo, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. [0142] In some embodiments, R
4 is 1,2,4-thiadiazolyl optionally substituted with one more substituents selected from halo, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 haloalkyl, C
3-C
8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1-C
6 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 C
3-C
8 halocycloalkyl, and combinations thereof. [0143] In some embodiments, R
4 is 1,3,4-thiadiazolyl optionally substituted with one more substituents selected from halo, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 haloalkyl, C
3-C
8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1-C
6 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 C
3-C
8 halocycloalkyl, and combinations thereof. [0144] In some embodiments, R
4 is 1,2,4-triazolyl optionally substituted with one more substituents selected from halo, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C
3-C
8 halocycloalkyl, and combinations thereof. [0145] In some embodiments, R
4 is 1, 3, 4-oxadiazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C
3-C
8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, 3- to 8-membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof. [0146] In some embodiments, R
4 is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1-C
6 cyanoalkyl, 3- to 8-membered
WSGR Docket No. 63243-701.601 heterocyclyl, C
3-C
8 haloalkylcycloalkyl, C
3-C
8 aminylalkylcycloalkyl, C
3-C
8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. [0147] In some embodiments, R
4 is:
WSGR Docket No. 63243-701.601
[0150] In some embodiments, R
5 is any suitable functional group described herein. In some embodiments, R
5 is H, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
8 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, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl and C
1-C
6 alkoxy. In some embodiments, R
5 is H or C
1-C
6 alkyl, wherein C
1-C
6 alkyl is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy. In some embodiments, R
5 is H. In some embodiments, R
5 is C1-C6 alkyl. In some embodiments, R
5 is methyl, ethyl, n-propyl, or isopropyl. [0151] In some embodiments, each R
6 is any suitable functional group described herein. In some embodiments, each R
6 is independently halo, C1-C6 alkyl, cyano, C1-C6 hydroxylalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkyl. In some embodiments, each R
6 is chloro or fluoro. In some embodiments, each R
6 is fluoro. In some embodiments, each R
6 is C1-C6 hydroxylalkyl. In some embodiments, each R
6 is C1-C6 hydroxylalkyl. In some embodiments,
WSGR Docket No. 63243-701.601 each R
6 is -CH
2CH
2OH. In other embodiments, each R
6 is cyano. In some embodiments, each R
6 is C1-C6 alkoxy. In some embodiments, each R
6 is methoxy. [0152] In some embodiments, A is:
[0153] In some embodiments, A is:
[0154] In some embodiments, the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: R
2a is C
3-C
4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R
4a is isoxazolyl optionally substituted with one more substituents selected from C
1- C
6 haloalkyl, C
3-C
8 cycloalkyl or C
3-C
8 haloalkylcycloalkyl. [0155] In some embodiments, R
2a is a branched C1-C6 alkyl substituted with hydroxyl. In some embodiments, R
2a is C
3-C
8 cycloalkyl. In some embodiments, R
2a is:
WSGR Docket No. 63243-701.601
[0156] In some embodiments, R
4a is isoxazolyl substituted with C3-C8 haloalkylcycloalkyl. In some embodiments, R
4a is C
3-C
8 fluoroalkylcycloalkyl. In some embodiments, R
4a is fluoroalkylcyclopropyl or fluoroalkylcyclobutyl. In some embodiments, R
4a is:
[0157] In some embodiments, the compound is a compound of Formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6; X is CH or N; Y is NH; R
1 is H or C1-C6 alkyl; R
2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C
6 alkynyl, C
1-C
6 alkoxy and 3-8 membered heterocyclyl; R
3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl and C1-C6 alkoxy;
WSGR Docket No. 63243-701.601 R
4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1-C
6 cyanoalkyl, 3- to 8-membered heterocyclyl, C
3-C
8 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; R
5 is H, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
3-C
8 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, C
1-C
6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R
6 is, at each occurrence, independently halo, C
1-C
6 alkyl, C
1-C
6 alkoxy, cyano, C
1-C
6 hydroxylalkyl or C1-C6 haloalkyl. [0158] In some embodiments, the compound of Formula (I) is a modulator of the NLRP3 inflammasome. [0159] In some embodiments, the compound of Formula (I) is an inhibitor of NEK7 in a patient or in a biological sample. [0160] In various different embodiments, the compound has one of the structures set forth in Table 1 below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof. [0161] In some embodiments, the compound of Formula (I) is a compound selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments the compound of Formula (I) is selected from the group consisting of compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments the compound of Formula (I) is selected from the group consisting of compound 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of Formula (I) is selected from compound 10. Table 1: Representative Compounds of Formula (I)
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WSGR Docket No. 63243-701.601
Pharmaceutical Composition [0162] Provided herein are pharmaceutical compositions comprising one or more compounds of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical composition comprises any one (or more) of the foregoing compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. [0163] In some embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules,
WSGR Docket No. 63243-701.601 liquids, gels, syrups, elixirs, slurries, suspensions and the like. In some embodiments, the compounds described herein are formulated in tablets. In some embodiments, the compounds described herein are formulated in capsules. [0164] In some embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. [0165] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses. [0166] In some embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.
WSGR Docket No. 63243-701.601 [0167] In treatment methods according to embodiments of the invention, an effective amount of at least one compound of Formula (I) is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition. Effective amounts or doses may be ascertained by methods such as modeling, dose escalation studies or clinical trials, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. [0168] The pharmaceutical composition described herein can be administered in any suitable effective dosage described herein. In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 10 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 5 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 5 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 4 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 3 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 2 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 1 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.5 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 10 mg of Compound 10 of Table 1. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 5 mg of Compound 10. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 10. In some embodiments, the pharmaceutical composition comprises about 4 mg of Compound 10. In some embodiments, the pharmaceutical composition comprises about 3 mg of Compound 10. In some embodiments, the pharmaceutical composition comprises about 2 mg of Compound 10. In some embodiments, the pharmaceutical composition comprises about 1 mg of Compound 10. In some embodiments, the pharmaceutical composition comprises about 0.5 mg of Compound 10. [0169] The pharmaceutical composition described herein can be administered by any suitable dosing schedule described herein. In some embodiments, the pharmaceutical composition is administered to the subject in a one-week cycle, wherein the one-week cycle
WSGR Docket No. 63243-701.601 consists of administering the composition for five days consecutively and then not administering the pharmaceutical composition for two days consecutively. [0170] In some embodiments, the pharmaceutical composition is administered in the one- week cycle for at least 2 weeks. In some embodiments, the pharmaceutical composition is administered in the one-week cycle for at least 4 weeks. In some embodiments, the pharmaceutical composition is administered in the one-week cycle for at least 8 weeks. In some embodiments, the pharmaceutical composition is administered in the one-week cycle for at least 12 weeks. In some embodiments, the pharmaceutical composition is administered in the one-week cycle for 16 weeks. In some embodiments, the pharmaceutical composition is administered in the one-week cycle for 20 weeks. In some embodiments, the pharmaceutical composition is administered in the one-week cycle for 24 weeks. In some embodiments, the pharmaceutical composition is administered in the one-week cycle for 28 weeks. In some embodiments, the pharmaceutical composition is administered in the one- week cycle for 32 weeks. [0171] In some embodiments, the pharmaceutical composition is administered to the subject daily. In some embodiments, the pharmaceutical composition is administered to the subject once daily. [0172] In some embodiments, the pharmaceutical composition is administered to the subject once daily for at least 2 weeks. In some embodiments, the pharmaceutical composition is administered once daily for at least 4 weeks. In some embodiments, the pharmaceutical composition is administered once daily for at least 8 weeks. In some embodiments, the pharmaceutical composition is administered once daily for at least 12 weeks. In some embodiments, the pharmaceutical composition is administered once daily for 16 weeks. In some embodiments, the pharmaceutical composition is administered once daily for 20 weeks. In some embodiments, the pharmaceutical composition is administered once daily for 24 weeks. In some embodiments, the pharmaceutical composition is administered once daily for 28 weeks. In some embodiments, the pharmaceutical composition is administered once daily for 32 weeks. In some embodiments, the compound of Formula (I) is administered to the subject daily. In some embodiments, the compound of Formula (I) is administered to the subject once daily. [0173] In some embodiments, the compound of Formula (I) is administered to the subject once daily for at least 2 weeks. In some embodiments, the compound of Formula (I) is administered once daily for at least 4 weeks. In some embodiments, the compound of Formula (I) is administered once daily for at least 8 weeks. In some embodiments, the
WSGR Docket No. 63243-701.601 compound of Formula (I) is administered once daily for at least 12 weeks. In some embodiments, the compound of Formula (I) is administered once daily for 16 weeks. In some embodiments, the compound of Formula (I) is administered once daily for 20 weeks. In some embodiments, the compound of Formula (I) is administered once daily for 24 weeks. In some embodiments, the compound of Formula (I) is administered once daily for 28 weeks. In some embodiments, the compound of Formula (I) is administered once daily for 32 weeks. In some embodiments, the compound of Formula (I) is administered once daily for 1 to 12 weeks. In some embodiments, the compound of Formula (I) is administered for more than 12 weeks. [0174] In some embodiments, the compound of Formula (I) is administered once daily for 1 to 12 weeks at a dose of about 2 mg. In some embodiments, the compound of Formula (I) is administered once daily for 1 to 12 weeks at a dose of about 3 mg. In some embodiments, the compound of Formula (I) is administered once daily for 1 to 12 weeks at a dose of about 4 mg. In some embodiments, the compound of Formula (I) is administered once daily for 1 to 12 weeks at a dose of about 5 mg. [0175] In some embodiments, Compound 10 is administered to the subject daily. In some embodiments, Compound 10 is administered to the subject once daily. [0176] In some embodiments, Compound 10 is administered to the subject once daily for at least 2 weeks. In some embodiments, Compound 10 is administered once daily for at least 4 weeks. In some embodiments, Compound 10 is administered once daily for at least 8 weeks. In some embodiments, Compound 10 is administered once daily for at least 12 weeks. In some embodiments, Compound 10 is administered once daily for 16 weeks. In some embodiments, Compound 10 is administered once daily for 20 weeks. In some embodiments, Compound 10 is administered once daily for 24 weeks. In some embodiments, Compound 10 is administered once daily for 28 weeks. In some embodiments, Compound 10 is administered once daily for 32 weeks. In some embodiments, Compound 10 is administered once daily for 1 to 12 weeks. In some embodiments, Compound 10 is administered for more than 12 weeks. [0177] In some embodiments, Compound 10 is administered once daily for 1 to 12 weeks at a dose of about 2 mg. In some embodiments, Compound 10 is administered once daily for 1 to 12 weeks at a dose of about 3 mg. In some embodiments, Compound 10 is administered once daily for 1 to 12 weeks at a dose of about 4 mg. In some embodiments, Compound 10 is administered once daily for 1 to 12 weeks at a dose of about 5 mg. [0178] The pharmaceutical composition can be in any suitable carrier for oral administration as described herein. In some embodiments, the pharmaceutical composition is
WSGR Docket No. 63243-701.601 in a capsule. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the capsule is a size 1, 2, or 3 capsule. In some embodiments, the capsule is a size 1 capsule. In some embodiments, the capsule is a size 2 capsule. In some embodiments, the capsule is a size 3 capsule. [0179] The capsule can have any suitable color described herein. In some embodiments, the capsule is opaque white, Swedish orange, or dark green. In some embodiments, the capsule is opaque white. In some embodiments, the capsule is Swedish orange. In some embodiments, the capsule is dark green. [0180] In some embodiments, the pharmaceutical composition is in a tablet. In some embodiments, the tablet is a film-coated tablet. In some embodiments the tablet is an immediate-release tablet. In some embodiments, the tablet is a film-coated immediate-release tablet. In some embodiments, the tablet is coated with Opadry II. In some embodiments, the tablet is coated with Opadry II Yellow. In some embodiments, the tablet is coated with Opadry II Red. In some embodiments, the tablet has a diameter of about 7 mm. [0181] The pharmaceutically acceptable excipients in the pharmaceutical composition described herein can be any suitable pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient is sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, magnesium stearate, or a combination of two or more thereof. In some embodiments the pharmaceutically acceptable excipient comprises at least two ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments the pharmaceutically acceptable excipient comprises at least three ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments the pharmaceutically acceptable excipient comprises at least four ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments the pharmaceutically acceptable excipient comprises at least five ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and
WSGR Docket No. 63243-701.601 magnesium stearate. In some embodiments the pharmaceutically acceptable excipient comprises at least six ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. [0182] In some embodiments, the sodium lauryl sulfate is Kolliphore SLS fine. In some embodiments, the partially pre-gelatinized maize starch is Starch 1500. In some embodiments, the microcrystalline cellulose is Avicel PH 101. In some embodiments, the sodium starch glycolate is type A. In some embodiments, the hydroxypropyl cellulose LF is Klucel HPC LF. In some embodiments, the colloidal silicon dioxide is Aerosil Pharma 200. In some embodiments, the pharmaceutically acceptable excipient is sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the sodium lauryl sulfate is Kolliphore SLS fine, the partially pre-gelatinized maize starch is Starch 1500, the microcrystalline cellulose is Avicel PH 101, the sodium starch glycolate is type A, the hydroxypropyl cellulose LF is Klucel HPC LF, and the colloidal silicon dioxide is Aerosil Pharma 200. [0183] The pharmaceutically acceptable excipients can have any suitable amounts described herein. Weight % measurements (%w/w) for excipients in the tablet refer to the percentage weight of each excipient relative to the total weight of the core tablet, before applying a coating. Weight % measurements (%w/w) for excipients in the capsule refer to the percentage weight of each excipient relative to the total weight of all ingredients excluding the outer capsule itself. [0184] In some embodiments, the sodium lauryl sulfate is in an amount of about 0.01% w/w to about 0.1% w/w. In some embodiments, the sodium lauryl sulfate is in an amount of about 0.01% w/w to about 0.8% w/w. In some embodiments, the sodium lauryl sulfate is in an amount of about 0.02% w/w to about 0.6% w/w. In some embodiments, the sodium lauryl sulfate is in the amount of about 0.04% w/w. [0185] In some embodiments, the partially pre-gelatinized maize starch is in an amount of about 30% w/w to about 50% w/w. In some embodiments, the partially pre-gelatinized maize starch is in an amount of about 40% w/w to about 50% w/w. In some embodiments, the partially pre-gelatinized maize starch is in an amount of about 40% w/w to about 45%
WSGR Docket No. 63243-701.601 w/w. In some embodiments, the partially pre-gelatinized maize starch is in an amount of about 43% w/w to about 44% w/w. [0186] In some embodiments, the microcrystalline cellulose is in an amount of about 30% w/w to about 50% w/w. In some embodiments, the microcrystalline cellulose is in an amount of about 40% w/w to about 50% w/w. In some embodiments, the microcrystalline cellulose is in an amount of about 42% w/w to about 50% w/w. In some embodiments, the microcrystalline cellulose is in an amount of about 44% w/w to about 48% w/w. [0187] In some embodiments, the sodium starch glycolate is in an amount of about 1% w/w to about 5% w/w. In some embodiments, the sodium starch glycolate is in an amount of about 2% w/w to about 4% w/w. In some embodiments, the sodium starch glycolate is in an amount of about 3% w/w to about 4% w/w. [0188] In some embodiments, wherein the hydroxypropyl cellulose LF is in an amount of about 1% w/w to about 5% w/w. In some embodiments, wherein the hydroxypropyl cellulose LF is in an amount of about 1% w/w to about 4% w/w. In some embodiments, wherein the hydroxypropyl cellulose LF is in an amount of about 2% w/w to about 3% w/w. [0189] In some embodiments, the colloidal silicon dioxide is in an amount of about 0.5% w/w to about 5% w/w. In some embodiments, the colloidal silicon dioxide is in an amount of about 0.5% w/w to about 3% w/w. in some embodiments, the colloidal silicon dioxide is in an amount of about 0.5% w/w to about 1.5% w/w. In some embodiments, the colloidal silicon dioxide is in the amount of about 1% w/w to about 1.5% w/w. In some embodiments, the colloidal silicon dioxide is in the amount of about 1% w/w to about 1.2% w/w. [0190] In some embodiments, the sodium lauryl sulfate is in the amount of about 0.04% w/w, the partially pre-gelatinized maize starch is in the amount of about 43% w/w to about 44% w/w, the microcrystalline cellulose is in the amount of about 44% w/w to about 48% w/w, the sodium starch glycolate is in the amount of about 3% w/w to about 4% w/w, the hydroxypropyl cellulose LF is in the amount of about 2% w/w to about 3% w/w, the colloidal silicon dioxide is in the amount of about 1% w/w to about 1.5% w/w, and the magnesium stearate is in the amount of about 1% w/w to about 1.5% w/w. [0191] In some embodiments, pharmaceutical compositions of the compounds of Formula (I) are modulators of the NLRP3 inflammasome. In some embodiments, pharmaceutical compositions of the compounds of Formula (I) inhibit NEK7 when administered to a patient or a biological sample.
WSGR Docket No. 63243-701.601 Method of Treatment [0192] Embodiments of the pharmaceutical composition described herein are useful as NEK7 inhibitors in a host species. The pharmaceutical composition comprising the compounds of Formula (I) can be allosteric inhibitors of NEK7. The compounds of Formula (I) can also inhibit other receptors such as the toll-like receptor (TLR) and interleukin family. The pharmaceutical composition comprising compounds of Formula (I) are also useful in the treatment of conditions mediated by effector signaling molecules like Il- ^ and IL-18. The host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats, and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatment of human disease. [0193] Described herein are pharmaceutical compositions useful as an inhibitor of the NLRP3 inflammasome activation mechanism. Therefore, the compounds of Formula (I) are also useful in the treatment of conditions resulting from that activation in a host species. [0194] Embodiments of the pharmaceutical compositions herein are useful as inhibitors of the NLRP3 (protein) -NEK7 (protein) interaction. Therefore, in some embodiments the compounds are also useful in the treatment of conditions resulting from the association of NLRP3-NEK7 in a host species. [0195] Embodiments of the pharmaceutical compositions are useful in treating human conditions mediated by effectors selected from the group consisting of IL- ^, IL-18, and caspase-1. The pharmaceutical composition can be useful as a potent inhibitor of the interleukin family, such as, in a non-limiting example, potent inhibition of IL-1 family cytokine generation. Common interleukin families include, but are not limited to IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL13, IL-15, and IL-17. [0196] Embodiments herein also relate to the use of pharmaceutical compositions and/or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or modulated by the NLRP3 inflammasome activity. Furthermore, embodiments herein relate to the use of pharmaceutical compositions and/or physiologically acceptable salts thereof for the production of a medicament for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or modulated by NLRP3 inflammasome activity. In certain embodiments, the disclosure provides the use of a pharmaceutical composition for the
WSGR Docket No. 63243-701.601 production of a medicament for the prophylactic or therapeutic treatment of a NLRP3 - mediated disorder. [0197] Described herein is a method of treating inflammatory diseases or conditions mediated by NLRP3 inflammasome by administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition described herein. [0198] In some embodiments, the diseases which can be treated with a pharmaceutical composition described herein include type II diabetes, atherosclerosis, Alzheimer’s disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, enteritis, hepatitis, peritonitis, silicosis, UV- induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative disease, multiple sclerosis, and Muckle-Wells syndrome. [0199] In some embodiments, the pharmaceutical composition is used in methods for treatment of disorders or diseases selected from auto-immune, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergy, asthma, pancreatitis, multi-organ failure, kidney diseases, platelet aggregation, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injuries, respiratory diseases, ischemic conditions, and cancer. In some more specific embodiments, the compounds of Formula (I) are used in methods for treatment of myelodysplastic syndrome (MDS). [0200] In some embodiments, the pharmaceutical composition comprising the compounds of Formula (I) are useful for treating subjects with MDS. The subject may have varying types of MDS. In a non-limiting example, the subject may have documented diagnosis of MDS, non-proliferative myelodysplastic/myeloproliferative neoplasm (MDS/MPN), MDS with low blasts, MDS with increased blasts, hypoplastic MDS, mutations in MDS with low blasts, such as isolated deletions or mutations, and leukemia, such as chronic myelomonocytic leukemia. In some embodiments, the pharmaceutical composition comprising the compounds of Formula (I) are useful for treating subjects with very low to intermediate risk of MDS, and the subject may also have symptomatic anemia. In some embodiments, the compound of Formula (I) is Compound 10, and the subject is treated with 0.5 mg to 5 mg Compound 10 (e.g., 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg). The subject may be administered Compound 10 daily, e.g., for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or longer. [0201] In some embodiments, the subject with MDS or risk of MDS is refractory, intolerant of, or ineligible of treatment with an erythroid stimulating agent (ESA). In some
WSGR Docket No. 63243-701.601 embodiments, the subject is refractory with treatment of ESA. In some embodiments, the subject is intolerant of treatment with ESA. In some embodiments, the subject is ineligible for treatment with ESA. In some embodiments, the subject is non-responsive to treatment with ESA. In some embodiments, the subject has discontinue treatment of ESA for at least 2 weeks prior to administration of the pharmaceutical composition comprising compounds of Formula (I) (e.g., Compound 10). [0202] In some embodiments, the disorders associated with NEK7 which are treatable with a pharmaceutical composition described herein, are selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn’s Disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndrome, cryopyrin associated periodic syndromes, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult's onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (Deficiency of IL-l Receptor Antagonist), Alzheimer’s disease, Parkinson’s disease, and cancer. [0203] Provided herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein. [0204] In some embodiments, the disease or disorder is an NLRP3-mediated disease or disorder. In some embodiments, the NLRP3-mediated disease or disorder is a myelodysplastic syndrome, an inflammatory disease or disorder, an auto-immune disease or disorder, a cardiovascular disease, a neurodegenerative disease or disorder, a bacterial and/or viral infection, an allergy, asthma, pancreatitis, multi-organ failure, a kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, a lung injury, a respiratory disease, an ischemic condition, or a combination thereof. [0205] In some embodiments, the NLRP3-mediated disease or disorder is myelodysplastic syndrome or inflammatory disease or disorder. In some embodiments, the NLRP3-mediated disease or disorder is myelodysplastic syndrome. In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome with multilineage dysplasia, myelodysplastic syndrome with single lineage dysplasia, myelodysplastic syndrome with ring sideroblasts, myelodysplastic syndrome with excess blasts, myelodysplastic syndrome with isolated del, or myelodysplastic syndrome unclassifiable.
WSGR Docket No. 63243-701.601 [0206] In some embodiments, the NLRP3-mediated disease or disorder is an inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder is acute inflammatory pain. [0207] In some aspects, described herein is a method of treating myelodysplastic syndrome (MDS) in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: A is C
6-C
10 aryl, C
3-C
10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6; X is CH or N; Y is NH; R
1 is H; R
2 is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl; R
3 is H; R
4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4- triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5- thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C
6 haloalkyl, C
3-C
8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1-C
6 cyanoalkyl, 3- to 8-membered heterocyclyl, C
3-C
8 haloalkylcycloalkyl, C
3-C
8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3-
WSGR Docket No. 63243-701.601 to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R
5 is H; and each R
6 is independently halo, C
1-C
6 alkyl, C
1-C
6 alkoxy, cyano, C
1-C
6 hydroxylalkyl or C1-C6 haloalkyl; wherein: (i) the subject has symptomatic anemia; (ii) the subject is refractory, intolerant of or ineligible for treatment with an erythroid stimulating agent (ESA), optionally wherein the subject has discontinued prior ESA at least two weeks prior to the administering; (iii) the subject has very low-risk MDS, low-risk MDS, or intermediate-risk MDS; (iv) administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, orally to the subject; (v) administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject daily; or (vi) a combination of two or more of (i) to (v). In some embodiments, the compound of Formula (I) is Compound 10, and the subject is treated with 0.5 mg to 5 mg Compound 10 (e.g., 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg). The subject may be administered Compound 10 daily, e.g., for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or longer. EXAMPLES [0208] The following illustrative examples are representative of embodiments of the stimulation, systems, and methods described herein and are not meant to be limiting in any way. Example 1. Composition of Capsules [0209] The below tables provide the composition of the active ingredient Compound 10 in various amounts for treating patients by modulating the NLRP3 inflammasome for treating a disease.
WSGR Docket No. 63243-701.601 Table 2. Composition of Compound 10 Capsules, 0.5 mg
Table 3. Composition of Compound 10 Capsules, 2 mg
Table 4. Composition of Compound 10 Capsules, 5 mg
Table 5. Composition of Compound 10 Capsules, 4 mg
WSGR Docket No. 63243-701.601
Example 2. Composition of Tablets [0210] The below tables provide the composition of the active ingredient Compound 10 in various amounts for treating patients by modulating the NLRP3 inflammasome for treating a disease. Table 6. Composition of Compound 10 Tablets: 0.5 mg and 2 mg
* water is removed as part of the tablet manufacturing process **target weight gain 50% extra quantity of Opadry reagent and water are dispensed to account for manufacturing losses (additional quantity not shown in the table) [0211] The compound 10 drug product is supplied as immediate-release, film-coated tablets containing 0.5 or 2 mg of the active ingredient compound 10. Tablets of both strengths are supplied as 7 mm diameter, round-shaped tablets that are plain-faced with a core tablet weight of 140 mg. They are distinguished by their film coat color – 0.5 mg tablets film- coated with yellow and 2 mg tablets film-coated with red. Similarly sized, shaped, and color film-coated placebo tablets to match 0.5 mg and 2 mg active tablets are manufactured to support clinical trials.
WSGR Docket No. 63243-701.601 Table 7. Composition of Compound 10 Tablets: 4.0 mg and 5.0 mg
* water is removed as part of the tablet manufacturing process **target weight gain 50% extra quantity of Opadry reagent and water are dispensed to account for manufacturing losses (additional quantity not shown in the table) Table 8. Function of Selected Excipients in Compound 10 Tablets
WSGR Docket No. 63243-701.601
Table 9. Physical parameters of Compound 10 Tablets: 0.5 mg
Table 10. Physical Parameters of Compound 10 Tablets: 2.0 mg
WSGR Docket No. 63243-701.601 Table 11. Stability Data of Compound 10 in 0.5 mg Strength Tablets
Table 12. Stability Data of Compound 10 in 2 mg Strength Tablets
Overall Stability of Compound 10 Active Tablets (0.5 mg and 2.0 mg) [0212] The Compound 10 clinical formulation as a tablet in either strength of 0.5 and 2 mg is stable with no degradant trends observed during formulation development as shown in table 11 and table 12 from prototype/developmental batches. This testing was carried out through 3 months at both 25 °C/60%RH long-term condition and 40 °C/75%RH accelerated condition after packaging the tablets in HDPE bottles.
WSGR Docket No. 63243-701.601 [0213] Data from technical batches indicate the active drug product of both the strengths, 0.5 mg and 2 mg, to be stable through 3 months of testing at all the storage conditions. No new impurities were detected and there is slight increase in some of the individual impurities as well as total impurities, especially at accelerated storage condition. However, all the values for impurities as well as for the other tested parameters were well within the specification. This data supports long-term storage of compound 10 drug product at the proposed controlled room temperature (20-25 °C) in HDPE bottles. Example 3. Pharmacokinetics of Compound 10 [0214] The subjects were treated with 1 mg to 4 mg of Compound 10 on a 5 days on, 2 days off cycle for 2 weeks. The table below shows the resulting PK parameters. Table 13. PK Parameters for Compound 10
[0215] The plasma concentration time profiles are shown in FIG.1. Example 4. Clinical Trials of Pharmaceutical Formulation of Compound 10 [0216] The subjects were treated with a pharmaceutical composition comprising the compounds described in any one of Tables 2 to 4. The subjects were treated with the pharmaceutical composition once daily for five days and then had two days without treatment, for a one-week cycle treatment. This cycle treatment was repeated for up to 16 weeks with a possible extension of another 16 weeks in case of positive response. Some subjects may have their blood (plasma) collected to determine trough concentrations of Compound 10 before the beginning of each cycle. [0217] The subjects will be selected via the following criteria: 1. A documented diagnosis of MDS or non-proliferative (WBC <13,000/µL) myelodysplastic/myeloproliferative neoplasm (MDS/MPN) according to World Health Organization (WHO) 2022 classification and Revised International Prognostic Scoring System (IPSS-R) classification of very low, low, or intermediate risk disease Following MDS subjects as per WHO 2022 criteria are eligible
WSGR Docket No. 63243-701.601 MDS with low blasts and isolated 5q deletion (MDS-5q) MDS with low blasts and SF3B1 mutation (MDS-SF3B1) MDS with low blasts (MDS-LB) MDS, hypoplastic (MDS-h) MDS with increased blasts (MDS-IB) : MDS-IB1 Following non-proliferative MDS/MPN subjects as per WHO 2022 criteria are eligible Chronic myelomonocytic leukaemia Myelodysplastic/myeloproliferative neoplasm with neutrophilia Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis Myelodysplastic/myeloproliferative neoplasm, not otherwise specified 2. Less than 10% bone marrow myeloblasts 3. Refractory or intolerant of, or ineligible for treatment with an erythroid stimulating agent (ESA) as defined by any of the following: a) Refractory to prior ESA treatment: Prior treatment with an ESA without response or no longer responding to an ESA alone or in combination with a myeloid growth factor (must have received recombinant erythropoietin (rHu EPO) with epoetin alfa ≥ 40,000 IU/week for > 8 weeks or darbepoetin alpha 300-500 μg Q 2-3 W for > 8 weeks) b) Intolerant to prior ESA treatment: Intolerant to prior ESA treatment with documentation of discontinuation due to intolerance or adverse event. c) ESA ineligible: Subject may be ESA ineligible due to low probability of response to ESAs based upon endogenous serum erythropoietin level > 200 U/L for subjects not previously treated with ESAs Example 5. Phase II Study of NLRP3 Inflammasome & Myddosome Inhibitor Compound 10 in Patients with Low or Intermediate Risk Myelodysplastic Syndrome (MDS) [0218] The compounds described herein include first-in class, allosteric inhibitors of the inflammasome scaffold protein NEK7. As representative of the class, Compound 10 is used in clinical studies. By inducing conformational changes that prevent NEK7-NLRP3 interaction necessary for NLRP3 inflammasome assembly and IRAK1/4 activation, Compound 10 inhibits both Toll-like receptor (TLR)-priming as well as NLRP3 inflammasome complex assembly. Unlike NLRP3, ATPase-targeted inhibitors, Compound
WSGR Docket No. 63243-701.601 10 effectively extinguishes NLRP3 activation and induces the disassembly of activated inflammasome complexes and circulating ASC specks. This results in potent inhibition of IL- 1-family cytokine generation (IL-1β release IC50 = 22 nM in THP-1 differentiated macrophages) and the abrogation of pyroptosis. The NLRP3 inflammasome is a key biological driver of ineffective hematopoiesis in MDS that is reinforced by non-canonical IRAK1/4 signaling propagating leukemic stem cell self-renewal. [0219] A first-in human phase I study performed in normal volunteers showed that oral administration of Compound 10 was readily absorbed, had a prolonged elimination half-life, and effectively blocked NLRP3 inflammasome activation at low doses. [0220] The Phase IIa study evaluates the efficacy, safety, and pharmacodynamics of Compound 10 administered to up to 40 adult patients with a diagnosis of very low, low, or intermediate-risk myelodysplastic syndrome (MDS) and symptomatic anemia, as defined by the Revised International Prognostic Scoring System (IPSS-R). [0221] All subjects will have signed informed consent, have symptomatic anemia, be refractory, intolerant of or ineligible for treatment with an erythroid stimulating agent (ESA), and have discontinued prior ESA at least 2 weeks prior to study treatment. The study will measure the rate of hematological improvement (according to IWG 2018 criteria), including transfusion dependence and changes in hemoglobin level as primary study endpoints. Secondary endpoints will further assess safety and tolerability, the effect of Compound 10 on biomarkers of inflammasome activation, and changes in clone size as measured by somatic gene mutation variant allele frequency. Compound 10 is administered orally on a weekly 5 days on and 2 days off schedule on a 28-day cycle. From cycle 5 to cycle 8, dosing with epoetin alfa subcutaneously (SC) weekly or darbepoetin alpha SC every 2 weeks is permitted in subjects not responding to Compound 10 monotherapy at week 16. Example 6. Phase II Study of NLRP3 Inflammasome & Myddosome Inhibitor Compound 10 in Patients with Low or Intermediate Risk Myelodysplastic Syndrome (MDS) [0222] The compounds described herein include first-in class, allosteric inhibitors of the inflammasome scaffold protein NEK7. As representative of the class, Compound 10 is used in clinical studies. By inducing conformational changes that prevent NEK7-NLRP3 interaction necessary for NLRP3 inflammasome assembly and IRAK1/4 activation, Compound 10 inhibits both Toll-like receptor (TLR)-priming as well as NLRP3 inflammasome complex assembly. Unlike NLRP3, ATPase-targeted inhibitors, Compound 10 effectively extinguishes NLRP3 activation and induces the disassembly of activated
WSGR Docket No. 63243-701.601 inflammasome complexes and circulating ASC specks. This results in potent inhibition of IL- 1-family cytokine generation (IL-1β release IC50 = 22 nM in THP-1 differentiated macrophages) and the abrogation of pyroptosis. The NLRP3 inflammasome is a key biological driver of ineffective hematopoiesis in MDS that is reinforced by non-canonical IRAK1/4 signaling propagating leukemic stem cell self-renewal. [0223] A first-in human phase I study performed in normal volunteers showed that oral administration of Compound 10 was readily absorbed, had a prolonged elimination half-life, and effectively blocked NLRP3 inflammasome activation at low doses. [0224] The Phase IIa study evaluates the efficacy, safety, and pharmacodynamics of Compound 10 administered to up to 40 adult patients with a diagnosis of very low, low, or intermediate-risk myelodysplastic syndrome (MDS) and symptomatic anemia, as defined by the Revised International Prognostic Scoring System (IPSS-R). [0225] All subjects will have signed informed consent, have symptomatic anemia, be refractory, intolerant of or ineligible for treatment with an erythroid stimulating agent (ESA), and have discontinued prior ESA at least 2 weeks prior to study treatment. The study will measure the rate of hematological improvement (according to IWG 2018 criteria), including transfusion dependence and changes in hemoglobin level as primary study endpoints. Secondary endpoints will further assess safety and tolerability, the effect of Compound 10 on biomarkers of inflammasome activation, and changes in clone size as measured by somatic gene mutation variant allele frequency. Compound 10 is administered daily at a 4 mg oral dose for up to 12 weeks. Example 7. Phase II Study of NLRP3 Inflammasome & Myddosome Inhibitor Compound 10 in Patients with Low or Intermediate Risk Myelodysplastic Syndrome (MDS) [0226] The compounds described herein include first-in class, allosteric inhibitors of the inflammasome scaffold protein NEK7. As representative of the class, Compound 10 is used in clinical studies. By inducing conformational changes that prevent NEK7-NLRP3 interaction necessary for NLRP3 inflammasome assembly and IRAK1/4 activation, Compound 10 inhibits both Toll-like receptor (TLR)-priming as well as NLRP3 inflammasome complex assembly. Unlike NLRP3, ATPase-targeted inhibitors, Compound 10 effectively extinguishes NLRP3 activation and induces the disassembly of activated inflammasome complexes and circulating ASC specks. This results in potent inhibition of IL- 1-family cytokine generation (IL-1β release IC50 = 22 nM in THP-1 differentiated macrophages) and the abrogation of pyroptosis. The NLRP3 inflammasome is a key
WSGR Docket No. 63243-701.601 biological driver of ineffective hematopoiesis in MDS that is reinforced by non-canonical IRAK1/4 signaling propagating leukemic stem cell self-renewal. [0227] A first-in human phase I study performed in normal volunteers showed that oral administration of Compound 10 was readily absorbed, had a prolonged elimination half-life, and effectively blocked NLRP3 inflammasome activation at low doses. [0228] The Phase IIa study evaluates the efficacy, safety, and pharmacodynamics of Compound 10 administered to up to 40 adult patients with a diagnosis of very low, low, or intermediate-risk myelodysplastic syndrome (MDS) and symptomatic anemia, as defined by the Revised International Prognostic Scoring System (IPSS-R). [0229] All subjects will have signed informed consent, have symptomatic anemia, be refractory, intolerant of or ineligible for treatment with an erythroid stimulating agent (ESA), and have discontinued prior ESA at least 2 weeks prior to study treatment. The study will measure the rate of hematological improvement (according to IWG 2018 criteria), including transfusion dependence and changes in hemoglobin level as primary study endpoints. Secondary endpoints will further assess safety and tolerability, the effect of Compound 10 on biomarkers of inflammasome activation, and changes in clone size as measured by somatic gene mutation variant allele frequency. Compound 10 is administered daily at a 5 mg oral dose for up to 12 weeks. Numbered Embodiments [0230] Some numbered examples of embodiments follow. [0231] (1) A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6; X is CH or N; Y is NH;
WSGR Docket No. 63243-701.601 R
1 is H; R
2 is C
1-C
6 alkyl, C
3-C
4 cycloalkyl, C
3-C
8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 alkoxy and 3- to 8-membered heterocyclyl; R
3 is H; R
4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1-C
6 cyanoalkyl, 3- to 8-membered heterocyclyl, C
3-C
8 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; R
5 is H; and each R
6 is independently halo, C
1-C
6 alkyl, C
1-C
6 alkoxy, cyano, C
1-C
6 hydroxylalkyl or C1-C6 haloalkyl; and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition comprises no more than 10 mg of Formula (I). [0232] (2) The pharmaceutical composition of embodiment 1, wherein R
2 is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 alkoxy and 3- to 8- membered heterocyclyl. [0233] (3) The pharmaceutical composition of embodiment 1 or 2, wherein R
2 is:
[0234] (4) The pharmaceutical composition of any one of embodiments 1 to 3, wherein R
4 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6
WSGR Docket No. 63243-701.601 alkynyl, C
1-C
6 haloalkyl, C
3-C
8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1-C
6 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 C
3-C
8 halocycloalkyl, and combinations thereof. [0235] (5) The pharmaceutical composition of embodiment 4, wherein R
4 is substituted with C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
3-C
8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C
1- C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8- membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C
3-C
8 halocycloalkyl, or combinations thereof. [0236] (6) The pharmaceutical composition of any one of embodiments 1 to 5, wherein R
4 has one of the following structures:
WSGR Docket No. 63243-701.601 [0237] (7) The pharmaceutical composition of any one of embodiments 1 to 6, 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 R
6. [0238] (8) The pharmaceutical composition of embodiment 1, wherein A is cyclohexyl, cyclohexenyl, phenyl, pyridinyl, or pyrimidinyl. [0239] (9) The pharmaceutical composition of embodiment 8, wherein A is phenyl. [0240] (10) The pharmaceutical composition of any one of embodiments 1 to 9, wherein A is unsubstituted. [0241] (11) The pharmaceutical composition of any one of embodiments 1 to 9, wherein A is substituted with one or more R
6. [0242] (12) The pharmaceutical composition of embodiment 11, wherein R
6 is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy. [0243] (13) The pharmaceutical composition of any one of embodiments 1 to 12, wherein A is:
[0244] (14) The pharmaceutical composition of embodiment 1, wherein the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein:
WSGR Docket No. 63243-701.601 R
2a is C
3-C
4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R
4a is isoxazolyl optionally substituted with one more substituents selected from C
1- C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl. [0245] (15) The pharmaceutical composition of embodiment 1, wherein R
2a is cyclopropyl. [0246] (16) The pharmaceutical composition of embodiment 1 or 15, wherein R
4a is:
[0247] (17) The pharmaceutical composition of any one of embodiments 1 to 16, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. [0248] (18) The pharmaceutical composition of any one of embodiments 1 to 17, wherein the pharmaceutical composition comprises about 0.5 mg to about 5 mg of the compound of Formula (I). [0249] (19) The pharmaceutical composition of embodiment 18, wherein the pharmaceutical composition comprises about 5 mg of the compound of Formula (I). [0250] (20) The pharmaceutical composition of embodiment 18, wherein the pharmaceutical composition comprises about 4 mg of the compound of Formula (I). [0251] (21) The pharmaceutical composition of embodiment 18, wherein the pharmaceutical composition comprises about 3 mg of the compound of Formula (I). [0252] (22) The pharmaceutical composition of embodiment 18, wherein the pharmaceutical composition comprises about 2 mg of the compound of Formula (I). [0253] (23) The pharmaceutical composition of embodiment 18, wherein the pharmaceutical composition comprises about 1 mg of the compound of Formula (I). [0254] (24) The pharmaceutical composition of embodiment 18, wherein the pharmaceutical composition comprises about 0.5 mg of the compound of Formula (I). [0255] (25) The pharmaceutical composition of any one of embodiments 1 to 24, wherein the pharmaceutical composition is administered to the subject in a one-week cycle, wherein the one-week cycle consists of administering the composition for five days consecutively and then not administering the pharmaceutical composition for two days consecutively.
WSGR Docket No. 63243-701.601 [0256] (26) The pharmaceutical composition of embodiment 25, wherein the pharmaceutical composition is administered in the one-week cycle for at least 2 weeks. [0257] (27) The pharmaceutical composition of embodiment 26, wherein the pharmaceutical composition is administered in the one-week cycle for 4 weeks. [0258] (28) The pharmaceutical composition of embodiment 26, wherein the pharmaceutical composition is administered in the one-week cycle for 16 weeks. [0259] (29) The pharmaceutical composition of embodiment 26, wherein the pharmaceutical composition is administered in the one-week cycle for 32 weeks. [0260] (30) The pharmaceutical composition of any one of embodiments 1 to 29, wherein the pharmaceutical composition is in a capsule. [0261] (31) The pharmaceutical composition of embodiment 30, wherein the capsule is a hard gelatin capsule. [0262] (32) The composition of embodiment 31, wherein the capsule is a size 3 capsule. [0263] (33) The composition of embodiment 32, wherein the capsule is opaque white, Swedish orange, or dark green. [0264] (34) The pharmaceutical composition of any one of embodiments 1 to 33, wherein the pharmaceutically acceptable excipient is sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. [0265] (35) The pharmaceutical composition of embodiment 34, wherein the sodium lauryl sulfate is Kolliphore SLS fine, the partially pre-gelatinized maize starch is Starch 1500, the microcrystalline cellulose is Avicel PH 101, the sodium starch glycolate is type A, the hydroxypropyl cellulose LF is Klucel HPC LF, and the colloidal silicon dioxide is Aerosil Pharma 200. [0266] (36) The pharmaceutical composition of embodiment 34 or 35, wherein the sodium lauryl sulfate is in an amount of about 0.01% w/w to about 0.1% w/w. [0267] (37) The pharmaceutical composition of embodiment 36, wherein the sodium lauryl sulfate is in the amount of about 0.04% w/w. [0268] (38) The pharmaceutical composition of any one of embodiments 34 to 37, wherein the partially pre-gelatinized maize starch is in an amount of about 30% w/w to about 50% w/w. [0269] (39) The pharmaceutical composition of embodiment 38, wherein the partially pre-gelatinized maize starch is in the amount of about 43% w/w to about 44% w/w.
WSGR Docket No. 63243-701.601 [0270] (40) The pharmaceutical composition of any one of embodiments 34 to 39, wherein the microcrystalline cellulose is in an amount of about 30% w/w to about 50% w/w. [0271] (41) The pharmaceutical composition of embodiment 40, wherein the microcrystalline cellulose is in the amount of about 44% w/w to about 48% w/w. [0272] (42) The pharmaceutical composition of any one of embodiments 34 to 41, wherein the sodium starch glycolate is in an amount of about 1% w/w to about 5% w/w. [0273] (43) The pharmaceutical composition of embodiment 42, wherein the sodium starch glycolate is in the amount of about 3% w/w to about 4% w/w. [0274] (44) The pharmaceutical composition of any one of embodiments 34 to 43, wherein the hydroxypropyl cellulose LF is in an amount of about 1% w/w to about 5% w/w. [0275] (45) The pharmaceutical composition of embodiment 44, wherein the hydroxypropyl cellulose LF is in the amount of about 2% w/w to about 3% w/w. [0276] (46) The pharmaceutical composition of any one of embodiments 34 to 45, wherein the colloidal silicon dioxide is in an amount of about 0.5% w/w to about 5% w/w. [0277] (47) The pharmaceutical composition of embodiment 46, wherein the colloidal silicon dioxide is in the amount of about 1% w/w to about 1.5% w/w. [0278] (48) The pharmaceutical composition of any one of embodiments 34 to 47, wherein the magnesium stearate is in an amount of about 0.5% w/w to about 5% w/w. [0279] (49) The pharmaceutical composition of embodiment 48, wherein the magnesium stearate is in the amount of about 1% w/w to about 1.5% w/w. [0280] (50) A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1 to 49. [0281] (51) The method of embodiment 50, wherein the disease or disorder is an NLRP3- mediated disease or disorder. [0282] (52) The method of embodiment 51, wherein the NLRP3-mediated disease or disorder is a myelodysplastic syndrome, an inflammatory disease or disorder, an auto- immune disease or disorder, a cardiovascular disease, a neurodegenerative disease or disorder, a bacterial and/or viral infection, an allergy, asthma, pancreatitis, multi-organ failure, a kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, a lung injury, a respiratory disease, an ischemic condition, or a combination thereof. [0283] (53) The method of embodiment 52, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome or inflammatory disease or disorder.
WSGR Docket No. 63243-701.601 [0284] (54) The method of embodiment 53, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome. [0285] (55) The method of embodiment 54, where the myelodysplastic syndrome is myelodysplastic syndrome with multilineage dysplasia, myelodysplastic syndrome with single lineage dysplasia, myelodysplastic syndrome with ring sideroblasts, myelodysplastic syndrome with excess blasts, myelodysplastic syndrome with isolated del, or myelodysplastic syndrome unclassifiable. [0286] (56) The method of embodiment 53, wherein the NLRP3-mediated disease or disorder is an inflammatory disease or disorder. [0287] (57) The method of embodiment 56, wherein the inflammatory disease or disorder is acute inflammatory pain. [0288] (58) A method of treating myelodysplastic syndrome (MDS) in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: A is C
6-C
10 aryl, C
3-C
10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6; X is CH or N; Y is NH; R
1 is H; R
2 is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 alkoxy and 3- to 8-membered heterocyclyl; R
3 is H; R
4 is 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-
WSGR Docket No. 63243-701.601 thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C
3-C
8 aminylalkylcycloalkyl, C
3-C
8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R
5 is H; and each R
6 is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1-C6 haloalkyl; wherein: (i) the subject has symptomatic anemia; (ii) the subject is refractory, intolerant of or ineligible for treatment with an erythroid stimulating agent (ESA), optionally wherein the subject has discontinued prior ESA at least two weeks prior to the administering; (iii) the subject has very low-risk MDS, low-risk MDS, or intermediate-risk MDS; (iv) administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, orally to the subject; (v) administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject in a weekly regimen comprising once a day administration for five days, and then no administration for two days, optionally wherein the weekly regimen is performed for about 4 to about 56 weeks; or (vi) a combination of two or more of (i) to (v). [0289] (59) A method of treating myelodysplastic syndrome (MDS) in a subject in need thereof, the method comprising administering to the subject epoetin alfa or darbepoetin alpha, and a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein:
WSGR Docket No. 63243-701.601 A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R
6; X is CH or N; Y is NH; R
1 is H; R
2 is C
1-C
6 alkyl, C
3-C
4 cycloalkyl, C
3-C
8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 alkoxy and 3- to 8-membered heterocyclyl; R
3 is H; R
4 is 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, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 haloalkyl, C
3-C
8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C
3-C
8 aminylalkylcycloalkyl, C
3-C
8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R
5 is H; and each R
6 is independently halo, C
1-C
6 alkyl, C
1-C
6 alkoxy, cyano, C
1-C
6 hydroxylalkyl or C1-C6 haloalkyl. [0290] (60) The method of embodiment 59, wherein prior to administering, the subject has not responded to monotherapy treatment with the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof. [0291] (61) The method of embodiment 59 or embodiment 60, wherein the epoetin alpha or darbepoetin alpha is administered every two weeks. [0292] (62) The method of any one of embodiments 59 to 61, wherein the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject in a regimen comprising once a day administration for five days, and then no administration for two days, for a 28-day cycle. [0293] (63) The method of embodiment 62, wherein the 28-day cycle is performed for about 1 to about 12 cycles.
WSGR Docket No. 63243-701.601 [0294] (64) The method of embodiment 63, wherein the 28-day cycle is performed for at least 8 cycles, and the epoetin alfa or darbepoetin alpha is administered during the fifth to eighth 28-day cycle. [0295] (65) The method of any one of embodiments 59 to 64, wherein the epoetin alpha or darbepoetin alpha is administered subcutaneously. [0296] (66) The method of any one of embodiments 59 to 65, wherein the subject has symptomatic anemia. [0297] (67) The method of any one of embodiments 59 to 66, wherein the subject has very low-risk MDS, low-risk MDS, or intermediate-risk MDS. [0298] (68) The method of any one of embodiments 59 to 67, wherein administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, orally to the subject. [0299] (69) The method of any one of embodiments 58-68, wherein each dose of the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is about 1 mg to about 4 mg. [0300] (70) The method of any one of embodiments 58 to 69, wherein R
2 is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8- membered heterocyclyl. [0301] (71) The pharmaceutical composition of any one of embodiments 58 to 70, wherein R
2 is:
[0302] (72) The pharmaceutical composition of any one of embodiments 58 to 71, wherein R
4 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, C
1-C
6 haloalkyl, C
3-C
8 cycloalkyl, cyano, aminyl, C
1-C
6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C
3-C
8 aminylalkylcycloalkyl, C
3-C
8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C
3- C8 halocycloalkyl, and combinations thereof.
WSGR Docket No. 63243-701.601 [0303] (73) The pharmaceutical composition of embodiment 72, wherein R
4 is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1- C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C
3-C
8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8- membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof. [0304] (74) The pharmaceutical composition of any one of embodiments 58 to 73, wherein R
4 has one of the following structures:
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 R
6. [0306] (76) The pharmaceutical composition of any one of embodiments 58 to 69, wherein A is cyclohexyl, cyclohexenyl, phenyl, pyridinyl, or pyrimidinyl. [0307] (77) The pharmaceutical composition of embodiment 76, wherein A is phenyl.
WSGR Docket No. 63243-701.601 [0308] (78) The pharmaceutical composition of any one of embodiments 58 to 77, wherein A is unsubstituted. [0309] (79) The pharmaceutical composition of any one of embodiments 58 to 78, wherein A is substituted with one or more R
6. [0310] (80) The pharmaceutical composition of embodiment 79, wherein R
6 is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy. [0311] (81) The pharmaceutical composition of any one of embodiments 58 to 80, wherein A is:
[0312] (82) The pharmaceutical composition of any one of embodiments 58 to 69, wherein the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt,
wherein: R
2a is C
3-C
4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R
4a is isoxazolyl optionally substituted with one more substituents selected from C
1- C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl.
WSGR Docket No. 63243-701.601 [0313] (83) The pharmaceutical composition of any one of embodiments 58 to 69, wherein R
2a is cyclopropyl. [0314] (84) The pharmaceutical composition of any one of embodiments 58 to 69, or embodiment 83, wherein R
4a is:
[0315] (85) The pharmaceutical composition of any one of embodiments 58 to 84, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. [0316] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1 is H; R2 is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl; R3 is H;
WSGR Docket No. 63243-701.601 R4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5 is H; and each R6 is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1-C6 haloalkyl; and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition comprises no more than 10 mg of Formula (I). [0004] An aspect of the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1 is H; R2 is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl;
WSGR Docket No. 63243-701.601 R3 is H; R4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5 is H; and each R6 is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1-C6 haloalkyl; and at least one pharmaceutically acceptable excipient, wherein the amount of a compound of Formula (I) in the pharmaceutical composition is from about 0.5 to about 5 mg. [0005] In some embodiments, the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, or magnesium stearate, or a combination of two or more thereof. [0006] An aspect of the present disclosure provides a method of treating an NLRP3- mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein. [0007] In some embodiments, the NLRP3-mediated disease or disorder is myelodysplastic syndrome. [0008] In some embodiments, the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
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[0135] In some embodiments, R2 is:
[0136] In some embodiments, R3 is any suitable functional group described herein. In some embodiments, R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy. In some embodiments, R3 is H or C1- C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy. In some embodiments, R3 is H. In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is methyl, ethyl, n-propyl, or isopropyl. [0137] In some embodiments, R4 is any suitable functional group described herein. In some embodiments, R4 is 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
WSGR Docket No. 63243-701.601 halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, , cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof. In some embodiments, R4 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3- C8 halocycloalkyl, and combinations thereof. [0138] In some embodiments, R4 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl or 1, 3, 4- oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. In some embodiments, R4 is isoxazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl. [0139] In some embodiments, R4 is isoxazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. [0140] In some embodiments, R4 is thiazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl,
WSGR Docket No. 63243-701.601 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. [0141] In some embodiments, R4 is isothiazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. [0142] In some embodiments, R4 is 1,2,4-thiadiazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8- membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. [0143] In some embodiments, R4 is 1,3,4-thiadiazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8- membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. [0144] In some embodiments, R4 is 1,2,4-triazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. [0145] In some embodiments, R4 is 1, 3, 4-oxadiazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, 3- to 8-membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof. [0146] In some embodiments, R4 is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered
WSGR Docket No. 63243-701.601 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. [0147] In some embodiments, R4 is:
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[0150] In some embodiments, R5 is any suitable functional group described herein. In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy. In some embodiments, R5 is H or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy. In some embodiments, R5 is H. In some embodiments, R5 is C1-C6 alkyl. In some embodiments, R5 is methyl, ethyl, n-propyl, or isopropyl. [0151] In some embodiments, each R6 is any suitable functional group described herein. In some embodiments, each R6 is independently halo, C1-C6 alkyl, cyano, C1-C6 hydroxylalkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. In some embodiments, each R6 is chloro or fluoro. In some embodiments, each R6 is fluoro. In some embodiments, each R6 is C1-C6 hydroxylalkyl. In some embodiments, each R6 is C1-C6 hydroxylalkyl. In some embodiments,
WSGR Docket No. 63243-701.601 each R6 is -CH2CH2OH. In other embodiments, each R6 is cyano. In some embodiments, each R6 is C1-C6 alkoxy. In some embodiments, each R6 is methoxy. [0152] In some embodiments, A is:
[0153] In some embodiments, A is:
[0154] In some embodiments, the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: R2a is C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R4a is isoxazolyl optionally substituted with one more substituents selected from C1- C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl. [0155] In some embodiments, R2a is a branched C1-C6 alkyl substituted with hydroxyl. In some embodiments, R2a is C3-C8 cycloalkyl. In some embodiments, R2a is:
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[0156] In some embodiments, R4a is isoxazolyl substituted with C3-C8 haloalkylcycloalkyl. In some embodiments, R4a is C3-C8 fluoroalkylcycloalkyl. In some embodiments, R4a is fluoroalkylcyclopropyl or fluoroalkylcyclobutyl. In some embodiments, R4a is:
[0157] In some embodiments, the compound is a compound of Formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1 is H or C1-C6 alkyl; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl and C1-C6 alkoxy;
WSGR Docket No. 63243-701.601 R4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R6 is, at each occurrence, independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1-C6 haloalkyl. [0158] In some embodiments, the compound of Formula (I) is a modulator of the NLRP3 inflammasome. [0159] In some embodiments, the compound of Formula (I) is an inhibitor of NEK7 in a patient or in a biological sample. [0160] In various different embodiments, the compound has one of the structures set forth in Table 1 below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof. [0161] In some embodiments, the compound of Formula (I) is a compound selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments the compound of Formula (I) is selected from the group consisting of compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments the compound of Formula (I) is selected from the group consisting of compound 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of Formula (I) is selected from compound 10. Table 1: Representative Compounds of Formula (I)
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WSGR Docket No. 63243-701.601
Table 4. Composition of Compound 10 Capsules, 5 mg
Table 5. Composition of Compound 10 Capsules, 4 mg
WSGR Docket No. 63243-701.601
Example 2. Composition of Tablets [0210] The below tables provide the composition of the active ingredient Compound 10 in various amounts for treating patients by modulating the NLRP3 inflammasome for treating a disease. Table 6. Composition of Compound 10 Tablets: 0.5 mg and 2 mg
WSGR Docket No. 63243-701.601
Table 9. Physical parameters of Compound 10 Tablets: 0.5 mg
Table 10. Physical Parameters of Compound 10 Tablets: 2.0 mg
WSGR Docket No. 63243-701.601 Table 11. Stability Data of Compound 10 in 0.5 mg Strength Tablets
Table 12. Stability Data of Compound 10 in 2 mg Strength Tablets
[0234] (4) The pharmaceutical composition of any one of embodiments 1 to 3, wherein R4 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6
WSGR Docket No. 63243-701.601 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8- membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. [0235] (5) The pharmaceutical composition of embodiment 4, wherein R4 is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1- C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8- membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof. [0236] (6) The pharmaceutical composition of any one of embodiments 1 to 5, wherein R4 has one of the following structures:
WSGR Docket No. 63243-701.601 [0237] (7) The pharmaceutical composition of any one of embodiments 1 to 6, 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. [0238] (8) The pharmaceutical composition of embodiment 1, wherein A is cyclohexyl, cyclohexenyl, phenyl, pyridinyl, or pyrimidinyl. [0239] (9) The pharmaceutical composition of embodiment 8, wherein A is phenyl. [0240] (10) The pharmaceutical composition of any one of embodiments 1 to 9, wherein A is unsubstituted. [0241] (11) The pharmaceutical composition of any one of embodiments 1 to 9, wherein A is substituted with one or more R6. [0242] (12) The pharmaceutical composition of embodiment 11, wherein R6 is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy. [0243] (13) The pharmaceutical composition of any one of embodiments 1 to 12, wherein A is:
[0244] (14) The pharmaceutical composition of embodiment 1, wherein the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein:
WSGR Docket No. 63243-701.601 R2a is C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R4a is isoxazolyl optionally substituted with one more substituents selected from C1- C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl. [0245] (15) The pharmaceutical composition of embodiment 1, wherein R2a is cyclopropyl. [0246] (16) The pharmaceutical composition of embodiment 1 or 15, wherein R4a is:
[0302] (72) The pharmaceutical composition of any one of embodiments 58 to 71, wherein R4 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-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.
WSGR Docket No. 63243-701.601 [0303] (73) The pharmaceutical composition of embodiment 72, wherein R4 is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1- C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8- membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof. [0304] (74) The pharmaceutical composition of any one of embodiments 58 to 73, wherein R4 has one of the following structures:
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. [0306] (76) The pharmaceutical composition of any one of embodiments 58 to 69, wherein A is cyclohexyl, cyclohexenyl, phenyl, pyridinyl, or pyrimidinyl. [0307] (77) The pharmaceutical composition of embodiment 76, wherein A is phenyl.
WSGR Docket No. 63243-701.601 [0308] (78) The pharmaceutical composition of any one of embodiments 58 to 77, wherein A is unsubstituted. [0309] (79) The pharmaceutical composition of any one of embodiments 58 to 78, wherein A is substituted with one or more R6. [0310] (80) The pharmaceutical composition of embodiment 79, wherein R6 is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy. [0311] (81) The pharmaceutical composition of any one of embodiments 58 to 80, wherein A is:
[0312] (82) The pharmaceutical composition of any one of embodiments 58 to 69, wherein the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt,
wherein: R2a is C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R4a is isoxazolyl optionally substituted with one more substituents selected from C1- C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl.
WSGR Docket No. 63243-701.601 [0313] (83) The pharmaceutical composition of any one of embodiments 58 to 69, wherein R2a is cyclopropyl. [0314] (84) The pharmaceutical composition of any one of embodiments 58 to 69, or embodiment 83, wherein R4a is:
[0315] (85) The pharmaceutical composition of any one of embodiments 58 to 84, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. [0316] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1 is H; R2 is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl; R3 is H; R4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5 is H; and each R6 is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1-C6 haloalkyl; and
WSGR Docket No. 63243-701.601 at least one pharmaceutically acceptable excipient, wherein the amount of a compound of Formula (I) in the pharmaceutical composition is from about 0.5 to about 5 mg. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, or magnesium stearate, or a combination of two or more thereof. 3. A method of treating an NLRP3-mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 1 or claim 2. 4. The method of claim 3, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome. 5. The pharmaceutical composition of claim 1 or claim 2, wherein the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: R2a is C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R4a is isoxazolyl optionally substituted with one more substituents selected from C1- C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl. 6. The pharmaceutical composition of claim 1 or claim 2, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.
WSGR Docket No. 63243-701.601 7. The pharmaceutical composition of claim 1 or claim 2, wherein the compound
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pharmaceutically acceptable salt or solvate thereof. 8. The pharmaceutical composition of any one of claims 1-2 or 5-7, wherein the compound of Formula (I) is Compound 10 of Table 1. 9. The pharmaceutical composition of any one of claims 1-2 or 5-8, wherein the amount of the compound of Formula (I) in the pharmaceutical composition is about 4 mg. 10. The pharmaceutical composition of any one of claims 1-2 or 5-8, wherein the amount of the compound of Formula (I) in the pharmaceutical composition is about 5 mg 11. The pharmaceutical composition of any one of claims 1-2 or 5-8, wherein the amount of the compound of Formula (I) in the pharmaceutical composition is about 2 mg. 12. The pharmaceutical composition of any one of claims 1-2 or 5-8, wherein the amount of the compound of Formula (I) in the pharmaceutical composition is about 0.5 mg 13. The pharmaceutical composition of any one of claims 1-2 or 5-12, wherein the pharmaceutical composition is in a tablet. 14. The pharmaceutical composition of claim 13, wherein the tablet is a film- coated immediate-release tablet. 15. The pharmaceutical composition of claim 13 or claim 14, wherein the tablet is coated with Opadry II. 16. The pharmaceutical composition of any one of claims 13-15, wherein the tablet has a diameter of about 7 mm.
WSGR Docket No. 63243-701.601 17. The pharmaceutical composition of any one of claims 1 or 5-16, wherein the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre- gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, magnesium stearate, or a combination of two or more thereof. 18. The pharmaceutical composition of any one of claims 1-2 or 5-17, wherein the pharmaceutically acceptable excipient comprises at least three ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. 19. The pharmaceutical composition of any one of claims 1-2 or 5-18, wherein the pharmaceutically acceptable excipient comprises at least four ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. 20. The pharmaceutical composition of any one of claims 1-2 or 5-19, wherein the pharmaceutically acceptable excipient comprises at least five ingredients selected from the group consisting of sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. 21. The pharmaceutical composition of any one of claims 1-2 or 5-20, wherein the pharmaceutically acceptable excipient comprises sodium lauryl sulfate, partially pre- gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. 22. The pharmaceutical composition of any one of claims 2 or 17-21, wherein the sodium lauryl sulfate is in an amount of about 0.01% w/w to about 0.1% w/w. 23. The pharmaceutical composition of any one of claims 2 or 17-22, wherein the partially pre-gelatinized maize starch is in an amount of about 30% w/w to about 50% w/w. 24. The pharmaceutical composition of any one of claims 2 or 17-23, wherein the microcrystalline cellulose is in an amount of about 30% w/w to about 50% w/w. 25. The pharmaceutical composition of any one of claims 2 or 17-24, wherein the sodium starch glycolate is in an amount of about 1% w/w to about 5% w/w. 26. The pharmaceutical composition of any one of claims 2 or 17-25, wherein the hydroxypropyl cellulose LF is in an amount of about 1% w/w to about 5% w/w.
WSGR Docket No. 63243-701.601 27. The pharmaceutical composition of any one of claims 2 or 17-26, wherein the colloidal silicon dioxide is in an amount of about 0.5% w/w to about 5% w/w. 28. The pharmaceutical composition of any one of claims 2 or 17-27, wherein the magnesium stearate is in an amount of about 0.5% w/w to about 5% w/w. 29. The pharmaceutical composition of claim 21, wherein the sodium lauryl sulfate is in the amount of about 0.01% w/w to about 0.1% w/w, the partially pre-gelatinized maize starch is in the amount of about 43% w/w to about 44% w/w, the microcrystalline cellulose is in the amount of about 44% w/w to about 48% w/w, the sodium starch glycolate is in the amount of about 3% w/w to about 4% w/w, the hydroxypropyl cellulose LF is in the amount of about 2% w/w to about 3% w/w, the colloidal silicon dioxide is in the amount of about 1% w/w to about 1.5% w/w, and the magnesium stearate is in the amount of about 1% w/w to about 1.5% w/w. 30. The pharmaceutical composition of any one of claims 1-2 or 5-29, wherein the sodium lauryl sulfate is Kolliphore SLS fine, the partially pre-gelatinized maize starch is Starch 1500, the microcrystalline cellulose is Avicel PH 101, the sodium starch glycolate is type A, the hydroxypropyl cellulose LF is Klucel HPC LF, and the colloidal silicon dioxide is Aerosil Pharma 200. 31. A method of treating an NLRP3-mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-2 or 5-30. 32. The method of claim 31, wherein the NLRP3-mediated disease or disorder is a myelodysplastic syndrome, an inflammatory disease or disorder, an auto-immune disease or disorder, a cardiovascular disease, a neurodegenerative disease or disorder, a bacterial and/or viral infection, an allergy, asthma, pancreatitis, multi-organ failure, a kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, a lung injury, a respiratory disease, an ischemic condition, or a combination thereof. 33. The method of claim 31, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome or inflammatory disease or disorder. 34. The method of claim 33, wherein the NLRP3-mediated disease or disorder is myelodysplastic syndrome. 35. The method of claim 34, where the myelodysplastic syndrome is myelodysplastic syndrome with multilineage dysplasia, myelodysplastic syndrome with single lineage dysplasia, myelodysplastic syndrome with ring sideroblasts, myelodysplastic
WSGR Docket No. 63243-701.601 syndrome with excess blasts, myelodysplastic syndrome with isolated del, or myelodysplastic syndrome unclassifiable. 36. The method of claim 33, wherein the NLRP3-mediated disease or disorder is an inflammatory disease or disorder. 37. The method of claim 36, wherein the inflammatory disease or disorder is acute inflammatory pain. 38. The method of any one of claims 31-37, wherein the pharmaceutical composition is administered daily. 39. The method of any one of claims 31-38, wherein the pharmaceutical composition is administered daily for about 1 week to about 12 weeks. 40. The method of any one of claims 31-38, wherein the pharmaceutical composition is administered daily for about 12 or more weeks. 41. A method of treating myelodysplastic syndrome (MDS) in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1 is H; R2 is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl; R3 is H;
WSGR Docket No. 63243-701.601 R4 is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4- triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5- thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5 is H; and each R6 is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1-C6 haloalkyl; wherein: (i) the subject has symptomatic anemia; (ii) the subject is refractory, intolerant of or ineligible for treatment with an erythroid stimulating agent (ESA), optionally wherein the subject has discontinued prior ESA at least two weeks prior to the administering; (iii) the subject has very low-risk MDS, low-risk MDS, or intermediate-risk MDS; (iv) administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, orally to the subject; (v) administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to the subject daily; or (vi) a combination of two or more of (i) to (v). 42. The method of claim 41, wherein the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily. 43. The method of claim 41 or claim 42, wherein the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily for about 1 week to about 12 weeks.
WSGR Docket No. 63243-701.601 44. The method of claim 41 or claim 42, wherein the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily for 12 or more weeks. 45. The method of any one of claims 41-44, wherein administering comprises administering the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, orally to the subject. 46. The method of any one of claims 41-45, wherein each dose of the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is about 0.5 mg to about 5 mg. 47. The method of any one of claims 41-46, wherein the compound of Formula (I) is a compound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
wherein: R2a is C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R4a is isoxazolyl optionally substituted with one more substituents selected from C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl. 48. The method of any one of claims 41-47, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. 49. The method of any one of claims 41-47, wherein the compound of Formula (I) is Compound 10 of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
WSGR Docket No. 63243-701.601 50. The method of any one of claims 41-46, wherein the compound of Formula (I) is
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pharmaceutically acceptable salt or solvate thereof.