Modulators of the NLRP3 inflammasome and related products and methods

Abstract

Compounds are provided for inhibiting the NLRP3 inflammasome generally, or for treating NLRP3 inflammasome-dependent conditions, each having the structure (A'): The present invention relates to a method for treating NLRP3 inflammasomes, comprising administering to a subject in need thereof an effective amount of a compound having the formula: TIFF2026502863000357.tif38128, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein rings A, Z1, Z2, R1, R2, R3, R4, n, and p are as defined herein. Pharmaceutical compositions containing such compounds, as well as the compounds themselves, are also provided.

Description

[Technical Field]

[0001] The invention relates to modulators of the NLRP3 inflammasome, products containing them, and methods of their use and preparation.

[0002] 2. Description of Related Art NOD-like receptor protein 3 (NLRP3) is a key protein that interacts with apoptosis-associated speck-like protein (ASC) and procaspase-1 to form the NLRP3 inflammasome. Activation of the NLRP3 inflammasome leads to the production of inflammatory mediators, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18), which contribute to the activation of the innate immune system. Dysregulation of innate immunity contributes to various diseases.

[0003] The innate immune response protects the host from invading microorganisms. Formation of the NLRP3 inflammasome activates caspase-1, which leads to the maturation and secretion of IL-1β and IL-18, the cleavage of gasdermin D, and ultimately the initiation of cell death via pyroptosis. The system alerts to the presence of invading microorganisms by releasing cytokines and works to resolve inflammation by eliminating infected cells.

[0004] However, non-microbial compounds, either endogenous or exogenous, are also effective inducers of NLRP3-dependent inflammation, allergic responses, or other forms of inflammation. For example, NLRP3 may be involved in Parkinson's disease and / or Alzheimer's disease, suggesting that misfolded, oligomerized, or aggregated proteins, such as alpha-synuclein, activate the NLRP3 inflammasome. Environmental particles, such as inhaled asbestos and silica, also activate the NLRP3 inflammasome, and elevated levels of IL-1β are involved in the development of asbestosis and silicosis, two progressive lung diseases that lead to fibrosis.

[0005] Emerging research has revealed that increased production of IL-1β and IL-18 by the NLRP3 inflammasome may contribute to the onset and progression of various diseases, such as neuroinflammation-related diseases, such as brain infections, acute injuries, multiple sclerosis, Alzheimer's disease, and neurodegenerative diseases; cardiovascular disease, cardiovascular risk reduction, atherosclerosis, type I and type II diabetes and related complications, inflammatory skin diseases, acne, hidradenitis suppurativa, asthma, age-related macular degeneration, or cancer-related diseases. These diseases, which are immune or inflammatory in nature, are usually difficult to diagnose or treat effectively.

[0006] Thus, there is a need in the art for compounds that modulate the NLRP3 inflammasome for the purpose of treating diseases in which modulation of the NLRP3 inflammasome would be beneficial.

[0007] The present invention fulfills these needs and provides other advantages that will become apparent from the following description. Summary of the Invention

[0008] overview In an embodiment, the compound of structure (I): TIFF2026502863000002.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, wherein ring A, Z1, Z2, R1, R2, R3, R4, n, and p are as defined herein.

[0009] In another aspect, there is provided a pharmaceutical composition comprising a carrier or excipient and a compound having structure (A') or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0010] In a further aspect, there is provided a method for treating an NLRP3 inflammasome-dependent condition by administering to a subject in need thereof an effective amount of a compound of structure (A'), or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, or a pharmaceutical composition comprising same. In some aspects, the NLRP3 inflammasome-dependent condition is a neuroinflammatory disorder or a neurodegenerative disease. DETAILED DESCRIPTION OF THE INVENTION

[0011] Detailed Description definition As used herein, the following terms have the meanings defined below unless the context indicates otherwise.

[0012] "Modulating" the NLRP3 inflammasome means that the compound interacts with NLRP3 in a manner that blocks its ATPase function and the downstream formation of the NLRP3 inflammasome complex. In the above context, the compound can also be described as an inhibitor, since the compound acts to inhibit or block the activation of the NLRP3 inflammasome.

[0013] NLRP3 refers to NOD-like receptor protein 3. NLRP3 is a gene encoding the protein, and an exemplary sequence can be found at https: / / www.uniprot.org / uniprot / Q96P20. Under normal conditions, NLRP3 functions as an autoinhibited ATPase. Unlike other inflammasomes, NLRP3 requires a two-step activation process, which can be triggered by various pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The first step stimulates the NLRP3 inflammasome through recognition of PAMPs, DAMPs, or pathogenic species via pattern recognition receptors (PRRs) (e.g., Toll-like receptors). Stimulation increases the expression of NLRP3, pro-IL1β, and pro-IL18. NLRP3 activation is mediated by ATP, K, and IL-1β. +Triggered by secondary signals such as efflux, other cellular stresses, or pathogenic species, this leads to ATP hydrolysis and enzyme activation. This activation leads to oligomerization of the inflammasome complex, leading to the autocleavage and activation of caspase-1. Active caspase-1 then cleaves pro-IL1β and pro-IL18. Active IL1β and IL18 are then released from the cell through gasdermin D-mediated pores, and the release of these cytokines triggers downstream inflammatory responses and cell death via pyroptosis.

[0014] "Effective amount" refers to the amount of a specified drug sufficient to achieve a desired effect in a subject being treated with the drug. Ideally, an effective amount of a drug is an amount sufficient to suppress or treat a disease without causing substantial toxicity in the subject. The effective amount of a drug will vary depending on the subject being treated, the severity of the disease, and the mode of administration of the pharmaceutical composition. In light of the present disclosure, one skilled in the art will understand how to determine an effective amount of the disclosed compounds sufficient to achieve a desired effect in a subject.

[0015] "Alkyl" (or "Ak") refers to a saturated or unsaturated, straight-chain or branched alkyl group having 1 to 8 carbon atoms, in some embodiments 1 to 6 carbon atoms, in some embodiments 1 to 4 carbon atoms, and in some embodiments 1 to 3 carbon atoms. Examples of saturated straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.

[0016] "Halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine (F, Cl, Br, I).

[0017] "Hydroxyl" refers to --OH.

[0018] "Cyano" refers to -CN.

[0019] "Oxo" refers to the =O substituent.

[0020] "Amino" specifically refers to -NH2.

[0021] "Haloalkyl" refers to an alkyl as defined above in which one or more hydrogen atoms have been replaced with a halogen. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, and the like.

[0022] "Alkoxy" refers to an alkyl, as defined above, attached through an oxygen atom (i.e., -O-alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.

[0023] "Haloalkoxy" refers to a haloalkyl, as defined above, attached through an oxygen atom (i.e., -O-haloalkyl). Examples of haloalkoxy groups include, but are not limited to, -OCF3, and the like.

[0024] "Aminyl" refers to -NH, -NHalkyl, or N(alkyl), where alkyl is as defined above. Examples of amino or aminyl include, but are not limited to, -NH, -NHCH, -N(CH), and the like.

[0025] "Aminylalkyl" refers to an amino or aminyl as described above linked through an alkyl as described above (i.e., -alkyl-aminyl). Examples of aminylalkyl are This includes, but is not limited to, TIFF2026502863000003.tif10128.

[0026] "Cycloalkyl" refers to a non-aromatic ring moiety containing three or more ring members. In some embodiments, cycloalkyls contain 3 to 8 ring members. In some embodiments, cycloalkyls contain 3 to 5 ring members. For example, cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0027] An "aryl" group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Representative aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6 to 14 carbons in the ring portion of the group. The terms "aryl" and "aryl group" include fused rings in which at least one ring, but not necessarily all rings, is aromatic, e.g., fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). In one embodiment, aryl is phenyl or naphthyl; in another embodiment, aryl is phenyl.

[0028] "Heterocycle" refers to an aromatic or non-aromatic ring moiety containing three or more ring members, one or more of which is a heteroatom, such as, but not limited to, N, O, S, or P. In some embodiments, a heterocyclyl contains 3 to 20 ring members, while other such groups contain 3 to 15 ring members. At least one ring contains a heteroatom, but not all rings in a polycyclic system need contain heteroatoms. For example, a dioxolanyl ring and a benzodioxolanyl ring system (a methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein.

[0029] Heterocyclyl groups also include fused ring species, including those with fused aromatic and non-aromatic groups. Heterocyclyl groups also include polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl, and heterocyclyl groups having substituents attached to one of the ring members, including, but not limited to, alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups. Heterocyclyl groups, as defined herein, can be heteroaryl groups or partially or fully saturated cyclic groups containing at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0030] "Isomers" is used herein to encompass all chiral, diastereomeric, or racemic forms of a structure (also called stereoisomers, in contrast to structural or positional isomers) unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds may be enriched or resolved optical isomers at any or all asymmetric atoms, to any degree of enrichment, as is apparent from the drawings. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, all within the scope of certain embodiments of the invention. Isomers resulting from the presence of chiral centers include non-superimposable pairs of isomers called "enantiomers." Single enantiomers of a pure compound are optically active (i.e., they are capable of rotating the plane of plane-polarized light and are designated R or S).

[0031] "Isolated optical isomer" means a compound that has been substantially purified from the corresponding optical isomer of the same formula. For example, the isolated isomer may be at least about 80% pure, at least 80%, or at least 85% pure by weight. In other embodiments, the isolated isomer is at least 90% pure, or at least 98% pure, or at least 99% pure by weight.

[0032] "Substantially enantiomerically or diastereomeric" pure means an enantiomeric or diastereomeric enrichment level of at least about 80%, more specifically greater than 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9% of one enantiomer relative to the other.

[0033] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is not optically active (i.e., it does not rotate plane-polarized light in either direction because its constituent enantiomers cancel each other out), and is therefore designated "(±)." All compounds marked with an asterisk (*) adjacent to a tertiary or quaternary carbon are optically active isomers, which can be purified from their respective racemates and / or synthesized by appropriate chiral syntheses.

[0034] A "hydrate" is a compound that exists in combination with water molecules. The combination may contain a stoichiometric amount of water, such as a monohydrate or dihydrate, or may contain a random amount of water. As used herein, "hydrate" refers to a solid form; that is, a compound in an aqueous solution may be hydrated, but is not a hydrate as the term is used herein.

[0035] A "solvate" is similar to a hydrate, except that a solvent other than water is present. For example, methanol and ethanol can form "alcoholates," which can also be stoichiometric or non-stoichiometric. As the term is used herein, "solvate" refers to a solid form, i.e., a compound in a solvent solution may be solvated, but is not a solvate as the term is used herein.

[0036] "Isotope" refers to an atom with the same number of protons but a different number of neutrons, and an isotope of a compound of structure (I) includes any such compound in which one or more atoms are replaced by an isotope of that atom. For example, carbon-12, the most common form of carbon, has six protons and six neutrons, while carbon-13 has six protons and seven neutrons, and carbon-14 has six protons and eight neutrons. Hydrogen has two stable isotopes: deuterium (one proton and one neutron) and tritium (one proton and two neutrons). Fluorine has many isotopes, with fluorine-19 being the longest-lived. Thus, isotopes of compounds having structure (I) include, but are not limited to, compounds of structure (I) in which one or more carbon-12 atoms have been replaced with carbon-13 and / or carbon-14 atoms, one or more hydrogen atoms have been replaced with deuterium and / or tritium, and / or one or more fluorine atoms have been replaced with fluorine-19.

[0037] "Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, combined with a counterion. For example, a salt formed between an anionic form of an acid and a cation is called an "acid addition salt." Conversely, a salt formed between a cationic form of a base and an anion is called a "base addition salt."

[0038] The term "pharmaceutically acceptable" refers to a drug that is approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to a non-toxic inorganic or organic acid and / or base addition salt (see, for example, Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated herein by reference).

[0039] Pharmaceutically acceptable base addition salts of the compounds of the invention include metallic salts, including, for example, alkali metal, alkaline earth metal, and transition metal salts, such as calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines, such as N,N'dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0040] Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, hippuric acid, malonic acid, oxalic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0041] The disclosed compounds (i.e., compounds of structure (I) and embodiments thereof) or pharmaceutically acceptable salts thereof may contain one or more centers of geometric asymmetry and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. Thus, the embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), e.g., using chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0042] Although pharmaceutically unacceptable salts generally are not useful as pharmaceuticals, such salts may be useful, for example, as intermediates in the synthesis of compounds having the structure of Formula I, and in their purification, for example, by recrystallization.

[0043] As used herein, the phrase "NLRP3 inflammasome-dependent condition" refers to a condition in which modulating NLRP3 confers a medical benefit to a patient or subject.

[0044] In some embodiments, methods are provided for modulating the activity of the NLRP3 inflammasome by contacting the NLRP3 inflammasome with an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, or a pharmaceutical composition comprising the same.

[0045] In some embodiments, a method for treating NLRP3 inflammasome-dependent conditions is provided by administering to a subject in need thereof an effective amount of a compound described herein, or its pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope, or a pharmaceutical composition comprising them. In certain embodiments, the NLRP3 inflammasome-dependent conditions are neuroinflammatory disorders or neurodegenerative diseases.

[0046] In some embodiments, the NLRP3 inflammasome-dependent condition is inflammation, an inflammatory disease, an immune disease, cancer, an infectious disease including a viral infection, a central nervous system disease, a metabolic disease, a cardiovascular disease, a respiratory disease, a liver disease, a kidney disease, an eye disease, a skin disease, a psychiatric disease, or a blood disease.

[0047] In one embodiment, the NLRP3 inflammasome-dependent condition is a neuroinflammatory-related disease or a neurodegenerative disease.

[0048] In one embodiment, the invention provides a method for inhibiting the NLRP3 inflammasome using an effective amount of the pharmaceutical composition described herein.

[0049] In another aspect, the invention provides a method for treating an NLRP3 inflammasome-dependent condition by administering an effective amount of the pharmaceutical composition described herein to a subject in need thereof. In certain aspects, the NLRP3 inflammasome-dependent condition is a neuroinflammatory disorder or a neurodegenerative disease.

[0050] As used herein, the term "inflammation" refers to inflammation, including inflammation resulting from an inflammatory disease, e.g., an autoinflammatory disease, inflammation occurring as a symptom of a non-inflammatory disease, inflammation resulting from an infection, or inflammation secondary to trauma, injury, or autoimmunity. Examples of inflammation that may be treated or prevented include inflammatory responses associated with or resulting from: (a) skin conditions such as contact sensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (b) joint conditions such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, crystal-induced arthropathy (e.g., pseudogout, gout), or seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, or Reiter's disease); (c) muscle conditions such as polymyositis or myasthenia gravis; (d) gastrointestinal conditions such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may affect sites distant from the gut (e.g., migraine, rhinitis, or eczema); (e) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic, or dust-induced asthma, and chronic or refractory asthma, such as late-onset asthma and airway hyperresponsiveness, among others), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, rhinitis sicca, hypertrophic rhinitis, pustular rhinitis, rhinitis sicca, medication-induced rhinitis, membranous rhinitis, seasonal rhinitis, e.g., hay fever, and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (f) vascular conditions such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (g) immune conditions, e.g., autoimmune diseases such as systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease; (h) ocular conditions such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (i) neurological conditions such as multiple sclerosis or encephalomyelitis; (j) an infectious disease or infection-related condition such as acquired immune deficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B, or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis, Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis / epididymitis, Legionnaires' disease, Lyme disease, influenza A, Epstein-Barr virus, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (k) renal conditions such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia, or nephrotic syndrome; (l) lymphatic conditions such as Castleman's disease; (m) conditions of or involving the immune system, such as hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (n) liver conditions such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH) or primary biliary cirrhosis; (o) cancer, including those listed herein below; (p) burns, wounds, trauma, hemorrhage or stroke; (q) radiation exposure; and / or (r) obesity; and / or (s) Pain such as inflammatory hyperalgesia.

[0051] As used herein, the term "inflammatory disease" refers to inflammation resulting from, for example, an inflammatory disorder, e.g., an autoinflammatory disease, such as cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold and autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multisystem inflammatory disease (NOMID), Majeed syndrome, septic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), adult-onset Still's disease (AOSD), A20 haploinsufficiency (HA20), childhood granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammatory antibody deficiency and immune dysregulation (APLAID), or sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay (SIFD).

[0052] As used herein, the term "immune disease" refers to, for example, autoimmune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid syndrome (APS), antisynthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular deficiency, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, and allergies. Lupus erythematosus, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS), myasthenia gravis, eyelid myoclonus syndrome (OMS), optic neuritis, ordothyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Reiter's syndrome, Sjögren's syndrome, and systemic sclerosis This means systemic connective tissue disease, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Belief's disease, Chagas disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, vitiligo, or vulvodynia.

[0053] As used herein, the term "cancer" includes, for example, lung cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), Langerhans cell histiocytosis (LCH), myeloproliferative neoplasms (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndromes (MDS), leukemia including acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML), promyelocytic leukemia (APML or APL), adrenal gland cancer, anal cancer, basal and squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing's tumor family, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumor, lymphoma including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymic cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0054] As used herein, the phrase "infectious diseases, including viral infections" refers to, for example, viral infections (e.g., influenza virus, human immunodeficiency virus (HIV), alphaviruses (such as chikungunya and Ross River virus), flaviviruses (such as dengue virus and Zika virus), herpesviruses (such as Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxviruses (such as vaccinia virus (modified vaccinia virus Ankara) and myxoma virus), adenoviruses (such as adenovirus type 5), or papillomaviruses), bacterial infections (e.g., Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordetella pertussis, Burkholderia pseudomallei, Corynebacterium diphtheriae, Corynebacterium tumefaciens, and the like), and / or bacterial infections (e.g., Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordetella pertussis, Burkholderia pseudomallei, Corynebacterium diphtheriae, Corynebacterium tumefaciens, and the like). diphtheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteurella multicida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae gonorrhoeae, Rickettsia, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosaaeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi or Yersinia pestis), fungal infections (e.g., caused by Candida or Aspergillus species), protozoal infections (e.g., caused by Plasmodium, Babesia, Giardia, Entamoeba histolytica, Leishmania or Trypanosoma), helminth infections (e.g., caused by Schistosoma, Ascaris, Tapeworms or Flukes), and prion infections.

[0055] As used herein, the term "central nervous system disease" refers to, for example, Parkinson's disease, Alzheimer's disease, frontotemporal dementia, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis.

[0056] As used herein, the expression "neuroinflammation-related disease" refers to, for example, multiple sclerosis, brain infection, acute injury, neurodegenerative disease, Parkinson's disease or Alzheimer's disease.

[0057] As used herein, the term "neurodegenerative disease" refers to, for example, Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

[0058] In one embodiment, the neurodegenerative disease is characterized by the intensive involvement of cell-mediated neuroinflammatory processes.

[0059] As used herein, the term "metabolic disease" refers to, for example, type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout.

[0060] As used herein, the term "cardiovascular disease" refers to, for example, hypertension, ischemia, reperfusion injury including ischemia-reperfusion injury after myocardial infarction, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, heart failure including congestive heart failure and heart failure with preserved ejection fraction, embolism, aneurysms including abdominal aortic aneurysms, cardiovascular risk reduction (CvRR), and pericarditis including Dressler's syndrome.

[0061] As used herein, the term "respiratory disease" refers to, for example, chronic obstructive pulmonary disease (COPD), asthma, including allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis.

[0062] As used herein, the term "liver disease" refers to, for example, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), including advanced fibrosis stages F3 and F4, alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH).

[0063] As used herein, the term "renal disease" refers to, for example, acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy.

[0064] As used herein, the term "ocular disease" refers to, for example, diseases of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infections, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma.

[0065] As used herein, the term "skin disease" refers to, for example, dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cystic skin diseases, and acne conglobata.

[0066] As used herein, the expression "mental illness" refers to, for example, depression and psychological stress.

[0067] As used herein, the term "blood disease" refers to, for example, sickle cell disease.

[0068] As used herein, the term "administration" refers to providing a compound described herein or a pharmaceutical composition containing a compound. The compound or composition can be administered to a subject by another person, or can be administered by the subject themselves. Non-limiting examples of administration routes include oral, parenteral (e.g., intravenous), or topical.

[0069] As used herein, the term "treatment" refers to an intervention that improves the signs or symptoms of a disease or condition. As used herein, the terms "treatment," "treat," and "treating" in reference to a disease, condition, or symptom also refer to any observable beneficial effect of treatment. A beneficial effect can be demonstrated, for example, by delaying the onset of clinical symptoms of a disease in a susceptible subject, reducing the severity of some or all of the clinical symptoms of a disease, delaying the progression of a disease, reducing the number of recurrences of a disease, improving the subject's overall health or well-being, or by other parameters known in the art that are specific to a particular disease. A preventive treatment is a treatment administered to a subject who does not show signs of a disease or who only shows early symptoms, with the aim of reducing the risk of developing a condition. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of a disease appear.

[0070] As used herein, the term "subject" refers to an animal (e.g., a mammal such as a human).The subject to be treated according to the methods described herein may be a subject who has been diagnosed with an NLRP3 inflammasome-dependent condition, such as inflammation, inflammatory disease, immune disease, cancer, infectious disease including viral infection, central nervous system disease, metabolic disease, cardiovascular disease, respiratory disease, liver disease, kidney disease, eye disease, skin disease, psychiatric disease, or blood disease.

[0071] Diagnosis may be performed by any method or technique known in the art. Those skilled in the art will understand that a subject to be treated according to the present disclosure may have undergone standard testing or may have been identified as being at risk due to the presence of one or more risk factors associated with a disease or condition, even in the absence of testing. The term "patient" may be used interchangeably with the term "subject." A subject may refer to an adult or pediatric subject.

[0072] compound As detailed above, the present invention provides compounds that exhibit significant activity as NLRP3 inflammasome antagonists (i.e., NLRP3 inflammasome inhibitors). Accordingly, in some embodiments, the compounds have the structure (A'): TIFF2026502863000004.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; Ring A is pyrrolidinyl, piperazinyl, morpholinyl, imidazolidinyl, oxazolidinyl, pyrazolyl, piperidinyl, phenyl, or pyridinyl; R1 is aminyl alkyl or TIFF2026502863000005.tif20128; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5 are each independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0073] In additional embodiments, the structure (A): TIFF2026502863000006.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; Ring A is piperidinyl, phenyl, or pyridinyl; R1 is aminyl alkyl or TIFF2026502863000007.tif20128; R2, R3, R4, and R5 are each independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0074] In some embodiments, Structure (I): TIFF2026502863000008.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; Ring A is phenyl or pyridinyl; R1 is aminyl alkyl or TIFF2026502863000009.tif20128; R2, R3, R4, and R5 are each independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0075] In a further aspect, structure (Ii): TIFF2026502863000010.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0076] In a further embodiment, structure (Iii): TIFF2026502863000011.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0077] In a further aspect, structure (III): TIFF2026502863000012.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0078] In another embodiment, structure (II): TIFF2026502863000013.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; Ring A is phenyl or pyridinyl; R1 is aminyl alkyl or TIFF2026502863000014.tif20128; R2, R3, R4, and R5 are each independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0079] In a further aspect, structure (IIi): TIFF2026502863000015.tif39128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0080] In a further aspect, structure (IIii): TIFF2026502863000016.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0081] In a further aspect, structure (IIiii): TIFF2026502863000017.tif39128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0082] In another embodiment, structure (IIa): TIFF2026502863000018.tif39128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; each R2, R3, R4, and R5 is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0083] In a further aspect, structure (IIa'): TIFF2026502863000019.tif39128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0084] In a further embodiment, structure (IIa″): TIFF2026502863000020.tif39128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0085] In some embodiments, structure (IIb): TIFF2026502863000021.tif39128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; Ra is H or alkyl; each R2, R3, and R4 is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5.

[0086] In another embodiment, structure (III): TIFF2026502863000022.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; Ring A is phenyl or pyridinyl; R1 is aminyl alkyl or TIFF2026502863000023.tif20128; R2, R3, R4, and R5 are each independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0087] In a further aspect, structure (IIIi): TIFF2026502863000024.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0088] In a further aspect, structure (IIIii): TIFF2026502863000025.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0089] In a further aspect, structure (IIIiii): TIFF2026502863000026.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0090] In a further aspect, structure (IIIa): TIFF2026502863000027.tif50128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; each R2, R3, R4, and R5 is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0091] In a further embodiment, structure (IIIa'): Provided is a compound having the formula TIFF2026502863000028.tif49128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0092] In a further embodiment, the structure (IIIa″): TIFF2026502863000029.tif50128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0093] In yet another embodiment, structure (IIIb): TIFF2026502863000030.tif43128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; Ra is H or alkyl; each R2, R3, and R4 is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5.

[0094] In another embodiment, structure (IV): TIFF2026502863000031.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; Ring A is phenyl or pyridinyl; R1 is aminyl alkyl or TIFF2026502863000032.tif20128; R2, R3, R4, and R5 are each independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0095] In a further embodiment, structure (IVi): TIFF2026502863000033.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0096] In a further embodiment, structure (IVii): TIFF2026502863000034.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0097] In a further embodiment, structure (IViii): TIFF2026502863000035.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0098] In a further embodiment, structure (IVa): TIFF2026502863000036.tif52128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; each R2, R3, R4, and R5 is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0099] In a further embodiment, structure (IVa'): TIFF2026502863000037.tif52128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0100] In a further embodiment, structure (IVa″): Provided is a compound having the formula TIFF2026502863000038.tif52128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0101] In yet another embodiment, structure (IVb): TIFF2026502863000039.tif51128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; Ra is H or alkyl; each R2, R3, and R4 is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5.

[0102] In another embodiment, structure (V): TIFF2026502863000040.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; Ring A is phenyl or pyridinyl; R1 is aminyl alkyl or TIFF2026502863000041.tif20128; R2, R3, R4, and R5 are each independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0103] In a further embodiment, the structure (Vi): TIFF2026502863000042.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0104] In a further embodiment, structure (Vii): TIFF2026502863000043.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0105] In a further embodiment, structure (Viii): TIFF2026502863000044.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0106] In a further embodiment, structure (Va): TIFF2026502863000045.tif48128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; each R2, R3, R4, and R5 is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0107] In a further embodiment, the structure (Va'): TIFF2026502863000046.tif48128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0108] In a further embodiment, the structure (Va″): TIFF2026502863000047.tif49128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0109] In yet another embodiment, Structure (Vb): TIFF2026502863000048.tif48128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR2-, or (2)x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently either =CH- or =CR2-; Ra is H or alkyl; each R2, R3, and R4 is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5.

[0110] In some embodiments, structure (VI): TIFF2026502863000049.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R1 is aminyl alkyl or TIFF2026502863000050.tif20128; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0111] In a further embodiment, structure (VIi): TIFF2026502863000051.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0112] In a further embodiment, structure (VIii): TIFF2026502863000052.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0113] In a further embodiment, structure (VIiii): TIFF2026502863000053.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0114] In another embodiment, structure (VI*a): TIFF2026502863000054.tif39128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0115] In another embodiment, structure (VI*a'): TIFF2026502863000055.tif39128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0116] In a further aspect, the structure (VI*a″): TIFF2026502863000056.tif39128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0117] In a further embodiment, the structure (VI*b): TIFF2026502863000057.tif39128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; Ra is H or alkyl; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5.

[0118] In some embodiments, structure (VII): TIFF2026502863000058.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R1 is aminyl alkyl or TIFF2026502863000059.tif20128; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0119] In a further embodiment, structure (VIIi): TIFF2026502863000060.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0120] In a further embodiment, structure (VIIii): TIFF2026502863000061.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0121] In a further embodiment, structure (VIIiii): TIFF2026502863000062.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0122] In another embodiment, structure (VII*a): TIFF2026502863000063.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0123] In another embodiment, structure (VII*a'): TIFF2026502863000064.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0124] In a further embodiment, the structure (VII*a″): TIFF2026502863000065.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0125] In a further embodiment, structure (VII*b): TIFF2026502863000066.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; Ra is H or alkyl; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5.

[0126] In some embodiments, structure (VIII): TIFF2026502863000067.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R1 is aminyl alkyl or TIFF2026502863000068.tif20128; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0127] In a further aspect, structure (VIIIi): TIFF2026502863000069.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0128] In a further embodiment, structure (VIIIii): TIFF2026502863000070.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0129] In a further aspect, structure (VIIIiii): TIFF2026502863000071.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0130] In another embodiment, structure (VIII*a): TIFF2026502863000072.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0131] In another embodiment, structure (VIII*a'): TIFF2026502863000073.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0132] In a further embodiment, the structure (VIII*a″): TIFF2026502863000074.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0133] In a further embodiment, the structure (VIII*b): TIFF2026502863000075.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; Ra is H or alkyl; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5.

[0134] In some embodiments, structure (IX): TIFF2026502863000076.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R1 is aminyl alkyl or TIFF2026502863000077.tif20128; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0135] In a further aspect, structure (IXi): TIFF2026502863000078.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0136] In a further aspect, structure (IXii): TIFF2026502863000079.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0137] In a further aspect, structure (IXiii): TIFF2026502863000080.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0138] In another embodiment, structure (IX*a): TIFF2026502863000081.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0139] In another embodiment, the structure (IX*a'): TIFF2026502863000082.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0140] In a further aspect, the structure (IX*a″): TIFF2026502863000083.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0141] In a further embodiment, the structure (IX*b): TIFF2026502863000084.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; Ra is H or alkyl; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5.

[0142] In some embodiments, the structure (X): TIFF2026502863000085.tif43128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R1 is aminyl alkyl or TIFF2026502863000086.tif20128; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0143] In a further aspect, the structure (Xi): TIFF2026502863000087.tif43128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0144] In a further embodiment, structure (Xii): Provided is a compound having the formula TIFF2026502863000088.tif43128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0145] In a further embodiment, structure (Xiii): TIFF2026502863000089.tif43128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0146] In another embodiment, the structure (X*a): TIFF2026502863000090.tif43128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0147] In another embodiment, the structure (X*a'): TIFF2026502863000091.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0148] In a further aspect, the structure (X*a″): TIFF2026502863000092.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0149] In a further embodiment, the structure (X*b): TIFF2026502863000093.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; Ra is H or alkyl; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5.

[0150] In some embodiments, structure (XI): TIFF2026502863000094.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R1 is aminyl alkyl or TIFF2026502863000095.tif20128; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0151] In a further embodiment, structure (XIi): TIFF2026502863000096.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0152] In a further embodiment, structure (XIii): TIFF2026502863000097.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0153] In a further aspect, structure (XIiii): Provided is a compound having the formula: TIFF2026502863000098.tif42128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0154] In another embodiment, structure (XI*a): TIFF2026502863000099.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0155] In another embodiment, structure (XI*a'): TIFF2026502863000100.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0156] In a further aspect, the structure (XI*a″): TIFF2026502863000101.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0157] In a further embodiment, the structure (XI*b): TIFF2026502863000102.tif40128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; Ra is H or alkyl; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5.

[0158] In some embodiments, structure (XII): TIFF2026502863000103.tif37128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R1 is aminyl alkyl or TIFF2026502863000104.tif20128; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0159] In a further aspect, structure (XIIi): TIFF2026502863000105.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0160] In a further aspect, structure (XIIii): TIFF2026502863000106.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0161] In a further aspect, structure (XIIiii): TIFF2026502863000107.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0162] In another embodiment, structure (XII*a): TIFF2026502863000108.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R6 is H, cycloalkyl, or alkyl optionally substituted with one or more R7; R7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is 0 to 2.

[0163] In another embodiment, structure (XII*a'): TIFF2026502863000109.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0164] In a further aspect, the structure (XII*a″): TIFF2026502863000110.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided.

[0165] In a further embodiment, the structure (XII*b): TIFF2026502863000111.tif38128 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided, During the ceremony Z1 and Z2 are each independently =CH-, =CR4-, or =N-; Ra is H or alkyl; R2, at each occurrence, is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R2 together with the atoms to which they are attached form an aromatic ring; R3, R4, and R5, each occurrence, is independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5.

[0166] In some embodiments, compounds are provided where Ring A is phenyl. In other embodiments, compounds are provided where Ring A is pyridyl. In particular embodiments, Ring A has the following structure: Compounds having one of the following structures are provided: TIFF2026502863000112.tif21128.

[0167] In a specific embodiment, ring A has the following structure: Compounds having one of the following structures are provided: TIFF2026502863000113.tif20128.

[0168] In additional specific embodiments, ring A has the following structure: Compounds having one of the following structures are provided: TIFF2026502863000114.tif19128.

[0169] In some embodiments, compounds are provided in which R1 is aminylalkyl. In a specific embodiment, a compound is provided in which R is The compound is provided as TIFF2026502863000116.tif10128.

[0170] In some embodiments, R1 is In some embodiments, compounds are provided in which R is In some embodiments, compounds are provided in which R is In some embodiments, compounds are provided in which R is The compound is provided as TIFF2026502863000120.tif23128.

[0171] In some embodiments, compounds are provided where R2 is halo. In particular embodiments, compounds are provided where R2 is F, Cl, Br, or I. In specific embodiments, compounds are provided where R2 is F or Cl. In specific embodiments, compounds are provided where R2 is F. In specific embodiments, compounds are provided where R2 is Cl.

[0172] In some embodiments, compounds are provided where R2 is CN.

[0173] In some embodiments, compounds are provided where R2 is OH.

[0174] In some embodiments, compounds are provided where R2 is alkyl. In certain embodiments, compounds are provided where R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In other embodiments, compounds are provided where R2 is methyl, ethyl, or isopropyl. In other embodiments, compounds are provided where R2 is methyl. In other embodiments, compounds are provided where R2 is ethyl. In other embodiments, compounds are provided where R2 is propyl. In yet other embodiments, compounds are provided where R2 is isopropyl. In additional embodiments, compounds are provided where R2 is n-butyl. In further embodiments, compounds are provided where R2 is sec-butyl. In some embodiments, compounds are provided where R2 is isobutyl. In other embodiments, compounds are provided where R2 is tert-butyl.

[0175] In some embodiments, compounds are provided where R2 is haloalkyl. In certain embodiments, compounds are provided where R2 is CHF2 or CF3. In certain embodiments, compounds are provided where R2 is CHF2. In certain embodiments, compounds are provided where R2 is CF3.

[0176] In some embodiments, compounds are provided where R2 is alkoxy. In certain embodiments, compounds are provided where R2 is methoxy, ethoxy, propoxy, or isopropoxy. In certain embodiments, compounds are provided where R2 is methoxy.

[0177] In some embodiments, compounds are provided where R2 is haloalkoxy. In certain embodiments, compounds are provided where R2 is OCHF2 or OCF3. In certain embodiments, compounds are provided where R2 is OCHF2. In certain embodiments, compounds are provided where R2 is OCF3.

[0178] In some embodiments, compounds are provided where R2 is aminylalkyl. The compound is provided as TIFF2026502863000121.tif9128.

[0179] In some embodiments, compounds are provided where R2 is cycloalkyl. In specific embodiments, compounds are provided where R2 is C3-C8 cycloalkyl. In certain embodiments, compounds are provided where R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, compounds are provided where R2 is cyclopropyl or cyclobutyl. In certain embodiments, compounds are provided where R2 is cyclopropyl.

[0180] In some embodiments, compounds are provided where R3 is halo. In particular embodiments, compounds are provided where R3 is F, Cl, Br, or I. In specific embodiments, compounds are provided where R3 is F or Cl. In specific embodiments, compounds are provided where R3 is F. In specific embodiments, compounds are provided where R3 is Cl.

[0181] In some embodiments, compounds are provided where R3 is CN.

[0182] In some embodiments, compounds are provided where R3 is OH.

[0183] In some embodiments, compounds are provided where R3 is alkyl. In certain embodiments, compounds are provided where R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In other embodiments, compounds are provided where R3 is methyl, ethyl, or isopropyl. In other embodiments, compounds are provided where R3 is methyl. In other embodiments, compounds are provided where R3 is ethyl. In other embodiments, compounds are provided where R3 is propyl. In still other embodiments, compounds are provided where R3 is isopropyl. In additional embodiments, compounds are provided where R3 is n-butyl. In further embodiments, compounds are provided where R3 is sec-butyl. In some embodiments, compounds are provided where R3 is isobutyl. In other embodiments, compounds are provided where R3 is tert-butyl.

[0184] In some embodiments, compounds are provided where R3 is haloalkyl. In certain embodiments, compounds are provided where R3 is CHF2 or CF3. In certain embodiments, compounds are provided where R3 is CHF2. In certain embodiments, compounds are provided where R3 is CF3.

[0185] In some embodiments, compounds are provided where R3 is alkoxy. In certain embodiments, compounds are provided where R3 is methoxy, ethoxy, propoxy, or isopropoxy. In certain embodiments, compounds are provided where R3 is methoxy.

[0186] In some embodiments, compounds are provided where R3 is haloalkoxy. In certain embodiments, compounds are provided where R3 is OCHF2 or OCF3. In certain embodiments, compounds are provided where R3 is OCHF2. In certain embodiments, compounds are provided where R3 is OCF3.

[0187] In some embodiments, compounds are provided where R3 is aminylalkyl. The compound is provided as TIFF2026502863000122.tif9128.

[0188] In some embodiments, compounds are provided where R3 is cycloalkyl. In specific embodiments, compounds are provided where R3 is C3-C8 cycloalkyl. In certain embodiments, compounds are provided where R3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, compounds are provided where R3 is cyclopropyl or cyclobutyl. In certain embodiments, compounds are provided where R3 is cyclopropyl.

[0189] In some embodiments, compounds are provided where R4 is halo. In particular embodiments, compounds are provided where R4 is F, Cl, Br, or I. In specific embodiments, compounds are provided where R4 is F or Cl. In specific embodiments, compounds are provided where R4 is F. In specific embodiments, compounds are provided where R4 is Cl.

[0190] In some embodiments, compounds are provided where R4 is CN.

[0191] In some embodiments, compounds are provided where R4 is OH.

[0192] In some embodiments, compounds are provided where R4 is alkyl. In certain embodiments, compounds are provided where R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In other embodiments, compounds are provided where R4 is methyl, ethyl, or isopropyl. In other embodiments, compounds are provided where R4 is methyl. In other embodiments, compounds are provided where R4 is ethyl. In other embodiments, compounds are provided where R4 is propyl. In still other embodiments, compounds are provided where R4 is isopropyl. In additional embodiments, compounds are provided where R4 is n-butyl. In further embodiments, compounds are provided where R4 is sec-butyl. In some embodiments, compounds are provided where R4 is isobutyl. In other embodiments, compounds are provided where R4 is tert-butyl.

[0193] In some embodiments, compounds are provided where R4 is haloalkyl. In certain embodiments, compounds are provided where R4 is CHF2 or CF3. In certain embodiments, compounds are provided where R4 is CHF2. In certain embodiments, compounds are provided where R4 is CF3.

[0194] In some embodiments, compounds are provided in which R4 is alkoxy. In certain embodiments, compounds are provided in which R4 is methoxy, ethoxy, propoxy, or isopropoxy. In certain embodiments, compounds are provided in which R4 is methoxy.

[0195] In some embodiments, compounds are provided where R4 is haloalkoxy. In certain embodiments, compounds are provided where R4 is OCHF2 or OCF3. In certain embodiments, compounds are provided where R4 is OCHF2. In certain embodiments, compounds are provided where R4 is OCF3.

[0196] In some embodiments, compounds are provided where R4 is aminylalkyl. In certain embodiments, R4 is The compound is provided as TIFF2026502863000123.tif9128.

[0197] In some embodiments, compounds are provided where R4 is cycloalkyl. In specific embodiments, compounds are provided where R4 is C3-C8 cycloalkyl. In certain embodiments, compounds are provided where R4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, compounds are provided where R4 is cyclopropyl or cyclobutyl. In certain embodiments, compounds are provided where R4 is cyclopropyl.

[0198] In some embodiments, compounds are provided where R4 is halo, CN, OH, alkyl, or haloalkyl. In certain embodiments, compounds are provided where R4 is F, Cl, CN, OH, methyl, CHF2, or CF3.

[0199] In some embodiments, R4 together with the ring to which it is attached has the following structure: Compounds having one of the following structures are provided: TIFF2026502863000124.tif85163.

[0200] In some embodiments, compounds are provided where R5 is halo. In certain embodiments, compounds are provided where R5 is F, Cl, Br, or I. In specific embodiments, compounds are provided where R5 is F or Cl. In specific embodiments, compounds are provided where R5 is F. In specific embodiments, compounds are provided where R5 is Cl.

[0201] In some embodiments, compounds are provided where R5 is CN.

[0202] In some embodiments, compounds are provided where R5 is OH.

[0203] In some embodiments, compounds are provided where R5 is alkyl. In certain embodiments, compounds are provided where R5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In other embodiments, compounds are provided where R5 is methyl, ethyl, or isopropyl. In other embodiments, compounds are provided where R5 is methyl. In other embodiments, compounds are provided where R5 is ethyl. In other embodiments, compounds are provided where R5 is propyl. In still other embodiments, compounds are provided where R5 is isopropyl. In additional embodiments, compounds are provided where R5 is n-butyl. In further embodiments, compounds are provided where R5 is sec-butyl. In some embodiments, compounds are provided where R5 is isobutyl. In other embodiments, compounds are provided where R5 is tert-butyl.

[0204] In some embodiments, compounds are provided where R5 is haloalkyl. In certain embodiments, compounds are provided where R5 is CHF2 or CF3. In certain embodiments, compounds are provided where R5 is CHF2. In certain embodiments, compounds are provided where R5 is CF3.

[0205] In some embodiments, compounds are provided in which R5 is alkoxy. In certain embodiments, compounds are provided in which R5 is methoxy, ethoxy, propoxy, or isopropoxy. In certain embodiments, compounds are provided in which R5 is methoxy.

[0206] In some embodiments, compounds are provided where R5 is haloalkoxy. In certain embodiments, compounds are provided where R5 is OCHF2 or OCF3. In certain embodiments, compounds are provided where R5 is OCHF2. In certain embodiments, compounds are provided where R5 is OCF3.

[0207] In some embodiments, compounds are provided in which R5 is aminylalkyl. The compound is provided as TIFF2026502863000125.tif9128.

[0208] In some embodiments, compounds are provided where R5 is cycloalkyl. In specific embodiments, compounds are provided where R5 is C3-C8 cycloalkyl. In certain embodiments, compounds are provided where R5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, compounds are provided where R5 is cyclopropyl or cyclobutyl. In certain embodiments, compounds are provided where R5 is cyclopropyl.

[0209] In some embodiments, compounds are provided wherein R6 is H.

[0210] In some embodiments, compounds are provided where R6 is alkyl. In certain embodiments, compounds are provided where R6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In other embodiments, compounds are provided where R6 is methyl, ethyl, or isopropyl. In other embodiments, compounds are provided where R6 is methyl or ethyl. In other embodiments, compounds are provided where R6 is methyl. In other embodiments, compounds are provided where R6 is ethyl. In other embodiments, compounds are provided where R6 is propyl. In still other embodiments, compounds are provided where R6 is isopropyl. In additional embodiments, compounds are provided where R6 is n-butyl. In further embodiments, compounds are provided where R6 is sec-butyl. In some embodiments, compounds are provided where R6 is isobutyl. In other embodiments, compounds are provided where R6 is tert-butyl.

[0211] In some embodiments, compounds are provided where R6 is alkyl substituted with one or more F. In certain embodiments, compounds are provided where R6 is -CH2CH2F. In other embodiments, compounds are provided where R6 is -CH2CHF2. In still other embodiments, compounds are provided where R6 is -CH2CF3. In some embodiments, compounds are provided where R6 is alkyl substituted with one or more cycloalkyl. In certain embodiments, R6 is In another embodiment, a compound is provided in which R6 is alkyl substituted with one or more OH. In a particular embodiment, R6 is The compound is provided as TIFF2026502863000127.tif5128.

[0212] In some embodiments, compounds are provided where R6 is cycloalkyl. In specific embodiments, compounds are provided where R6 is C3-C8 cycloalkyl. In other embodiments, compounds are provided where R6 is cyclopropyl. In yet other embodiments, compounds are provided where R6 is cyclobutyl. In additional embodiments, compounds are provided where R6 is cyclopentyl.

[0213] In some embodiments, compounds are provided where R7 is halo. In particular embodiments, compounds are provided where R7 is F, Cl, Br, or I. In specific embodiments, compounds are provided where R7 is F or Cl. In specific embodiments, compounds are provided where R7 is F. In specific embodiments, compounds are provided where R7 is Cl.

[0214] In some embodiments, compounds are provided where R7 is OH.

[0215] In some embodiments, compounds are provided where R7 is cycloalkyl. In specific embodiments, compounds are provided where R7 is C3-C8 cycloalkyl. In other embodiments, compounds are provided where R7 is cyclopropyl. In yet other embodiments, compounds are provided where R7 is cyclobutyl. In additional embodiments, compounds are provided where R7 is cyclopentyl.

[0216] In some embodiments, compounds are provided wherein m is 0 to 6. In other embodiments, compounds are provided wherein m is 0 to 5. In other embodiments, compounds are provided wherein m is 0 to 4. In other embodiments, compounds are provided wherein m is 0 to 3. In other embodiments, compounds are provided wherein m is 0 to 2. In other embodiments, compounds are provided wherein m is 0 to 1. In other embodiments, compounds are provided wherein m is 1 to 3. In other embodiments, compounds are provided wherein m is 1 to 2. In certain embodiments, compounds are provided wherein m is 0. In certain embodiments, compounds are provided wherein m is 1. In certain embodiments, compounds are provided wherein m is 2. In certain embodiments, compounds are provided wherein m is 3. In certain embodiments, compounds are provided wherein m is 4. In certain embodiments, compounds are provided wherein m is 5. In other embodiments, compounds are provided wherein m is 6.

[0217] In some embodiments, compounds are provided wherein n is 0 to 5. In other embodiments, compounds are provided wherein n is 0 to 4. In other embodiments, compounds are provided wherein n is 0 to 3. In other embodiments, compounds are provided wherein n is 1 to 3. In certain embodiments, compounds are provided wherein n is 0. In certain embodiments, compounds are provided wherein n is 1. In certain embodiments, compounds are provided wherein n is 2. In certain embodiments, compounds are provided wherein n is 3. In certain embodiments, compounds are provided wherein n is 4. In certain embodiments, compounds are provided wherein n is 5.

[0218] In some embodiments, compounds are provided wherein p is 0 to 3. In other embodiments, compounds are provided wherein p is 0 to 2. In other embodiments, compounds are provided wherein p is 0 to 1. In certain embodiments, compounds are provided wherein p is 0. In certain embodiments, compounds are provided wherein p is 1. In certain embodiments, compounds are provided wherein p is 2. In certain embodiments, compounds are provided wherein p is 3.

[0219] In some embodiments, compounds are provided wherein q is 0 to 2. In other embodiments, compounds are provided wherein q is 0 to 1. In other embodiments, compounds are provided wherein q is 1 to 2. In particular embodiments, compounds are provided wherein q is 0. In particular embodiments, compounds are provided wherein q is 1. In particular embodiments, compounds are provided wherein q is 2.

[0220] In some embodiments, compounds are provided wherein y is 0 to 5. In other embodiments, compounds are provided wherein y is 0 to 4. In other embodiments, compounds are provided wherein y is 0 to 3. In other embodiments, compounds are provided wherein y is 0 to 2. In other embodiments, compounds are provided wherein y is 0 to 1. In other embodiments, compounds are provided wherein y is 1 to 3. In certain embodiments, compounds are provided wherein y is 0. In certain embodiments, compounds are provided wherein y is 1. In certain embodiments, compounds are provided wherein y is 2. In certain embodiments, compounds are provided wherein y is 3. In certain embodiments, compounds are provided wherein y is 4. In certain embodiments, compounds are provided wherein y is 5.

[0221] In some embodiments, x 1 , x 2 , and x 3 In another embodiment, compounds are provided in which x 1 , x 2 and x 3 In an additional embodiment, compounds are provided in which one of x is =N- and the other two are each independently =CH- or =CR2-. 1 , x 2 , and x 3are each independently =CH-. In some of the above embodiments, compounds are provided where R2 in =CR2- is as described anywhere in this application. In some of the above embodiments, compounds are provided where R2 in =CR2- is alkyl. In some of the above embodiments, compounds are provided where R2 in =CR2- is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In another embodiment, compounds are provided where R2 in =CR2- is methyl, ethyl, or isopropyl. In another embodiment, compounds are provided where R2 in =CR2- is methyl or ethyl. In another embodiment, compounds are provided where R2 in =CR2- is methyl. In another embodiment, compounds are provided where R2 in =CR2- is ethyl.

[0222] In some embodiments, compounds are provided wherein Ra is H.

[0223] In some embodiments, compounds are provided wherein Ra is H and Ak is methyl.

[0224] In some embodiments, compounds are provided where Ra is alkyl. In certain embodiments, compounds are provided where Ra is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In other embodiments, compounds are provided where Ra is methyl, ethyl, or isopropyl. In other embodiments, compounds are provided where Ra is methyl or ethyl. In other embodiments, compounds are provided where Ra is methyl. In other embodiments, compounds are provided where Ra is ethyl. In other embodiments, compounds are provided where Ra is propyl. In still other embodiments, compounds are provided where Ra is isopropyl. In additional embodiments, compounds are provided where Ra is n-butyl. In further embodiments, compounds are provided where Ra is sec-butyl. In some embodiments, compounds are provided where Ra is isobutyl. In other embodiments, compounds are provided where Ra is tert-butyl.

[0225] In some embodiments, compounds are provided where Z1 is =CH- and Z2 is =CH-. In another embodiment, compounds are provided where Z1 is =CH- and Z2 is =CR4-. In an additional embodiment, compounds are provided where Z1 is =CR4- and Z2 is =CH-. In a further embodiment, compounds are provided where Z1 is =CR4- and Z2 is =CR4-. In yet another embodiment, compounds are provided where Z1 is =N- and Z2 is =CR4-. In some embodiments, compounds are provided where Z1 is =CR4- and Z2 is =N-. In another embodiment, compounds are provided where Z1 is =N- and Z2 is =CH-. In an additional embodiment, compounds are provided where Z1 is =CH- and Z2 is =N-. In some of the above embodiments, compounds are provided where R4 in =CR4- is as described elsewhere herein.

[0226] In one embodiment, the compound is selected from one of the compounds listed in Table 1 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. [Table 1] TIFF2026502863000129.tif241162TIFF2026502863000130.tif234162TIFF2026502863000131.tif234162TIFF2026502863000132.tif253162TIFF2026502863000133.tif241162TIFF2026502863000134.tif241162TIFF2026502863000135.tif241162TIFF2026502863000136.tif241162TIFF2026502863000137.tif241162TIFF2026502863000138.tif241162TIFF2026502863000139.tif241162TIFF2026502863000140.tif231162TIFF2026502863000141.tif225162TIFF2026502863000142.tif247162TIFF2026502863000143.tif238162TIFF2026502863000144.tif236162TIFF2026502863000145.tif241162TIFF2026502863000146.tif245162TIFF2026502863000147.tif253162TIFF2026502863000148.tif234162TIFF2026502863000149.tif238162TIFF2026502863000150.tif241162TIFF2026502863000151.tif241162TIFF2026502863000152.tif241162TIFF2026502863000153.tif241162TIFF2026502863000154.tif241162TIFF2026502863000155.tif241162TIFF2026502863000156.tif241162TIFF2026502863000157.tif241162TIFF2026502863000158.tif242162TIFF2026502863000159.tif244162TIFF2026502863000160.tif239162TIFF2026502863000161.tif239162TIFF2026502863000162.tif239162TIFF2026502863000163.tif239162TIFF2026502863000164.tif239162TIFF2026502863000165.tif239162TIFF2026502863000166.tif239162TIFF2026502863000167.tif239162TIFF2026502863000168.tif234162TIFF2026502863000169.tif239162TIFF2026502863000170.tif239162TIFF2026502863000171.tif239162TIFF2026502863000172.tif229162TIFF2026502863000173.tif236162TIFF2026502863000174.tif236162TIFF2026502863000175.tif236162TIFF2026502863000176.tif226162TIFF2026502863000177.tif233162TIFF2026502863000178.tif248162TIFF2026502863000179.tif251162TIFF2026502863000180.tif231162TIFF2026502863000181.tif231162TIFF2026502863000182.tif224162TIFF2026502863000183.tif241162TIFF2026502863000184.tif241162TIFF2026502863000185.tif241162TIFF2026502863000186.tif241162TIFF2026502863000187.tif241162TIFF2026502863000188.tif221162TIFF2026502863000189.tif241162TIFF2026502863000190.tif241162TIFF2026502863000191.tif255162TIFF2026502863000192.tif241162TIFF2026502863000193.tif241162TIFF2026502863000194.tif241162TIFF2026502863000195.tif241162TIFF2026502863000196.tif223162TIFF2026 502863000197.tif249162TIFF2026502863000198.tif254162TIFF2026502863000199.tif23 3162TIFF2026502863000200.tif238162TIFF2026502863000201.tif237162TIFF202650286 3000202.tif234162TIFF2026502863000203.tif233162TIFF2026502863000204.tif158162.

[0227] Treatment methods In some embodiments, the invention provides methods for treating NLRP3 inflammasome-dependent conditions, where "treatment" refers to an intervention that improves the signs or symptoms of a disease or condition. As used herein, the terms "treatment," "treat," and "treating" in reference to a disease, condition, or condition also refer to any observable beneficial effect of treatment. A beneficial effect can be demonstrated, for example, by delaying the onset of clinical symptoms of a disease in a susceptible subject, reducing the severity of some or all of the clinical symptoms of a disease, delaying disease progression, reducing the number of disease relapses, improving the subject's overall health or well-being, or other parameters known in the art that are specific to a particular disease. A preventative treatment is a treatment administered to a subject who shows no signs of a disease or only early symptoms, with the aim of reducing the risk of developing a condition. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of a disease appear.

[0228] In some embodiments, the invention provides a method for treating an NLRP3 inflammasome-dependent condition in a subject, where "subject" refers to an animal (e.g., a mammal such as a human). The subject to be treated according to the methods described herein may be a subject who has been diagnosed with an NLRP3 inflammasome-dependent condition, such as inflammation, an inflammatory disease, an immune disease, a cancer, an infectious disease including a viral infection, a central nervous system disease, a metabolic disease, a cardiovascular disease, a respiratory disease, a liver disease, a kidney disease, an eye disease, a skin disease, a psychiatric disease, or a blood disease.

[0229] Diagnosis may be performed by any method or technique known in the art. Those skilled in the art will understand that a subject to be treated according to the present disclosure may have undergone standard testing or may have been identified as being at risk due to the presence of one or more risk factors associated with a disease or condition, even in the absence of testing. The term "patient" may be used interchangeably with the term "subject." A subject may refer to an adult or pediatric subject.

[0230] The route of administration can be any route that effectively delivers the active compounds of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, including intravenous, subcutaneous and / or intramuscular. In one embodiment, the route of administration is oral. In another embodiment, the route of administration is topical.

[0231] The dosage form can be administered once a day, or more frequently, such as twice or three times a day. Alternatively, if deemed appropriate by the prescribing physician or the drug's prescription information, the dosage form can be administered less frequently, such as every other day or once a week. The administration regimen can include, for example, gradually increasing the dosage to the extent necessary or useful for the indication being treated, thereby allowing the patient's body to adapt to the treatment, minimize or avoid undesirable side effects associated with the treatment, and / or maximize the therapeutic effect of the compound. Other dosage forms include delayed or controlled release forms. Suitable administration regimens and / or dosage forms include, for example, those described in the latest edition of the "Physicians' Desk Reference," which is incorporated herein by reference.

[0232] In one embodiment, the invention provides an oral pharmaceutical composition comprising a compound of the structure described herein, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, together with at least one pharmaceutically acceptable oral carrier, diluent, or excipient. In another embodiment, the invention provides a topical pharmaceutical composition comprising a compound of the structure described herein, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, together with at least one pharmaceutically acceptable topical carrier, diluent, or excipient. In another embodiment, the invention provides a parenteral pharmaceutical composition comprising a compound of the structure described herein, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, together with at least one pharmaceutically acceptable topical carrier, diluent, or excipient.

[0233] In some embodiments, the invention provides methods for treating NLRP3 inflammasome-dependent conditions, wherein modulating NLRP3 provides a medical benefit to the patient or subject.

[0234] In some embodiments, the NLRP3 inflammasome-dependent condition is inflammation, an inflammatory disease, an immune disease, cancer, an infectious disease including a viral infection, a central nervous system disease, a metabolic disease, a cardiovascular disease, a respiratory disease, a liver disease, a kidney disease, an eye disease, a skin disease, a psychiatric disease, or a blood disease.

[0235] In one embodiment, the NLRP3 inflammasome-dependent condition is a neuroinflammatory-related disease or a neurodegenerative disease.

[0236] In one embodiment, the invention provides a method for inhibiting the NLRP3 inflammasome using an effective amount of the pharmaceutical composition described herein.

[0237] In another aspect, the invention provides a method for treating an NLRP3 inflammasome-dependent condition by administering an effective amount of the pharmaceutical composition described herein to a subject in need thereof. In certain aspects, the NLRP3 inflammasome-dependent condition is a neuroinflammatory disorder or a neurodegenerative disease.

[0238] In another aspect, the invention provides a method for treating NLRP3 inflammasome-dependent conditions, including inflammatory diseases, e.g., inflammation resulting from autoinflammatory diseases, inflammation occurring as a symptom of noninflammatory diseases, inflammation resulting from infection, or inflammation secondary to trauma, injury, or autoimmunity. Examples of inflammation that can be treated or prevented include inflammatory responses associated with or resulting from: (a) skin conditions such as contact sensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (b) joint conditions such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, crystal-induced arthropathy (e.g., pseudogout, gout), or seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, or Reiter's disease); (c) muscle conditions such as polymyositis or myasthenia gravis; (d) gastrointestinal conditions such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer, celiac disease, proctitis, pancreatitis, pancrinesinopilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may affect areas distant from the gut (e.g., migraine, rhinitis, or Iema); (e) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic, or dust-induced asthma, and chronic or refractory asthma, such as late-onset asthma and airway hyperresponsiveness, among others), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, rhinitis sicca, hypertrophic rhinitis, pustular rhinitis, rhinitis sicca, medication-induced rhinitis, membranous rhinitis, seasonal rhinitis, e.g., hay fever, and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (f) vascular conditions such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (g) immune conditions, e.g., autoimmune diseases such as systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease; (h) ocular conditions such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (i) neurological conditions such as multiple sclerosis or encephalomyelitis; (j) an infectious disease or infection-related condition such as acquired immune deficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B, or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis, Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis / epididymitis, Legionella, Lyme disease, Epstein-Barr virus, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (k) renal conditions such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia, or nephrotic syndrome; (l) lymphatic conditions such as Castleman's disease; (m) conditions of or involving the immune system, such as hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (n) liver conditions such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH) or primary biliary cirrhosis; (o) cancer, including those listed herein below; (p) burns, wounds, trauma, hemorrhage or stroke; (q) radiation exposure; and / or (r) obesity; (s) pain, such as inflammatory hyperalgesia; and / or (t) Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

[0239] In another aspect, the invention provides a method for treating an NLRP3 inflammasome-dependent condition, such as an inflammatory disease, resulting from an inflammatory disorder, e.g., an autoinflammatory disease, such as cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multisystem inflammatory disease (NOMID), Majeed syndrome, septic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), adult-onset Still's disease (AOSD), A20 haploinsufficiency (HA20), childhood granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammatory antibody deficiency and immune dysregulation (APLAID), or sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay (SIFD).

[0240] In another aspect, the invention provides a method for treating NLRP3 inflammasome-dependent conditions, such as immune disorders, including autoimmune disorders such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid syndrome (APS), antisynthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular deficiency, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, and systemic lupus erythematosus (SLE). Lupus erythematosus, including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS), multiple sclerosis (MS), including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS), myasthenia gravis, eyelid myoclonus syndrome (OMS), optic neuritis, ordothyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Reiter's syndrome, Sjogren's syndrome, and systemic sclerosis Systemic connective tissue disease, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Belief's disease, Chagas disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, vitiligo, or vulvodynia.

[0241] In another aspect, the invention provides a method for treating NLRP3 inflammasome-dependent conditions, such as cancer, for example, lung cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), Langerhans cell histiocytosis (LCH), myeloproliferative neoplasms (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndromes (MDS), leukemias including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), promyelocytic leukemia (APML or APL), adrenal cancer, anal cancer, basal and squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing's tumor family, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GI stromal tumors), and gallbladder cancer. ST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, pulmonary carcinoid tumor, lymphoma including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymic cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0242] In another aspect, the invention provides a method for treating an NLRP3 inflammasome-dependent condition, such as an infectious disease, including a viral infection (e.g., influenza virus, human immunodeficiency virus (HIV), alphaviruses (e.g., chikungunya and Ross River virus), flaviviruses (e.g., dengue virus and Zika virus), herpesviruses (e.g., Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxviruses (e.g., vaccinia virus (modified vaccinia virus Ankara) and myxoma virus), adenoviruses (e.g., adenovirus type 5), or papillomavirus), bacterial infections (e.g., Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordetella pertussis, Bacillus pseudomallei, Corynebacterium diphtheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, and Streptococcus pneumoniae). infections (e.g., caused by Candida or Aspergillus species), protozoal infections (e.g., caused by Plasmodium, Babesia, Giardia, Entamoeba histolytica, Leishmania or Trypanosoma), helminth infections (e.g., caused by Schistosoma, Ascaris, Cestode or Fluke), and prion infections.

[0243] In another aspect, the invention provides methods for treating NLRP3 inflammasome-dependent conditions, such as central nervous system diseases, including Parkinson's disease, Alzheimer's disease, frontotemporal dementia, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis.

[0244] In another aspect, the invention provides a method for treating an NLRP3 inflammasome-dependent condition, such as a neuroinflammation-related disease, for example, multiple sclerosis, brain infection, acute injury, neurodegenerative disease, Parkinson's disease, or Alzheimer's disease.

[0245] In another aspect, the invention provides a method of treating an NLRP3 inflammasome-dependent condition, such as a neurodegenerative disease, for example, Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

[0246] In one embodiment, the neurodegenerative disease is characterized by the intensive involvement of cell-mediated neuroinflammatory processes.

[0247] In another aspect, the invention provides methods for treating NLRP3 inflammasome-dependent conditions, such as metabolic diseases, for example, type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout.

[0248] In another aspect, the invention provides methods of treating NLRP3 inflammasome-dependent conditions such as cardiovascular diseases, for example, hypertension, ischemia, reperfusion injury, including ischemia-reperfusion injury after myocardial infarction, stroke, including ischemic stroke, transient ischemic attack, myocardial infarction, including recurrent myocardial infarction, heart failure, including congestive heart failure and heart failure with preserved ejection fraction, embolism, aneurysm, including abdominal aortic aneurysm, cardiovascular risk reduction (CvRR), and pericarditis, including Dressler syndrome.

[0249] In another aspect, the invention provides methods for treating NLRP3 inflammasome-dependent conditions, such as respiratory diseases, for example, chronic obstructive pulmonary disease (COPD), asthma, including allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis.

[0250] In another aspect, the invention provides methods for treating NLRP3 inflammasome-dependent conditions, such as liver diseases, such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), including advanced fibrosis stages F3 and F4, alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH).

[0251] In another aspect, the invention provides methods for treating NLRP3 inflammasome-dependent conditions, such as kidney diseases, including acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy.

[0252] In another aspect, the invention provides methods for treating NLRP3 inflammasome-dependent conditions, such as ocular diseases, such as diseases of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infections, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma.

[0253] In another aspect, the invention provides methods for treating NLRP3 inflammasome-dependent conditions, such as skin disorders, including dermatitis, such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cystic skin disorders, and acne conglobata.

[0254] In another aspect, the invention provides methods for treating NLRP3 inflammasome-dependent conditions, such as psychiatric disorders, for example, depression and psychological stress.

[0255] In another aspect, the invention provides methods for treating NLRP3 inflammasome-dependent conditions, such as hematological disorders, e.g., sickle cell disease.

[0256] Pharmaceutical Compositions In certain embodiments, the invention provides pharmaceutical compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, together with at least one pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, the invention provides pharmaceutical compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, together with at least one pharmaceutically acceptable excipient. For example, the active compound will usually be mixed with a carrier, diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier functions as a diluent, it may be a solid, semi-solid, or liquid substance that acts as a vehicle, excipient, or medium for the active compound. The active compound may be adsorbed onto a granular solid carrier, for example, in a sachet. Some examples of suitable carriers are water, saline, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxymethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can comprise any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

[0257] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, formulated with a pharmaceutically acceptable carrier, which may also contain other additives, and which is manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a disease in a mammal. Pharmaceutical compositions can be formulated, for example, in unit dosage form, for oral administration (e.g., tablets, capsules, caplets, gelcaps, or syrups); for topical administration (e.g., creams, gels, lotions, or ointments); for intravenous administration (e.g., as a sterile solution free of particulate plugs and in a solvent system suitable for intravenous administration), for administration to pediatric subjects (e.g., solutions, syrups, suspensions, elixirs, powders for reconstitution as suspensions or solutions, dispersible / effervescent tablets, chewable tablets, lollipops, freezer pops, lozenges, mouth flakes, orally disintegrating tablets, orally disintegrating pieces, and oral powders or granules for sprinkling); or any other formulation described herein. Conventional procedures and ingredients for the selection and preparation of suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0258] In some embodiments, the pharmaceutical composition comprising a compound of structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, together with at least one pharmaceutically acceptable carrier, diluent, or excipient, further comprises a second therapeutic agent.

[0259] As used herein, the term "pharmaceutically acceptable carrier" refers to any component (e.g., a carrier capable of suspending or dissolving an active compound) other than the disclosed compounds or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof, which has the properties of being non-toxic and non-inflammatory to a patient. Excipients can include, for example, anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Exemplary excipients include, but are not limited to, dibutylhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0260] The formulation can be mixed with an auxiliary agent that does not adversely react with the active compound. Such additives can include wetting agents, emulsifying and suspending agents, salts for influencing osmotic pressure, buffers and / or coloring substances, preservatives, sweeteners, or flavoring agents. The composition can also be sterilized if desired.

[0261] The route of administration can be any route that effectively delivers the active compounds of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, including intravenous, subcutaneous and / or intramuscular. In one embodiment, the route of administration is oral. In another embodiment, the route of administration is topical.

[0262] The dosage form can be administered once a day, or more frequently, such as twice or three times a day. Alternatively, if deemed appropriate by the prescribing physician or the drug's prescription information, the dosage form can be administered less frequently, such as every other day or once a week. The administration regimen can include, for example, gradually increasing the dosage to the extent necessary or useful for the indication being treated, thereby allowing the patient's body to adapt to the treatment, minimize or avoid undesirable side effects associated with the treatment, and / or maximize the therapeutic effect of the compound. Other dosage forms include delayed or controlled release forms. Suitable administration regimens and / or dosage forms include, for example, those described in the latest edition of the "Physicians' Desk Reference," which is incorporated herein by reference.

[0263] In one embodiment, the invention provides an oral pharmaceutical composition comprising a compound of structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, in association with at least one pharmaceutically acceptable oral carrier, diluent, or excipient. In another embodiment, the invention provides a topical pharmaceutical composition comprising a compound of structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, in association with at least one pharmaceutically acceptable topical carrier, diluent, or excipient.

[0264] In another aspect, a method for making a composition of the compounds described herein is provided, comprising combining the compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method may further comprise formulating the composition into a tablet or capsule. In another embodiment, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method further comprises lyophilizing the composition to form a lyophilized formulation. In some embodiments, the composition is formulated into a pediatric dosage form suitable for treating pediatric subjects.

[0265] In certain embodiments, the invention provides a compound having structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof. Such compounds can be synthesized using standard synthetic techniques known to those skilled in the art. For example, compounds of the invention can be synthesized using appropriately modified synthetic procedures described in the Examples and Reaction Schemes below.

[0266] For this reason, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the experimental section below, but rather are intended as a guide for those skilled in the art. For example, the reactions may be carried out in any suitable solvent or other reagent to effect the necessary transformations. Generally, a suitable solvent is a protic or aprotic solvent that does not substantially react with the reactants, intermediates, or products at the temperature at which the reaction is carried out (i.e., a temperature that may range from the freezing point to the boiling point). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, a solvent suitable for a particular post-reaction workup may be employed.

[0267] All reagents not described for synthesis in the experimental section are commercially available, known compounds, or can be formed from known compounds by methods known to those skilled in the art. Compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be multiple methods for purifying the same compound. In some cases, purification may not be necessary. In some cases, compounds may be purified by crystallization. In some cases, impurities may be removed by stirring with a suitable solvent. In some cases, compounds may be purified by chromatography, particularly flash column chromatography, using custom or pre-packed silica gel cartridges and eluents of gradient solvents such as heptane, ether, ethyl acetate, acetonitrile, ethanol, etc. In some cases, compounds may be purified by preparative HPLC using the methods described.

[0268] The purification method described herein can provide compounds of the present invention having sufficiently basic or acidic functional groups in the form of salts, such as trifluoroacetate or formate salts in the case of sufficiently basic compounds of the present invention, or ammonium salts in the case of sufficiently acidic compounds of the present invention.Salts of this type can be converted into free base or free acid forms, respectively, by various methods known to those skilled in the art, or can be used as salts in subsequent biological assays.It should be understood that the specific form of the compound of the present invention isolated and described herein is not necessarily the only form in which the compound can be applied to biological assays to determine specific biological activity.

[0269] Chemical names were generated using ChemDraw naming software (version 22.0.0.22) by PerkinElmer Informatics, Inc. In some cases, commonly accepted names of commercially available reagents were used in place of names generated by the naming software. [Example]

[0270] Schematic method 1 H NMR (400 MHz) spectra were acquired in deuterated chloroform (CDCl3), deuterated methanol (CD3OD), or hexadeuterated dimethyl sulfoxide (DMSO-d6). High-performance liquid chromatography (HPLC) retention time, purity, and liquid chromatography-mass spectrometry (LCMS) were acquired using a Shimadzu LCMS 2010 (Shim-pack XR-ODS 3.0*30mm 2.2μm) operating in ES(+) ionization mode. Flow rate: 0.8 mL / min, acquisition time: 3 min, wavelength: UV220, oven temperature: 50°C.

[0271] The following additional abbreviations are used: ethyl acetate (EtOAc), petroleum ether (PE), water (HO), triethylamine (TEA), diethylamine (EtNH), dimethylformamide (DMF), hydrochloric acid (HCl), methanol (MeOH), dimethyl sulfoxide (DMSO), trifluoroacetic acid (TFA), bis(triphenylphosphine)palladium(II) dichloride (PdCl(PPh)), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), tris(o -tolyl)phosphine (P(o-tolyl)3), palladium(II) chloride (PdCl2), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), palladium on carbon (Pd / C), sodium sulfate (Na2SO4), sodium nitrite (NaNO2), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), ammonia (NH3), tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile (MeCN or ACN), diatomaceous earth (brand name "Celite"), time (h), proton nuclear magnetic resonance (NMR) ( 1HNMR), formaldehyde (HCHO), acetic acid (AcOH), degrees Celsius (°C), milligrams (mg), grams (g), millimole (mmol), milliliters (mL), moles (M), pH, sodium cyanoborohydride (NaBHCN), preparative high-performance liquid chromatography (preparative HPLC), normalized concentration (N), ethanol (EtOH), supercritical fluid chromatography (SFC), megahertz (MHz), minutes (min), percent (%), pounds per square inch (psi), millimeters (mm), micrometers (μM), microliters (μL), carbon dioxide (CO2), Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum (FBS).

[0272] General Scheme A TIFF2026502863000205.tif201170

[0273] Schematic Scheme B TIFF2026502863000206.tif90154

[0274] Schematic Scheme C TIFF2026502863000207.tif98162

[0275] Schematic Scheme D TIFF2026502863000208.tif148165

[0276] Example 1 Synthesis of (S)-4-methyl-8-(1-methylpiperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)cinnoline and (R)-4-methyl-8-(1-methylpiperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)cinnoline (Compound 1-1I and Compound 1-1(R)) TIFF2026502863000209.tif37137 Compounds 1-1(S) and 1-1(R) were made using the procedure of general Scheme A according to the steps below.

[0277] Synthesis of 1-(prop-1-yn-1-yl)-4-(trifluoromethyl)benzene To a solution of 1-bromo-4-(trifluoromethyl)benzene (4 g, 17.8 mmol) in DMSO (30 mL) was added but-2-ynoic acid (1.79 g, 21.3 mmol), PdCl(PPh) (1.25 g, 1.78 mmol), 1,4-bis(diphenylphosphino)butane (1.52 g, 3.56 mmol), and DBU (8.12 g, 53.3 mmol). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 2 h. The mixture was poured into water (30 mL) and extracted with DCM (3 × 30 mL). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (15% EtOAc in PE) to give the desired product 1-prop-1-ynyl-4-(trifluoromethyl)benzene (1.5 g, 46% yield) as a colorless oil.

[0278] Synthesis of (Z)-1-(2-chloro-6-iodophenyl)-3,3-diethyltriaz-1-ene To a solution of 2-chloro-6-iodoaniline (3.21 g, 12.7 mmol) in THF (10 mL), MeCN (10 mL), and water (12 mL) was added 12 M aqueous HCl (8.4 mL, 101 mmol) and NaNO (1.75 g, 25.3 mmol) in water (10 mL) dropwise over 0.2 h at −5 °C. The resulting mixture was stirred under a nitrogen atmosphere at −5 °C for 0.5 h. EtNH (5.55 g, 75.9 mmol) was then added to the mixture. The resulting mixture was stirred under a nitrogen atmosphere at 0 °C for 0.5 h. The mixture was poured into water (150 mL), neutralized to approximately pH 7 with a saturated aqueous solution of NaHCO, and extracted with EtOAc (3 × 150 mL). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (15% EtOAc in PE) to give the desired product, (Z)-1-(2-chloro-6-iodophenyl)-3,3-diethyltriaz-1-ene (3.1 g, 73% yield) as a yellow oil.

[0279] Synthesis of 8-chloro-4-methyl-3-(4-(trifluoromethyl)phenyl)cinnoline To a solution of 1-(prop-1-yn-1-yl)-4-(trifluoromethyl)benzene (2.29 g, 12.4 mmol) in DMF (10 mL) was added (Z)-1-(2-chloro-6-iodophenyl)-3,3-diethyltriaz-1-ene (1.4 g, 4.15 mmol), PdCl (70 mg, 0.42 mmol), P(o-tolyl) (250 mg, 0.825 mmol), and TEA (839 mg, 8.29 mmol). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 14 h. The mixture was then poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (15% EtOAc in PE) to give the desired product 8-chloro-4-methyl-3-(4-(trifluoromethyl)phenyl)cinnoline (479 mg, 36% yield) as a yellow solid.

[0280] Synthesis of tert-butyl 5-(4-methyl-3-(4-(trifluoromethyl)phenyl)cinnolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of 8-chloro-4-methyl-3-(4-(trifluoromethyl)phenyl)cinnoline (200 mg, 0.620 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (383 mg, 1.24 mmol) in dioxane (2 mL) and water (0.2 mL) was added Pd(dppf)Cl (91 mg, 0.12 mmol) and NaCO (171 mg, 1.24 mmol). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 14 h. The mixture was then poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (30% EtOAc in PE) to give the desired product, tert-butyl 5-(4-methyl-3-(4-(trifluoromethyl)phenyl)cinnolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (232 mg, 79% yield), as a yellow oil.

[0281] Synthesis of tert-butyl 3-(4-methyl-3-(4-(trifluoromethyl)phenyl)cinnolin-8-yl)piperidine-1-carboxylate TIFF2026502863000214.tif28142 To a solution of tert-butyl 5-(4-methyl-3-(4-(trifluoromethyl)phenyl)cinnolin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.426 mmol) in methanol (2 mL) was added 10% wet Pd / C (20 mg). The mixture was stirred under a hydrogen atmosphere (15 Psi) at room temperature for 14 hours. The mixture was then filtered through Celite, and the filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure to give the desired crude product, tert-butyl 3-(4-methyl-3-(4-(trifluoromethyl)phenyl)cinnolin-8-yl)piperidine-1-carboxylate (196 mg), as a brown solid. The crude product was used in the next step without further purification.

[0282] Synthesis of 4-methyl-8-(piperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)cinnoline To a solution of tert-butyl 3-(4-methyl-3-(4-(trifluoromethyl)phenyl)cinnolin-8-yl)piperidine-1-carboxylate (196 mg) in DCM (2 mL) was added a 4N solution of HCl in 1,4-dioxane (2 mL). The resulting mixture was stirred at room temperature for 3 hours. The mixture was then concentrated under reduced pressure to give the desired crude product, 4-methyl-8-(piperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)cinnoline (197 mg), as a yellow solid. The crude product was used in the next step without further purification.

[0283] Synthesis of (S)-4-methyl-8-(1-methylpiperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)cinnol (Compound 1-1(S)) and (R)-4-methyl-8-(1-methylpiperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)cinnoline (Compound 1-1(R)) To a solution of 4-methyl-8-(piperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)cinnoline (197 mg) in THF (2 mL) and water (0.2 mL) was added 37% aqueous HCHO (38 mg, 0.46 mmol), NaBHCN (44 mg, 0.69 mmol), and AcOH (28 mg, 0.46 mmol). The resulting mixture was stirred at 50 °C for 2 h. The mixture was then poured into water (30 mL), neutralized to approximately pH 7 with a saturated aqueous solution of NaHCO, and extracted with EtOAc (3 × 30 mL). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by preparative HPLC (0.05% NH3.HO as additive) to give the racemic product 4-methyl-8-(1-methyl-3-piperidyl)-3-[4-(trifluoromethyl)phenyl]cinnoline (39 mg, 22% yield) as a yellow solid. The racemic product was further purified by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm)), mobile phase: [0.1% NH3HO EtOH]; B%: 35%-35%, min) to give the desired product: (S)-4-methyl-8-(1-methylpiperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)cinnoline (Compound 1-1(S)) (12 mg, 31% yield) TIFF2026502863000217.tif27159 and (R)-4-methyl-8-(1-methylpiperidin-3-yl)-3-(4-(trifluoromethylphenyl)cinnoline) (compound 1-1(R)) (14 mg, yield 35%) was obtained as a white solid. TIFF2026502863000218.tif28159

[0284] The compounds listed in Table 2 were made using the procedures in Scheme A, substituting appropriate starting materials where necessary.

[0285] [Table 2] TIFF2026502863000220.tif231161TIFF2026502863000221.tif255161TIFF2026502863000222.t if232161TIFF2026502863000223.tif252161TIFF2026502863000224.tif255161TIFF20265028630 00225.tif255161TIFF2026502863000226.tif244161TIFF2026502863000227.tif255161TIFF202 6502863000228.tif253161TIFF2026502863000229.tif252161TIFF2026502863000230.tif198161

[0286] Example 2 Synthesis of (R)-ethyl-8-(1-methylpiperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine (Compound 5-1(R)) TIFF2026502863000231.tif39128 Compound 5-1(R) was made using the procedure of general Scheme B according to the steps below.

[0287] Synthesis of 3,6-dichloro-4-(3-chloropropyl)-5-methylpyridazine To a solution of 3,6-dichloro-4-methylpyridazine (2 g, 12.3 mmol) and 4-chlorobutanoic acid (1.65 g, 13.5 mmol) in 80 mL of HO was added AgNO (2.08 g, 12.3 mmol). The mixture was heated to 50 °C, and then concentrated HSO (2 mL, 36.8 mmol) was added. The resulting mixture was heated to 60 °C, and 1.6 M aqueous (NH)SO (23 mL, 36.8 mmol) was added dropwise. The mixture was stirred at 70 °C under a nitrogen atmosphere for 14 h. The pH was adjusted to approximately 7 by adding concentrated NH.HO, and the mixture was extracted with EtOAc (5 × 100 mL). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (15% EtOAc in PE) to give the desired product, 3,6-dichloro-4-(3-chloropropyl)-5-methylpyridazine (846 mg, 29% yield) as an off-white solid.

[0288] Synthesis of (R)-3-chloro-4-methyl-8-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine TIFF2026502863000233.tif29128To a solution of 3,6-dichloro-4-(3-chloropropyl)-5-methylpyridazine (846 mg) and TEA (676 mg, 6.68 mmol) in DMSO (5 mL) was added (R)-1-methylpiperidin-3-amine (400 mg, 1.67 mmol). The resulting mixture was stirred at 150 °C in a microwave under a nitrogen atmosphere for 1 hour. The mixture was then poured into water (20 mL) and extracted with EtOAc (5 × 20 mL). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (15% EtOAc in PE) to give the desired product, (R)-Ihloro-4-methyl-8-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine (140 mg, 30% yield) as a yellow oil.

[0289] Synthesis of (R)-4-methyl-8-(1-methylpiperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-I]pyridazine (Compound 5-1(R)) TIFF2026502863000234.tif40152 To a solution of (R)-3-chloro-4-methyl-8-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine (70 mg, 0.26 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (60 mg, 0.32 mmol) in dioxane (1 mL) and HO (0.1 mL) was added XPhosPdG (22 mg, 0.026 mmol) and CsCO (256 mg, 0.787 mmol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 14 h. The mixture was then poured into water (20 mL) and extracted with EtOAc (5 × 20 mL). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (15% EtOAc in PE) to give the impure but desired product, (R)-4-methyl-8-(1-methylpiperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3I]pyridazine (60 mg) as a yellow oil. The desired product was further purified by preparative HPLC (0.05% NH3HO as an additive) to give the desired product, (R)-4-methyl-8-(1-methylpiperidin-3-yl)-3-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine (compound 5-1(R)) (20 mg, 20% yield) as a yellow solid. TIFF2026502863000235.tif27159

[0290] The compounds listed in Table 3 were made using the procedure in Scheme B, substituting the appropriate starting materials where necessary. [Table 3] TIFF2026502863000237.tif252170TIFF2026502863000238.tif244170TIFF2026502863000239.tif23 9170TIFF2026502863000240.tif246170TIFF2026502863000241.tif233170TIFF2026502863000242.t if233170TIFF2026502863000243.tif247170TIFF2026502863000244.tif233170TIFF20265028630002 45.tif255170TIFF2026502863000246.tif242170TIFF2026502863000247.tif246170TIFF2026502863 000248.tif237170TIFF2026502863000249.tif242170TIFF2026502863000250.tif255170TIFF202650 2863000251.tif250170TIFF2026502863000252.tif244170TIFF2026502863000253.tif250170TIFF20 26502863000254.tif246170TIFF2026502863000255.tif233170TIFF2026502863000256.tif233170TI FF2026502863000257.tif225170TIFF2026502863000258.tif235170TIFF2026502863000259.tif63170

[0291] Example 3 Synthesis of (R)-3-hydroxy-5-methyl-4-(5-methyl-8-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-3-yl)benzonitrile (Compound 8-4(R)) TIFF2026502863000260.tif40128 Compound 8-4(R) was made using the procedure of general Scheme C according to the steps below.

[0292] Synthesis of 2-((3,6-dichloropyridazin-4-yl)(methyl)amino)ethan-1-ol To a solution of 3,4,6-trichloropyridazine (5 g, 27.3 mmol) in DMF (50 mL) was added 2-(methylamino)ethanol (2.05 g, 27.3 mmol) and TEA (5.52 g, 54.5 mmol). The mixture was stirred at 50 °C for 14 h. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (50% EtOAc in PE) to give the desired product, 2-((3,6-dichloropyridazin-4-yl)(methyl)amino)ethan-1-ol (5.47 g, 90% yield) as a white solid.

[0293] Synthesis of 2-((3,6-dichloropyridazin-4-yl)(methyl)amino)ethyl methanesulfonate To a solution of 2-[(3,6-dichloropyridazin-4-yl)-methyl-amino]ethanol (5.47 g, 24.6 mmol) in DCM (50 mL) was added TEA (7.48 g, 73.9 mmol) and DMAP (600 mg, 4.93 mmol) at 0 °C. Methanesulfonic anhydride (6.44 g, 36.9 mmol) was then added, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (60% EtOAc in PE) to give the desired product, 2-((3,6-dichloropyridazin-4-yl)(methyl)amino)ethyl methanesulfonate (7.19 g, 97% yield), as a yellow oil.

[0294] Synthesis of (R)-3-chloro-5-methyl-8-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazine TIFF2026502863000263.tif24128To a solution of 2-[(3,6-dichloropyridazin-4-yl)-methyl-amino]ethyl methanesulfonate (1 g, 3.33 mmol) in DMF (5 mL) was added (3R)-1-methylpiperidin-3-amine (380 mg, 3.33 mmol) and TEA (1.01 g, 9.99 mmol). The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 14 hours. The mixture was poured into water (30 mL) and extracted with EtOAc (3×30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (22% MeOH in DCM) to give the desired product (R)-3-chloro-5-methyl-8-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazine (402 mg) as a brown oil.

[0295] Synthesis of (R)-3-hydroxy-5-methyl-4-(5-methyl-8-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-3-yl)benzonitrile (Compound 8-4(R)) To a solution of (R)-3-chloro-5-methyl-8-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazine (100 mg) in dioxane (2 mL) and water (0.2 mL) was added 3-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (126 mg, 0.46 mmol), XPhosPdG (30 mg, 0.036 mmol), and CsCO (289 mg, 0.89 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 14 h. The mixture was then poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (10% MeOH in DCM) to give the desired product, (R)-3-hydroxy-5-methyl-4-(5-methyl-8-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-3-yl)benzonitrile (67 mg) as a yellow oil. TIFF2026502863000265.tif28162

[0296] The compounds listed in Table 4 were made using the procedure in Scheme C, substituting the appropriate starting materials where necessary.

[0297] [Table 4] TIFF2026502863000267.tif240162TIFF2026502863000268.tif255162TIFF2026502863000269.tif248162TIFF2026502863000270.tif231162 TIFF2026502863000271.tif242162TIFF2026502863000272.tif255162TIFF2026502863000273.tif247162TIFF2026502863000274.tif165162

[0298] Example 4 Synthesis of (R)-5-fluoro-3-methyl-2-(1-(1-methylpiperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl)phenol (Compound 12-2(R)) TIFF2026502863000275.tif39128 Compound 12-2(R) was made using the procedure of general Scheme D according to the steps below.

[0299] Synthesis of 5-chloro-1H-pyrazolo[3,4-c]pyridazin-3-amine TIFF2026502863000276.tif23128 To a solution of 3,6-dichloropyridazine-4-carbonitrile (3 g, 17.2 mmol) in MeOH (30 mL) was added NH2NH2.HO (2.03 g, 34.5 mmol) dropwise. The resulting mixture was stirred at 65 °C for 1 h. The mixture was then cooled to room temperature and filtered through a Celite pad. The filter cake was washed with EtOAc (2 × 20 mL) and dried in vacuo to give the desired product, 5-chloro-1H-pyrazolo[3,4-c]pyridazin-3-amine (2.37 g, 81% yield), as a yellow solid.

[0300] Synthesis of 5-chloro-1H-pyrazolo[3,4-c]pyridazine-3-diazonium To a suspension of 5-chloro-1H-pyrazolo[3,4-c]pyridazin-3-amine (1.5 g, 8.85 mmol) in AcOH (15 mL) was added a solution of NaNO (1.22 g, 17.7 mmol) in HO (8 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 14 h. The mixture was then poured into water (70 mL) and extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the desired crude product, 5-chloro-1H-pyrazolo[3,4-c]pyridazine-3-diazonium (860 mg), as a yellow solid. The crude product was used in the next step without further purification.

[0301] Synthesis of 5-chloro-1H-pyrazolo[3,4-c]pyridazine To a solution of 5-chloro-1H-pyrazolo[3,4-c]pyridazine-3-diazonium (860 mg, 4.74 mmol) in DME (9 mL) was added 0.1 N HCl (54 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The pH was then adjusted to approximately 7 by adding saturated aqueous NaHCO3, and the mixture was extracted with DCM (3 × 15 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel chromatography (49% EtOAc in PE) to give the desired product, 5-chloro-1H-pyrazolo[3,4-c]pyridazine (404 mg, 55% yield), as a yellow solid.

[0302] Synthesis of (R)-tert-butyl 3-(5-chloro-1H-pyrazolo[3,4-c]pyridazin-1-yl)piperidine-1-carboxylate To a solution of 5-chloro-1H-pyrazolo[3,4-c]pyridazine (450 mg, 2.91 mmol) in THF (7 mL) was added tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (1.03 g, 5.1 mmol) and PPh3 (2.29 g, 8.73 mmol) at 0 °C. DIAD (1.77 g, 8.73 mmol) was then added dropwise, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was then poured into water (20 mL) and extracted with EtOAc (3 × 10 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel chromatography (21% EtOAc in PE) to give the desired product, (R)-tert-butyl 3-(5-chloro-1H-pyrazolo[3,4-c]pyridazin-1-yl)piperidine-1-carboxylate (960 mg) as a yellow oil.

[0303] Synthesis of tert-butyl (R)-3-(5-(4-fluoro-2-methoxy-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridazin-1-yl)piperidine-1-carboxylate To a solution of (R)-tert-butyl 3-(5-chloro-1H-pyrazolo[3,4-c]pyridazin-1-yl)piperidine-1-carboxylate (200 mg, 0.178 mmol) in dioxane (2 mL) and water (0.2 mL) was added 2-(4-fluoro-2-methoxy-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (71 mg, 0.266 mmol), XPhosPdG (15 mg, 0.0178 ml), and CsCO (145 mg, 0.444 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 14 h. The mixture was then poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (40% EtOAc in PE) to give the desired product, (R)-tert-butyl 3-(5-(4-fluoro-2-methoxy-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridazin-1-yl)piperidine-1-carboxylate (106 mg).

[0304] Synthesis of (R)-5-fluoro-3-methyl-2-(1-(piperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl)phenol To a solution of tert-butyl (R)-3-(5-(4-fluoro-2-methoxy-6-thylphenyl)-1H-pyrazolo[3,4-c]pyridazin-1-yl)piperidine-1-carboxylate (106 mg) in DCM (1 mL) was added BBr3 (358 mg, 1.1 mmol) at -78 °C. The resulting mixture was stirred at room temperature for 12 h. The pH was then adjusted to approximately 7 by adding a saturated aqueous solution of NaHCO3, and the mixture was extracted with EtOAc (3 × 30 mL). The combined TI organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the desired crude product, (R)-5-fluoro-3-methyl-2-(1-(piperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl)phenol (135 mg) as a brown solid, which was used in the next step without further purification.

[0305] Synthesis of (R)-5-fluoro-3-methyl-2-(1-(1-methylpiperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl)phenol To a solution of (R)-5-fluoro-3-methyl-2-(1-(piperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl)phenol (135 mg) in THF (2 mL) and water (0.2 mL) was added 37% aqueous HCHO (33 mg, 0.412 mmol), NaBHCN (39 mg, 0.619 mmol), and IOH (25 mg, 0.412 mmol). The mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours, then a saturated aqueous solution of NaHCO was added to adjust the pH to approximately 7, and the mixture was extracted with EtOAc (3 × 30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by preparative HPLC (0.05% NH3.H2O and NH4HCO3 as additives) to give the desired product, (R)-5-fluoro-3-methyl-2-(1-(1-methylpiperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl)phenol (compound 12-2(R)) (18 mg, 12% yield) as a white solid. TIFF2026502863000283.tif28160

[0306] The compounds listed in Table 5 were made using the procedure in Scheme D, substituting the appropriate starting materials where necessary. [Table 5] TIFF2026502863000285.tif238162TIFF2026502863000286.tif247162TIFF2026502863000287.tif252162TIFF2026502863000288.tif101162

[0307] Example 5 Assessment of NLRP3 inflammasome activation and cell viability in THP1 macrophages THP1 human acute monocytic leukemia cells (ATCC, Cat. No. TIB-202) were cultured in Gibco RPMI-1640 medium (ThermoFisher Cat. No. 72400054) supplemented with 10% heat-inactivated FBS at a density of 3–8 × 10^5 viable cells / ml. The cell concentration was then increased to 8 × 10^5 cells / ml. 5 When the cell density reached 10 cells / mL (every 2 to 3 days), the cells were subcultured.

[0308] Compound IC 50 To determine the β-amyloid activity, 1.75 × 10 cells were plated in 50 ul / well of DMEM (ThermoFisher, Cat. No. 10393021), 10% FBS, 1x GlutaMax (ThermoFisher, Cat. No. 35050038) + 20 nM PMA (Sigma, Cat. No. P1585) in a CELLSTAR 384-well plate (Greiner Cat. No. 781091). 4 Only the inner 224 wells of a 384-well plate were used. Parameter wells were filled with 50 μl of PBS and cultured at 37°C, 5% CO2 for 48 hours.

[0309] After 48 hours of culture, the PMA-containing medium was removed and replaced with 40 ul / well of fresh DMEM, 10% FBS, and 1x GlutaMax, and the cells were cultured at 37°C, 5% CO2 for 24 hours.

[0310] The next day, cells were stimulated with 20 ng / ml LPS (E. coli) (Sigma, Cat. No. L3129) in DMEM, 10% FBS, 1x GlutaMax for 3 hours at 37°C, 5% CO2.

[0311] Following the LPS stimulation step, cells were treated with eight 1:4 dilutions of compounds (10 μM, 2.5 μM, 0.625 μM, 0.156 μM, 0.039 μM, 0.0097 μM, 0.0024 μM, 0.0006 μM) at a maximum final concentration of 10 μM. DMSO was used as a vehicle control and MCC950 (InvivoGen, catalog number inh-mcc) was used as a positive control at 1 μM, and the cells were incubated at 37°C, 5% CO for 1 hour.

[0312] After 1 hour of compound incubation, the NLRP3 inflammasome activation step was performed by treating cells with nigericin (InvivoGen, catalog no. tlrl-nig) at a final concentration of 6.7 uM for 3 hours at 37°C, 5% CO2.

[0313] A 30ul sample of the cell supernatant was then taken for cytokine analysis, which was run against Hu IL-1β AlphaLISA (Perkin Elmer, Cat. No. AL220C) and Hu IL-6 AlphaLISA (Perkin Elmer, Cat. No. AL220C). Cell viability was assessed using the CellTiter-Glo luminescent assay (Promega, Cat. No. G7572) according to the manufacturer's protocol.

[0314] The cell viability assessment for each selected NLRP3 inflammasome modulator is shown in Table 6.

[0315] For IL-1β activity, the activity ranges are as follows: "++++" indicates IL-1β activity ≦100 nM; "+++" indicates IL-1β activity >100 nM and ≦500 nM; "++" indicates IL-1β activity >500 nM and ≦1,000 nM; "+" indicates IL-1β activity >1,000 nM; and "*" indicates not yet tested.

[0316] For IL-6 activity, the activity ranges are as follows: "++++" indicates IL-6 activity ≦1 μM; "+++" indicates IL-6 activity >1 μM and ≦5 μM; "++" indicates IL-6 activity >5 μM and ≦10 μM; "+" indicates IL-6 activity >10 μM. "*" indicates not tested. [Table 6] TIFF2026502863000290.tif249162TIFF2026502863000291.tif255162TIFF2026502863000292.tif253162TIFF2026502863000293.tif255162TIFF2026502863000294.tif253162TIFF2026502863000295.tif249162TIFF2026502863000296.tif249162TIFF2026502863000297.tif249162TIFF2026502863000298.tif249162TIFF2026502863000299.tif249162TIFF2026502863000300.tif249162TIFF2026502863000301.tif249162TIFF2026502863000302.tif249162TIFF2026502863000303.tif247162TIFF2026502863000304.tif246162TIFF2026502863000305.tif249162TIFF2026502863000306.tif249162TIFF2026502863000307.tif249162TIFF2026502863000308.tif253162TIFF2026502863000309.tif249162TIFF2026502863000310.tif249162TIFF2026502863000311.tif249162TIFF2026502863000312.tif249162TIFF2026502863000313.tif249162TIFF2026502863000314.tif249162TIFF2026502863000315.tif194162

[0317] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent literature mentioned herein and / or listed in the Application Data Sheet, including but not limited to U.S. Provisional Patent Application No. 63 / 477,027, filed December 23, 2022, and U.S. Provisional Patent Application No. 63 / 477,031, filed December 23, 2022, are incorporated herein by reference in their entirety. If necessary, concepts from various patents, applications, and literature can be employed to modify aspects of the embodiments and provide further embodiments.

[0318] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments, along with the full range of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

1. Formula (A'): or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, having the structure: During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; Ring A is pyrrolidinyl, piperazinyl, morpholinyl, imidazolidinyl, oxazolidinyl, pyrazolyl, piperidinyl, phenyl, or pyridinyl; R 1 is an aminyl alkyl or and R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R 6 is H, cycloalkyl, or one or more R 7 is alkyl optionally substituted with R 7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is between 0 and 2, The compound or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

2. Formula (I): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; Ring A is phenyl or pyridinyl; R 1 is an aminyl alkyl or and R 2 , R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R 6 is H, cycloalkyl, or one or more R 7 is alkyl optionally substituted with R 7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is between 0 and 2, 10. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

3. Formula (Iia): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR 2 - or (2) x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently =CH- or =CR 2 -either; Each R 2 , R 3 , R 4 , and R 5 are independently halo, CN, OH, alkyl, haloalkyl, or alkoxy; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R 6 is H, cycloalkyl, or one or more R 7 is alkyl optionally substituted with R 7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is between 0 and 2, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

4. Formula (IIa'):

4. The compound of any one of claims 1 to 3, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

5. Formula (IIa''):

4. The compound of any one of claims 1 to 3, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

6. Formula (IIb): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR 2 - or (2) x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently =CH- or =CR 2 -either; Ra is H or alkyl; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5, 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

7. Formula (IIIa): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR 2 - or (2) x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently =CH- or =CR 2 -either; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R 6 is H, cycloalkyl, or one or more R 7 is alkyl optionally substituted with R 7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is between 0 and 2, 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

8. Formula (IIIa'):

10. The compound of any one of claims 1, 2, or 7, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

9. Formula (IIIa''):

10. The compound of any one of claims 1, 2, or 7, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

10. Formula (IIIb): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; (1)x 1 , x 2 , and x 3 are each independently =CH- or =CR 2 - or (2) x 1 , x 2 , and x 3 one of which is =N- and the other two are each independently =CH- or =CR 2 -either; Ra is H or alkyl; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

11. 11. The compound of any one of claims 1 to 10, wherein ring A is phenyl.

12. 11. The compound of any one of claims 1 to 10, wherein Ring A is pyridinyl.

13. 2. The compound of claim 1, wherein Ring A is piperidinyl.

14. Formula (VI*a): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R 6 is H, cycloalkyl, or one or more R 7 is alkyl optionally substituted with R 7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is between 0 and 2, 14. The compound of claim 1 or 13, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

15. Formula (VI*a'):

15. The compound of any one of claims 1, 13, or 14, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

16. Formula (VI*a″):

15. The compound of any one of claims 1, 13, or 14, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

17. Formula (VI*b): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; Ra is H or alkyl; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5, 14. The compound of any one of claims 1 or 13, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

18. 2. The compound of claim 1, wherein Ring A is pyrrolidinyl.

19. Formula (VII*a): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R 6 is H, cycloalkyl, or one or more R 7 is alkyl optionally substituted with R 7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is between 0 and 2, 20. The compound of claim 1 or 18, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

20. Formula (VII*a'):

20. The compound of any one of claims 1, 18, or 19, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

21. Formula (VII*a″):

20. The compound of any one of claims 1, 18, or 19, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

22. Formula (VII*b): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; Ra is H or alkyl; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5, 20. The compound of claim 1 or 18, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

23. 2. The compound of claim 1, wherein ring A is piperazinyl.

24. Formula (VIII*a): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R 6 is H, cycloalkyl, or one or more R 7 is alkyl optionally substituted with R 7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is between 0 and 2, 24. The compound of claim 1 or 23, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

25. Formula (VIII*a'):

25. The compound of any one of claims 1, 23, or 24, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

26. Formula (VIII*a″):

25. The compound of any one of claims 1, 23, or 24, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

27. Formula (VIII*b): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; Ra is H or alkyl; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5, 24. The compound of claim 1 or 23, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

28. 2. The compound of claim 1, wherein Ring A is morpholinyl.

29. Formula (IX*a): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R 6 is H, cycloalkyl, or one or more R 7 is alkyl optionally substituted with R 7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is between 0 and 2, 30. The compound of claim 1 or 28, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

30. Formula (IX*a'):

30. The compound of any one of claims 1, 28, or 29, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

31. Formula (IX*a''):

30. The compound of any one of claims 1, 28, or 29, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

32. Formula (IX*b): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; Ra is H or alkyl; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5, 30. The compound of claim 1 or 28, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

33. 2. The compound of claim 1, wherein Ring A is imidazolidinyl.

34. Formula (X*a): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R 6 is H, cycloalkyl, or one or more R 7 is alkyl optionally substituted with R 7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is between 0 and 2, 34. The compound of claim 1 or 33, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

35. Formula (X*a'):

35. The compound of any one of claims 1, 33, or 34, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

36. Formula (X*a''):

35. The compound of any one of claims 1, 33, or 34, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

37. Formula (X*b): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; Ra is H or alkyl; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5, 34. The compound of claim 1 or 33, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

38. 2. The compound of claim 1, wherein Ring A is oxazolidinyl.

39. Formula (XI*a): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R 6 is H, cycloalkyl, or one or more R 7 is alkyl optionally substituted with R 7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is between 0 and 2, 40. The compound of claim 1 or 38, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

40. Formula (XI*a'):

40. The compound of any one of claims 1, 38, or 39, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

41. Formula (XI*a''):

40. The compound of any one of claims 1, 38, or 39, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

42. Formula (XI*b): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; Ra is H or alkyl; R 2 each occurrence is independently oxo, halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl, or two R 2 form an aromatic ring together with the atoms to which they are attached; R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5, 40. The compound of claim 1 or 38, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

43. 2. The compound of claim 1, wherein ring A is pyrazolyl.

44. Formula (XII*a): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; R 2 , R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; R 6 is H, cycloalkyl, or one or more R 7 is alkyl optionally substituted with R 7 is halo, OH, or cycloalkyl; m is 0 to 6; n is 0 to 5; p is 0 to 3; and q is between 0 and 2, 44. The compound of claim 1 or 43, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

45. Formula (XII*a'):

45. The compound of any one of claims 1, 43, or 44, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

46. Formula (XIIa''):

45. The compound of any one of claims 1, 43, or 44, having the structure: or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

47. Formula (XII*b): having the structure During the ceremony Z 1 and Z 2 are independently =CH-, =CR 4 - or =N-; Ra is H or alkyl; R 2 , R 3 , R 4 , and R 5 is, at each occurrence, independently halo, CN, OH, alkyl, haloalkyl, alkoxy, haloalkoxy, aminylalkyl, or cycloalkyl; Ak is alkyl; n is 0 to 5; p is 0 to 3; and y is between 0 and 5, 44. The compound of claim 1 or 43, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

48. R 1 13. The compound of any one of claims 1-2 or 11-12, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

49. R 1 but 13. The compound of any one of claims 1-2 or 11-12, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

50. At least one R 2 50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein is alkyl.

51. At least one R 2 51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein is methyl, ethyl, or isopropyl.

52. At least one R 2 52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein is methyl.

53. R 3 53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein is alkyl.

54. R 3 54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein is methyl, ethyl, or isopropyl.

55. R 3 55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein is methyl.

56. At least one R 4 56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein is halo, CN, OH, alkyl, or haloalkyl.

57. At least one R 4 F, Cl, CN, OH, methyl, CHF 2 , or CF 3 57. The compound of any one of claims 1 to 56, wherein:

58. At least one R 5 58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein is halo.

59. At least one R 5 59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein

60. R 6 60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein is alkyl.

61. R 6 61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein is methyl, ethyl, or isopropyl.

62. R 6 62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein

63. R 6 62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein

64. 64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein n is 1.

65. 64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein n is 2.

66. 66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein p is 0.

67. 66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein p is 1.

68. 68. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein q is 1.

69. 69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein m is 0.

70. 70. The compound of any one of claims 1-69, wherein y is 1.

71. x 1 , x 2 , and x 3 each independently represents ═CH— or ═CR 2 71. The compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

72. x 1 , x 2 , and x 3 one of which is =N- and the other two are independently =CH- or =CR 2 72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

73. x 1 , x 2 , and x 3 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

74. R 2 73. The compound of claim 71 or 72, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein is methyl.

75. 75. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein Ra is H.

76. 75. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein Ra is alkyl.

77. 77. The compound of claim 76, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein Ra is methyl.

78. 78. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein Ak is methyl.

79. Z 1 is =CH- and Z 2 79. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

80. Z 1 is =CH- and Z 2 GA=CR 4 79. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein

81. Z 1 GA=CR 4 - and Z 2 79. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

82. Z 1 GA=CR 4 - and Z 2 GA=CR 4 79. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein

83. Z 1 is = N- and Z 2 GA=CR 4 79. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein

84. Z 1 GA=CR 4 - and Z 2 79. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

85. Z 1 is = N- and Z 2 79. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

86. Z 1 is =CH- and Z 2 79. The compound of any one of claims 1-78, wherein is =N-.

87. 2. The compound of claim 1, wherein the compound has the structure of a compound in Table 1, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

88. 88. A pharmaceutical composition comprising the compound of any one of claims 1-87, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, and at least one pharmaceutically acceptable excipient.

89. NLRP3 inflammasome, an effective amount of a compound of any one of claims 1 to 87, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof; or an effective amount of the pharmaceutical composition of claim 88. A method for modulating NLRP3 inflammasome activity by contacting

90. 89. A method of treating an NLRP3 inflammasome-dependent condition by administering an effective amount of the pharmaceutical composition of claim 88 to a subject in need thereof.

91. The method of claim 90, wherein the NLRP3 inflammasome-dependent condition is a neuroinflammatory-related disorder or a neurodegenerative disease.

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