Modulators of the NLRP3 inflammasome and related products and methods

Abstract

Compounds are provided for modulating the NLRP3 inflammasome, or more specifically for treating NLRP3 inflammasome-dependent pathologies, which comprise contacting an effective amount of a compound having structure (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, with the NLRP3 inflammasome or administering it to a subject in need thereof, wherein X, R 1 R 2 R 3 R 4 R 5 R 8 R 9 R 10 R 11 R 12 R 13 and n are as defined herein. Also provided are pharmaceutical compositions containing such compounds, as well as the compounds themselves. TIFF2025517702000171.tif40128

Description

Technical Field

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

Background Art

[0002] Description of Related Art NOD-like receptor protein 3 (NLRP3) is an important protein that interacts with apoptosis-associated speck-like protein (ASC) and procaspase-1 to form the NLRP3 inflammasome. Activation of the NLRP3 inflammasome produces inflammatory mediators such as interleukin-1β (IL-1β) and interleukin-18 (IL-18), thereby contributing 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, cleavage of gasdermin-D, and ultimately the initiation of cell death via pyroptosis. This system alerts the presence of invading microorganisms by cytokine release and works to resolve inflammation by eliminating infected cells.

[0004] However, non-microbial compounds, either of endogenous or exogenous origin, are also effective inducers of NLRP3 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 proteins form aggregates that lead to activation of the NLRP3 inflammasome. Also, environmental particles such as inhaled asbestos and silica activate the NLRP3 inflammasome, and high levels of IL-1β are involved in the development of asbestosis and silicosis, two progressive lung diseases that lead to fibrosis.

[0005] Recent studies have revealed that the increased production of IL-1β and IL-18 by the NLRP3 inflammasome is involved in the onset and progression of various diseases such as neuroinflammation-related disorders, for example, brain infections, acute injuries, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other neurodegenerative diseases; cardiovascular diseases, cardiovascular risk reduction, atherosclerosis, type I and type II diabetes and associated complications, inflammatory skin diseases, acne, hidradenitis suppurativa, asthma, age-related macular degeneration, or cancer-related diseases. These disorders with an immune or inflammatory nature are usually difficult to diagnose or treat efficiently.

[0006] Therefore, there is a need in the art for compounds that modulate the NLRP3 inflammasome for the treatment of diseases where blockade of the NLRP3 inflammasome would be beneficial.

[0007] In addition, there is a need for compounds that modulate the NLRP3 inflammasome and have a low risk of off-target effects. For example, the human ether-a-go-go related gene (hERG) potassium channel is essential for normal electrical activity of the heart. The hERG channel is involved in the repolarization of cardiac action potentials, and a decrease in hERG function prolongs the ventricular action potential, prolongs the QT interval on the electrocardiogram, and potentially increases the risk of lethal ventricular arrhythmias. To reduce the risk of investing resources in drug candidates that cannot pass preclinical safety tests due to QT prolongation, it is important to screen compounds early in the lead optimization process for off-target activity against the hERG channel. Therefore, it is beneficial to develop compounds that modulate the NLRP3 inflammasome while showing little or no hERG activity and thus a reduced potential for cardiotoxicity.

[0008] As will be apparent from the following description, the present invention meets these requirements and provides other advantages. SUMMARY OF THE INVENTION

[0009] Brief Summary In one aspect, there is provided a compound having structure (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000002.tif40128wherein X, R 1 、R 2 、R 3 、R 4 、R 5 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、and n are as defined herein.

[0010] In another aspect, there is provided a pharmaceutical composition comprising a carrier or excipient and a compound having structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0011] In a further aspect, there is provided a method for treating an NLRP3 inflammasome-dependent pathology by administering to a subject in need thereof an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, or a pharmaceutical composition comprising the same. In some aspects, the NLRP3 inflammasome-dependent pathology is a neuroinflammation-related disorder or a neurodegenerative disease. In some aspects, the NLRP3 inflammasome activity is modulated such that there is no cardiotoxicity risk at a physiologically relevant exposure with respect to the NLRP modulation effect.

Mode for Carrying Out the Invention

[0012] Detailed Description Definitions As used herein, the following terms have the meanings defined below unless the context otherwise indicates.

[0013] To "modulate" the NLRP3 inflammasome means that a compound interacts with NLRP3 in such a way as to block its ATPase function and downstream NLRP3 inflammasome complex formation. In the above context, the compound acts to inhibit or block the activation of the NLRP3 inflammasome, and thus this compound can also be described as an inhibitor.

[0014] NLRP3 refers to NOD-like receptor protein 3. NLRP3 is a protein-coding gene, and an exemplary sequence can be found at https: / / www.uniprot.org / uniprot / Q96P20. NLRP3 functions as an ATPase that is auto-inhibited under normal conditions. NLRP3, unlike other inflammasomes, requires a two-step activation process, which can be induced by a variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). The first step primes the NLRP3 inflammasome through the recognition of PAMPs, DAMPs, or pathological species via pattern recognition receptors (PRRs) (e.g., Toll-like receptors). Priming increases the expression of NLRP3, pro-IL1β, and pro-IL18. Activation of NLRP3 is induced by a second signal, such as ATP, K + efflux, other cellular stresses, or pathological species, which leads to ATP hydrolysis and activation of the enzyme. This activation leads to oligomerization of the inflammasome complex, resulting in autoproteolysis 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 pores, and the release of such cytokines induces downstream inflammatory responses and cell death via pyroptosis.

[0015] "hERG" refers to the rapidly activating delayed rectifier potassium channel (I KrRefers to the human ether-à-go-go related gene (hERG) that encodes the pore-forming subunit of (

[0016] "Effective amount" refers to the amount of an agent sufficient to achieve a desired effect in a subject being treated with the specified agent. Ideally, the effective amount of an agent is an amount sufficient to inhibit or treat a disease without causing significant toxicity in the subject. The effective amount of an agent depends on the subject being treated, the severity of the affliction, and the mode of administration of the pharmaceutical composition. A method for determining the effective amount of the disclosed compounds sufficient to achieve the desired effect in a subject will be understood by one of ordinary skill in the art in light of the present disclosure.

[0017] "Alkyl" means a saturated or unsaturated straight-chain or branched-chain alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 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-chain alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.

[0018] "Halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0019] "Hydroxyl" refers to -OH.

[0020] "Cyano" refers to -CN.

[0021] "Carboxyl" or "carboxy" refers to -CO 2 OH.

[0022] "Oxo" refers to the =O substituent.

[0023] "Haloalkyl" refers to alkyl as defined above, where one or more hydrogen atoms are replaced by halogen. Examples of haloalkyl groups include, but are not limited to, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CH 2 CHF 2 and the like.

[0024] "Alkoxy" refers to alkyl as defined above, connected via 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, etc.

[0025] "Haloalkoxy" refers to haloalkyl as defined above, connected via an oxygen atom (i.e., -O-haloalkyl). Examples of haloalkoxy groups include, but are not limited to, -OCF 3 and the like.

[0026] "Aminyl" refers to -NH 2 , -NH alkyl or N(alkyl) 2 , where alkyl is as defined above. Examples of amino or aminyl include, but are not limited to, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 and the like.

[0027] "Cycloalkyl" refers to a non-aromatic ring moiety containing 3 or more ring members. In some embodiments, cycloalkyl contains 3 to 8 ring members. In some embodiments, cycloalkyl contains 3 to 5 ring members. For example, cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0028] "Heterocycle" refers to aromatic and non-aromatic ring moieties containing 3 or more ring members, one or more of which is a heteroatom (but not limited to, N, O, S, or P, etc.). In some embodiments, heterocyclyl contains 3 to 20 ring members, while other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but not all rings in a polycyclic system need to contain a heteroatom. For example, both the dioxolanyl ring and the benzodioxolanyl ring system (methylenedioxyphenyl ring system) are heterocyclyl groups within the scope of their meaning herein. For example, heterocyclic rings include dioxane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, and the like.

[0029] Heterocyclic groups include fused ring species including those having fused aromatic and non-aromatic groups. Heterocyclic groups include polycyclic ring systems containing heteroatoms such as quinuclidyl, although not limited thereto, and also heterocyclic groups having a substituent (including, although not limited to, an alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio or alkoxy group) bonded to one of the ring members. A heterocyclic group as defined herein can be a heteroaryl group or a partially or fully saturated cyclic group containing at least one ring heteroatom. Heterocyclic 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] "Isomer" is used herein to include all chiral, diastereomeric or racemic forms of a structure (also referred to as a stereoisomer with respect to a structural or positional isomer), unless a specific stereochemistry or isomeric form is specifically designated. Such compounds can, as is apparent from the description, have any or all of the asymmetric carbon atoms as enantiomers in any degree of enrichment or resolution. Both racemic and diastereomeric mixtures and individual enantiomers can be synthesized so as to be substantially free of their enantiomers and diastereomeric partners, all of which are within the scope of certain embodiments of the present invention. Isomers resulting from the presence of chiral centers include a pair of non-superimposable isomers called "enantiomers". A single enantiomer of a pure compound is optically active (i.e., they can rotate the plane of plane-polarized light and are designated as R or S).

[0031] "Isolated optical isomer" means a compound that is substantially purified from the corresponding optical isomers of the same formula. For example, an isolated isomer can be at least about 80%, 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 diastereomerically" pure means that the level of enrichment of the enantiomer or diastereomer of one enantiomer exceeds at least about 80%, more specifically 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9% with respect to the other enantiomer or diastereomer.

[0033] The terms "racemate" and "racemic mixture" refer to an equimolar mixture of two enantiomers. Since a racemate is not optically active (i.e., its constituent enantiomers cancel each other out and do not rotate plane-polarized light in either direction), it is designated "(±)". All compounds having an asterisk (*) in the vicinity of 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 can contain water in stoichiometric amounts, such as a monohydrate or dihydrate, or can contain water in random amounts. When the term is used in this specification, "hydrate" refers to the solid form; i.e., a compound in an aqueous solution may be hydrated but is not a hydrate as the term is used in this specification.

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

[0036] "Isotope" refers to atoms that have the same number of protons but different numbers of neutrons. Isotopes of a compound of structure (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), (Ic-1'''), (II), (III), (IV) or (V) include 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 6 protons and 6 neutrons, while carbon-13 has 6 protons and 7 neutrons, and carbon-14 has 6 protons and 8 neutrons. Hydrogen has two stable isotopes, namely deuterium (1 proton and 1 neutron) and tritium (1 proton and 2 neutrons). Fluorine has a number of isotopes, but fluorine-19 has the longest half-life. Thus, isotopes of a compound having the structure of (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), (Ic-1'''), (II), (III), (IV) or (V) include, but are not limited to, compounds of structure (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), (Ic-1'''), (II), (III), (IV) or (V) in which one or more carbon-12 atoms are replaced by carbon-13 and / or carbon-14 atoms, one or more hydrogen atoms are replaced by deuterium and / or tritium, and / or one or more fluorine atoms are replaced by fluorine-19.

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

[0038] The term "pharmaceutically acceptable" refers to agents that are approved for human consumption and are generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to addition salts of non-toxic inorganic or organic acids and / or bases (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 present invention include, for example, metal salts including salts of alkali metals, alkaline earth metals and transition metals, such as salts of calcium, magnesium, potassium, sodium and zinc. Pharmaceutically acceptable base addition salts also include, for example, 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 can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from organic acids of the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic acid, and sulfonic acid classes, 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 compounds of the present disclosure (i.e., compounds of structure (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), (Ic-1'''), (II), (III), (IV) or (V), and aspects thereof), or pharmaceutically acceptable salts thereof, may contain one or more geometrically asymmetric centers and thus can give rise to enantiomers, diastereomers and other stereoisomeric forms which are defined as (R)- or (S)- with respect to absolute stereochemistry or, in the case of amino acids, (D)- or (L)-. Accordingly, aspects 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 a chiral synthon or chiral reagent or may be resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemate (or a racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are included.

[0042] Pharmaceutically unacceptable salts are generally not useful as pharmaceuticals, but such salts may be useful as intermediates, for example, in the synthesis of compounds having structure (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), (Ic-1'''), (II), (III), (IV) or (V), or in their purification, for example, by recrystallization.

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

[0044] In some aspects, NLRP3 inflammasome-dependent disorders are inflammation, inflammatory diseases, immune diseases, cancer, infectious diseases including viral infections; central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, eye diseases, skin diseases, mental diseases or blood diseases.

[0045] In one aspect, NLRP3 inflammasome-dependent disorders are neuroinflammation-related disorders or neurodegenerative diseases.

[0046] In one aspect, the present invention provides a method for inhibiting the NLRP3 inflammasome using an effective amount of a pharmaceutical composition as described herein. In one aspect, the pharmaceutical composition is selective for modulating NLRP3 inflammasome activity over hERG activity. In certain aspects, the selectivity for NLRP3 inflammasome activity is ≧1,000-fold over hERG activity. In certain aspects, the selectivity for NLRP3 inflammasome activity is ≧10-fold over hERG activity. In certain aspects, the selectivity for NLRP3 inflammasome activity is ≧100-fold over hERG activity.

[0047] In another aspect, the present invention provides a method of treating an NLRP3 inflammasome-dependent disorder by administering to a subject in need thereof an effective amount of a pharmaceutical composition as described herein. In certain aspects, the NLRP3 inflammasome-dependent disorder is a neuroinflammation-related disorder or a neurodegenerative disease.

[0048] As used herein, the term "inflammation" refers to inflammation resulting from an inflammatory disorder (e.g., an autoinflammatory disease), inflammation resulting as a symptom of a non-inflammatory disorder, inflammation resulting from an 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 the following: (a) Skin diseases, such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic eczema, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (b) Arthropathies, such as osteoarthritis, systemic juvenile idiopathic arthritis, adult 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) Myopathic conditions, such as polymyositis or myasthenia gravis; (d) Gastrointestinal pathologies, such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastro-enteritis, mastocytosis, antiphospholipid antibody syndrome, or food-related allergies that can have effects remote from the gastrointestinal tract (e.g., migraine, rhinitis or eczema); (e) Respiratory pathologies, such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or habitual asthma such as late-onset asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, rhinitis caseosa, hypertrophic rhinitis, purulent rhinitis, dry rhinitis, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis such as 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 pathologies, such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (g)Immune pathologies, such as autoimmune pathologies, 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 pathologies, such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (i)Nervous system pathologies, such as multiple sclerosis or encephalomyelitis; (j)Infections or infection-related pathologies, such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infections, acute or chronic parasitic infections, acute or chronic viral infections, acute or chronic fungal infections, 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, influenza A, Epstein-Barr virus, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (k)Renal pathologies, such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia, or nephrotic syndrome; (l)Lymphatic pathologies, such as Castleman's disease; (m)Pathologies of the immune system, or pathologies in which it is involved, such as hyper IgE syndrome, lepromatous Hansen's disease, familial hemophagocytic syndrome, or graft-versus-host disease; (n)Liver pathologies, such as chronic active hepatitis, non-alcoholic fatty liver disease (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH) or primary biliary cirrhosis; (o)Cancers, including the cancers listed hereinbelow; (p)Burns, wounds, traumas, bleeding or strokes; (q)Radiation exposure; and / or (r)Obesity; (s) Pain, for example, inflammatory hyperalgesia; and / or (t) neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

[0049] As used herein, the phrase "inflammatory disease" means, for example, an inflammatory disorder, such as an autoinflammatory disease, such as cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multisystem inflammatory disease (NOMID), Magid syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), adult Still's disease (AOSD), A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-related antibody deficiency immunodeficiency (PLAID), PLCG2-related autoinflammatory, antibody deficiency immunodeficiency (APLAID), or B cell immunodeficiency, periodic fever, and iron-deficient anemia with developmental delay (SIFD)-resulting inflammation.

[0050] As used herein, the term "immune disease" means, for example, autoimmune diseases such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti-synthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyendocrine insufficiency, 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, lupus erythematosus including systemic lupus erythematosus (SLE), primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing - remitting multiple sclerosis (RRMS) including multiple sclerosis (MS), myasthenia gravis, opsoclonus - myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, 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, systemic scleroderma, systemic connective tissue disorders, Takayasu arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Beliefs disease, Chagas disease, autonomic neuropathy, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler's syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, vitiligo or vulvodynia.

[0051] As used herein, the term "cancer" means, for example, lung cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), Langerhans cell histiocytosis (LCH), myeloproliferative neoplams (MPN), pancreatic cancer, gastrointestinal cancer, myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), leukemia including promyelocytic leukemia (APML, or APL), adrenal cancer, anal cancer, basal cell carcinoma of the skin, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumors, lymphomas including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal and paranasal cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, sublingual gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymic cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms tumor.

[0052] As used herein, the phrase "infectious diseases including viral infections" means, for example, viral infections (e.g., by influenza virus, human immunodeficiency virus (HIV), alphavirus (such as chikungunya and Ross River virus), flavivirus (such as dengue virus and Zika virus), herpesvirus (such as Epstein - Barr virus, cytomegalovirus, varicella - zoster virus, and KSHV), poxvirus (such as vaccinia virus (modified vaccinia virus Ankara) and myxoma virus), adenovirus (such as adenovirus 5), or papillomavirus), bacterial infections (e.g., by Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordetella pertussis, Burkholderia pseudomallei, Corynebacterium diphtheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Haemophilus influenzae, Pasteurella multocida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi or Yersinia pestis), fungal infections (e.g., by Candida or Aspergillus species), protozoal infections (e.g., by malaria, Babesia, Giardia, Entamoeba, Leishmania or Trypanosoma), helminth infections (e.g., by schistosomes, nematodes, cestodes or trematodes), and prion infections.

[0053] As used herein, the phrase "central nervous system disease" means, for example, Parkinson's disease, Alzheimer's disease, frontotemporal dementia, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain injury due to pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis.

[0054] As used herein, the phrase "neuroinflammation-related disease" means, for example, multiple sclerosis, brain infection, acute injury, neurodegenerative disease, Parkinson's disease or Alzheimer's disease.

[0055] As used herein, the phrase "neurodegenerative disease" means, for example, Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

[0056] In one aspect, neurodegenerative diseases are characterized by a deep involvement of cell-mediated neuroinflammatory processes.

[0057] As used herein, the phrase "metabolic disease" means, for example, type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout.

[0058] As used herein, the phrase "cardiovascular disease" means, for example, hypertension, ischemia, reperfusion injury including post-MI ischemic reperfusion injury, attacks including ischemic attacks, transient ischemic attacks, 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's syndrome.

[0059] As used herein, the phrase "respiratory disease" means, for example, chronic obstructive pulmonary disease (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis.

[0060] As used herein, the term "liver disease" means, for example, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), including progressive fibrosis stages F3 and F4, alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH).

[0061] As used herein, the term "kidney disease" means, for example, acute kidney disease, hyperoxaluria, chronic kidney disease, nephrolithiasis, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy;

[0062] As used herein, the term "eye disease" means, for example, diseases of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet forms), uveitis, corneal infections, diabetic retinopathy, optic neuropathy, dry eye, and glaucoma.

[0063] As used herein, the term "skin disease" means, for example, dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-inducing skin diseases, and acne conglobata.

[0064] As used herein, the term "mental disorder" means, for example, depression and mental stress.

[0065] As used herein, the term "blood disease" means, for example, sickle cell disease.

[0066] As used herein, the term "administration" refers to providing a compound as described herein, or a pharmaceutical composition comprising the compound. The compound or composition can be administered to a subject by another person or by the subject themselves. Non-limiting examples of routes of administration are oral, parenteral (e.g., intravenous), or topical.

[0067] As used herein, the term "treatment" refers to an intervention that ameliorates the signs or symptoms of a disease or pathological condition. As used herein, the terms "treatment", "treating" and "treatment of" in relation to a disease, pathological condition or symptom also refer to any observable beneficial effect of that treatment. Beneficial effects 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, slowing the progression of a disease, reducing the number of recurrences of a disease, improving the overall health or well-being of a subject, or by other parameters well known in the art specific to a particular disease. A prophylactic treatment is a treatment administered to a subject who does not show signs of a disease or shows only initial signs, for the purpose of reducing the risk of developing the disease state. A therapeutic treatment is a treatment administered to a subject after the signs and symptoms of a disease have appeared.

[0068] As used herein, the term "subject" refers to an animal (e.g., a mammal such as a human). A subject to be treated according to the methods described herein can be a subject diagnosed with an NLRP3 inflammasome-dependent pathology such as an 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 mental disease or a blood disease.

[0069] Diagnosis can be performed by any method or technique known in the art. One of ordinary skill in the art will understand that a subject to be treated according to the present disclosure may have received a standard test, or may have been identified as at risk based on the presence of one or more risk factors associated with a disease or condition, without testing. The term "patient" can be used interchangeably with the term "subject". A subject can refer to an adult or pediatric subject.

[0070] Compound As detailed above, the present disclosure provides compounds that exhibit significant activity as NLRP3 inflammasome antagonists (i.e., as NLRP3 inflammasome inhibitors). Thus, in one aspect, there is provided a compound having structure (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000003.tif40128Wherein, (1) When X is CR a R b ; Here, R a and R b are each independently H or C 1-6 alkyl; R 1 is H, OH, CF 3 , C 1-6 alkyl, C 3-5 cycloalkyl, CN, halo, OCF 1-6 alkyl or OCF 3 ; R 2 and R 5 are independently H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OCF 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OCF 1-6 alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl optionally substituted with one or more R 1-6 ; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R13 is, independently, H or halo; R 11 and R 12 are each independently H, halo, CF 3 , C 1-6 alkyl, CN or OC 1-6 alkyl; n is 0, 1 or 2; or (2) when X is NR a or O; wherein R a and R b are each independently H or C 1-6 alkyl; R 1 is H, OH, CF 3 , C 1-6 alkyl, C 3-5 cycloalkyl, CN, halo, OCF 1-6 alkyl or OCF 3 ; R 2 and R 5 are independently H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl optionally substituted with one or more R 1-6 ; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13is, independently, H or halo; R 11 and R 12 are, each independently, H, halo, CF 3 C 1-6 alkyl, CN or OC 1-6 alkyl; n is 0, 1 or 2; and wherein X is NR a or O, and R 1 is Cl, CH 3 CF 3 OCF 3 or methyl, one of R 2 and R 5 is not H.

[0071] In another aspect, there is provided a compound having the following structure (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000004.tif40128wherein, (1) when X is CR a R b ; wherein R a and R b are, each independently, H or C 1-6 alkyl; R 1 is H, OH, CF 3 C 1-6 alkyl, C 3-5 cycloalkyl, CN, halo, OCF 1-6 alkyl or OCF 3 ; R 2 and R 5 are, independently, H, OH, CF 3 C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH, CF 3 C 1-6Alkyl, CN, halo, OCF 3 or OC 1-6 is alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C with one or more R 9' optionally substituted by 1-6 alkyl; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13 are each independently H or halo; R 11 and R 12 are each independently H, halo, CF 3 , C 1-6 alkyl, CN or OC 1-6 alkyl; n is 0, 1 or 2; or (2) When X is NR a or O; where R a and R b are each independently H or C 1-6 alkyl; (A) R 1 is H, OH, C 2-6 alkyl, C 3-5 cycloalkyl, CN, F, Br or OC 1-6 alkyl; R 2 and R 5 are independently H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6is alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl which may be substituted with one or more R 1-6 is alkyl; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13 are independently H or halo; R 11 and R 12 are each independently H, halo, CF 3 C 1-6 alkyl, CN or OCF 1-6 alkyl; and n is 0, 1 or 2; or (B) R 1 is CF 3 methyl, Cl or OCF 3 ; R 2 and R 5 one of which is OH, CF 3 C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl, and the other is H, OH, CF 3 C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 3 or R 4 one of which is OH, and the other is H, OH, CF 3 C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C9' C may be replaced by 1-6 alkyl; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13 are each independently H or halo; R 11 and R 12 are each independently H, halo, CF 3 , C 1-6 alkyl, CN or OC 1-6 alkyl; and n is 0, 1 or 2.

[0072] In one aspect, there is provided a compound having the following structure (I'), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000005.tif41128wherein, X is CR a R b , NR a or O; wherein R a and R b are each independently H or C 1-6 alkyl; R 1 is H, OH, C 2-6 alkyl, C 3-5 cycloalkyl, CN, F, Br or OCF 1-6 alkyl; R 2 and R 5 are each independently H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC1-6 is alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C optionally substituted with one or more R 9' alkyl; 1-6 is alkyl; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13 are each independently H or halo; R 11 and R 12 are each independently H, halo, CF 3 C 1-6 alkyl, CN or OC 1-6 alkyl; and n is 0, 1 or 2.

[0073] In one aspect, there is provided a compound having the following structure (I''), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000006.tif40128wherein, X is CR a R b NR a or O; wherein, R a and R b are each independently H or C 1-6 alkyl; R 1 is H, F, CN, C 2-6 alkyl or C 3-5 cycloalkyl; R 2 and R 5 are each independently H or C 1-6 alkyl; R 3 or R 4 one of is OH and the other is H, OH or C 1-6 alkyl; R 11 and R 12 are each independently H, F or C 1-6 alkyl; and n is 0, 1 or 2.

[0074] In one aspect, there is provided a compound having the following structure (Ia), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000007.tif41128 wherein, R a is H or C 1-6 alkyl; and (A) R 1 is H, OH, C 2-6 alkyl, C 3-5 cycloalkyl, CN, F, Br or O C 1-6 alkyl; R 2 and R 5 are independently H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or O C 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or O C 1-6 alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl optionally substituted with one or more R 1-6 ; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13 are independently H or halo; R11 and R 12 is, independently of one another, H, halo, CF 3 , C 1-6 alkyl, CN or OC 1-6 alkyl; and n is 0, 1 or 2; or (B) R 1 is CF 3 , methyl, Cl or OCF 3 ; R 2 and R 5 one of which is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl, and the other is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl which may be substituted with one or more R 1-6 ; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13 are independently of one another H or halo; R 11 and R 12 are, independently of one another, H, halo, CF 3 , C 1-6 alkyl, CN or OC 1-6 alkyl; and n is 0, 1 or 2.

[0075] In one aspect, there is provided a compound having the following structure (Ia), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000008.tif41128wherein, R a is H or C 1-6 alkyl; R 1 is H, OH, C 2-6 alkyl, C 3-5 cycloalkyl, CN, F, Br or OCF 1-6 alkyl; R 2 and R 5 are each independently H, OH, CF 3 3, C 1-6 alkyl, CN, halo, OCF 3 or OCF 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH, CF 3 3, C 1-6 alkyl, CN, halo, OCF 3 or OCF 1-6 alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl optionally substituted with one or more R 1-6 alkyl; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13 are independently H or halo; R 11 and R 12 are each independently H, halo, CF 3 3, C 1-6 alkyl, CN or OCF 1-6is alkyl; and n is 0, 1 or 2.

[0076] In one aspect, there is provided a compound having the following structure (Ia'), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000009.tif41128 wherein, R a is H or C 1-6 alkyl; R 1 is H, F, CN, C 2-6 alkyl or C 3-5 cycloalkyl; R 2 and R 5 are each independently H or C 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH or C 1-6 alkyl; R 11 and R 12 are each independently H, F or C 1-6 alkyl; and n is 0, 1 or 2.

[0077] In one aspect, there is provided a compound having the following structure (Ib), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000010.tif40128 wherein, (A)R 1 is H, OH, C 2-6 alkyl, C 3-5 cycloalkyl, CN, F, Br or O C 1-6 alkyl; R 2 and R 5 are independently H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or O C 1-6is alkyl; R 3 or R 4 is OH, and the other is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl which may be substituted with one or more R 1-6 alkyl; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13 are independently H or halo; R 11 and R 12 are each independently H, halo, CF 3 , C 1-6 alkyl, CN or OC 1-6 alkyl; and n is 0, 1 or 2; or (B) R 1 is CF 3 , methyl, Cl or OCF 3 ; R 2 and R 5 one of which is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl, and the other is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 3 or R 4 one of which is OH, and the other is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF3 or OC 1-6 is alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl which may be substituted with one or more R 1-6 is alkyl; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13 are independently H or halo; R 11 and R 12 are each independently H, halo, CF 3 , C 1-6 alkyl, CN or OC 1-6 alkyl; and n is 0, 1 or 2.

[0078] In one aspect, there is provided a compound having the following structure (Ib), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000011.tif40128 wherein, R 1 is H, OH, C 2-6 alkyl, C 3-5 cycloalkyl, CN, F, Br or OC 1-6 alkyl; R 2 and R 5 are each independently H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6is alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl which may be substituted with one or more R 1-6 is alkyl; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13 are each independently H or halo; R 11 and R 12 are each independently H, halo, CF 3 , C 1-6 alkyl, CN or OC 1-6 alkyl; and n is 0, 1 or 2.

[0079] In one aspect, there is provided a compound having the following structure (Ib'), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000012.tif40128 wherein, R 1 is H, F, C 2-6 alkyl or C 3-5 cycloalkyl; R 2 and R 5 are each independently H or C 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH or C 1-6 alkyl; R 11 and R 12 are each independently H or C 1-6 alkyl; and n is 0, 1 or 2.

[0080] In one aspect, there is provided a compound having the following structure (Ic), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000013.tif41128 wherein, R a and R b are each independently H or C 1-6 alkyl; R 1 is H, OH, CF 3 3, C 1-6 1 - 6 alkyl, C 3-5 3 - 8 cycloalkyl, CN, halo, OCF 1-6 3 or OCF 3 3; R 2 and R 5 are independently H, OH, CF 3 3, C 1-6 1 - 6 alkyl, CN, halo, OCF 3 3 or O 1-6 1 - 6 alkyl; R 3 or R 4 is OH and the other is H, OH, CF 3 3, C 1-6 1 - 6 alkyl, CN, halo, OCF 3 3 or O 1-6 1 - 6 alkyl; R 8 is H or halo; R 9 is H, C 3-5 3 - 8 cycloalkyl, or C 9' 1 - 6 alkyl optionally substituted with one or more R 1-6 groups; R 9' is OH, F or C 3-5 3 - 8 cycloalkyl; R 10 and R 13 are independently H or halo; R 11 and R 12 are each independently H, halo, CF 3 3, C 1-6 1 - 6 alkyl, CN or O 1-6is alkyl; and n is 0, 1 or 2.

[0081] In one aspect, there is provided a compound having the following structure (Ic), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000014.tif41128wherein, R a and R b are each independently H or C 1-6 alkyl; R 1 is H, OH, C 2-6 alkyl, C 3-5 cycloalkyl, CN, F, Br or O C 1-6 alkyl; R 2 and R 5 are each independently H, OH, CF 3 C 1-6 alkyl, CN, halo, OCF 3 or O C 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH, CF 3 C 1-6 alkyl, CN, halo, OCF 3 or O C 1-6 alkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl optionally substituted with one or more R 1-6 alkyl; R 9' is OH, F or C 3-5 cycloalkyl; R 10 and R 13 are independently H or halo; R 11 and R 12 are each independently H, halo, CF3 , C 1-6 alkyl, CN or OC 1-6 is alkyl; and n is 0, 1 or 2.

[0082] In one aspect, there is provided a compound having the following structure (Ic'), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000015.tif41128 wherein, R a and R b are each independently H or C 1-6 alkyl; R 1 is H, F, C 2-6 alkyl or C 3-5 cycloalkyl; R 2 and R 5 are each independently H or C 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H, OH or C 1-6 alkyl; R 11 and R 12 are each independently H or C 1-6 alkyl; and n is 0, 1 or 2.

[0083] In more specific aspects of each of structures (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), and (Ic'), such structures optionally include the following more specific aspects.

[0084] In one aspect, X is CR a R b wherein.

[0085] In another aspect, X is NR a wherein.

[0086] In yet another aspect, X is O.

[0087] In one aspect, R 11 and R 12 are not H.

[0088] In some aspects, R 11 is halo, CF 3 , C 1-6 alkyl, CN, or OC 1-6 alkyl, and R 12 is H.

[0089] In other aspects, R 11 is H, and R 12 is halo, CF 3 , C 1-6 alkyl, CN, or OC 1-6 alkyl.

[0090] In still other aspects, both R 11 and R 12 are H.

[0091] In some aspects, both R 11 and R 12 are not H.

[0092] In one aspect, R 1 is H.

[0093] In another aspect, R 1 is OH.

[0094] In other aspects, R 1 is CF 3 .

[0095] In yet another aspect, R 1 is F.

[0096] In one aspect, R 1 is Cl.

[0097] In another aspect, R 1is Br.

[0098] In another aspect, R 1 is I.

[0099] In some aspects, R 1 is OCF 3 is.

[0100] In one aspect, R 1 is CN.

[0101] In some aspects, R 1 is C 1-6 alkyl.

[0102] In a particular aspect, R 1 is methyl.

[0103] In other aspects, R 1 is C 2-6 alkyl.

[0104] In a particular aspect, R 1 is ethyl.

[0105] In a particular aspect, R 1 is isopropyl.

[0106] In one aspect, R 1 is OC 1-6 alkyl.

[0107] In a particular aspect, R 1 is OCH 3 is.

[0108] In one aspect, R 1 is C 3-5 cycloalkyl.

[0109] In a particular aspect, R 1 is cyclopropyl.

[0110] In a particular aspect, R1 is cyclobutyl.

[0111] In one aspect, R 2 and R 5 are independently H, C 1-6 alkyl, F, Cl, CF 3 or CN.

[0112] In another aspect, R 2 is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl, and R 5 is H.

[0113] In some aspects, R 2 is R 2 is H, and R 5 is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl.

[0114] In one aspect, R 2 is H.

[0115] In another aspect, R 2 is OH.

[0116] In some aspects, R 2 is CF 3 .

[0117] In other aspects, R 2 is C 1-6 alkyl.

[0118] In certain aspects, R 2 is methyl.

[0119] In other aspects, R 2 is ethyl.

[0120] In yet another aspect, R 2 is isopropyl.

[0121] In another aspect, R 2 is CN.

[0122] In some aspects, R 2 is F.

[0123] In yet another aspect, R 2 is Cl.

[0124] In some aspects, R 2 is Br.

[0125] In another aspect, R 2 is I.

[0126] In one aspect, R 2 is OCF 3 .

[0127] In yet another aspect, R 2 is OC 1-6 alkyl.

[0128] In one aspect, R 2 is OCH 3 .

[0129] In some aspects, R 5 is H.

[0130] In one aspect, R 5 is OH.

[0131] In some aspects, R 5 is CF 3 .

[0132] In another aspect, R 5 is C 1-6 alkyl.

[0133] In yet another aspect, R 5is methyl.

[0134] In certain embodiments, R 5 is ethyl.

[0135] In other embodiments, R 5 is isopropyl.

[0136] In yet other embodiments, R 5 is CN.

[0137] In one embodiment, R 5 is F.

[0138] In some embodiments, R 5 is Cl.

[0139] In another embodiment, R 5 is Cl.

[0140] In other embodiments, R 5 is Br.

[0141] In another embodiment, R 5 is I.

[0142] In one embodiment, R 5 is OCF 3 .

[0143] In yet other embodiments, R 5 is OC 1-6 alkyl.

[0144] In one embodiment, R 5 is OCH 3 .

[0145] In some embodiments, R 3 is OH, and R 4 is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl.

[0146] In other embodiments, R 4 is OH, and R 3 is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl.

[0147] In one embodiment, R 3 is OH, and R 4 is H or C 1-6 alkyl.

[0148] In another embodiment, R 4 is OH, and R 3 is H or C 1-6 alkyl.

[0149] In one embodiment, R 3 is OH.

[0150] In other embodiments, R 3 is H.

[0151] In another embodiment, R 3 is CF 3 .

[0152] In some embodiments, R 3 is C 1-6 alkyl.

[0153] In other embodiments, R 3 is methyl.

[0154] In certain embodiments, R 3 is ethyl.

[0155] In some embodiments, R 3 is isopropyl.

[0156] In other embodiments, R 3 is CN.

[0157] In yet another aspect, R 3 is F.

[0158] In one aspect, R 3 is Cl.

[0159] In some aspects, R 3 is Br.

[0160] In another aspect, R 3 is I.

[0161] In another aspect, R 3 is OCF 3 is.

[0162] In yet another aspect, R 3 is OC 1-6 alkyl.

[0163] In one aspect, R 3 is OCH 3 is.

[0164] In some aspects, R 4 is OH.

[0165] In one aspect, R 4 is H.

[0166] In another aspect, R 4 is CF 3 is.

[0167] In yet another aspect, R 4 is C 1-6 alkyl.

[0168] In some aspects, R 4 is methyl.

[0169] In other aspects, R 4 is ethyl.

[0170] In some aspects, R 4is isopropyl.

[0171] In one aspect, R 4 is CN.

[0172] In another aspect, R 4 is F.

[0173] In yet another aspect, R 4 is Cl.

[0174] In yet another aspect, R 4 is Br.

[0175] In another aspect, R 4 is I.

[0176] In another aspect, R 4 is OCF 3 is.

[0177] In still other aspects, R 4 is OC 1-6 alkyl.

[0178] In some aspects, R 4 is OCH 3 is.

[0179] In one aspect, R 8 is H.

[0180] In another aspect, R 8 is F.

[0181] In yet another aspect, R 8 is Cl.

[0182] In another aspect, R 8 is Br.

[0183] In another aspect, R 8 is I.

[0184] In some aspects, R9 is H.

[0185] In one aspect, R 9 is not H.

[0186] In another aspect, R 9 is C 1-6 alkyl.

[0187] In some aspects, R 9 is methyl.

[0188] In other aspects, R 9 is ethyl.

[0189] In yet another aspect, R 9 is isopropyl.

[0190] In one aspect, R 9 is C 1-6 alkyl which may be substituted with one or more Fs.

[0191] In a particular aspect, R 9 is -CH 2 CH 2 F.

[0192] In still another aspect, R 9 is -CH 2 CHF 2 .

[0193] In some aspects, R 9 is -CH 2 CF 3 .

[0194] In one aspect, R 9 is C 3-5 cycloalkyl.

[0195] In a particular aspect, R 9 is cyclopropyl.

[0196] In one aspect, R9 is a C optionally substituted with one or more C 3-5 alkyl which may be cycloalkyl-substituted C 1-6 alkyl.

[0197] In certain embodiments, R 9 is TIFF2025517702000016.tif9128.

[0198] In some embodiments, R 9 is R 9 is a C alkyl optionally substituted with one or more OH 1-6 alkyl.

[0199] In other embodiments, R 9 is TIFF2025517702000017.tif5128.

[0200] In another embodiment, R 10 and R 13 are both H.

[0201] In one embodiment, R 10 and R 13 are both halo.

[0202] In certain embodiments, R 10 and R 13 are both F.

[0203] In another embodiment, R 10 is H and R 13 is halo.

[0204] In yet another embodiment, R 10 is H and R 13 is F.

[0205] In one embodiment, R 10 is H.

[0206] In another embodiment, R 10 is F.

[0207] In certain embodiments, R 10 is Cl.

[0208] In other embodiments, R 10 is Br.

[0209] In another embodiment, R 10 is I.

[0210] In one embodiment, R 13 is H.

[0211] In some embodiments, R 13 is F.

[0212] In other embodiments, R 13 is Cl.

[0213] In yet other embodiments, R 13 is Br.

[0214] In another embodiment, R 13 is I.

[0215] In some embodiments, n is 0.

[0216] In other embodiments, n is 1.

[0217] In other embodiments, n is 2.

[0218] 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.

[0219] (Table 1) Representative compounds having structure (I) TIFF2025517702000018.tif226160TIFF2025517702000019.tif229160TIFF2025517702000020.tif216160TIFF2025517702000021.tif232160TIFF2025517702000022.tif234160TIFF2025517702000023.tif226160TIFF2025517702000024.tif216160TIFF2025517702000025.tif219160TIFF2025517702000026.tif223160TIFF2025517702000027.tif234160TIFF2025517702000028.tif237160TIFF2025517702000029.tif102160

[0220] In one aspect, there is provided a compound having structure (I'''), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000030.tif40128wherein, X is CR a R b , NR a or O; R a and R b are each independently H or C 1-6 alkyl; R 1 is H, F or CN; R 2 and R 5 are each independently H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 3 or R 4 one of which is OH and the other is H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6is haloalkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl which may be substituted with one or more R 1-6 ; R 9' is OH, halo or C 3-5 cycloalkyl; R 10 and R 13 are each independently H or halo; R 11 and R 12 are each independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl; R 16 is H or CO 2 H; and n is 0, 1 or 2.

[0221] In another aspect, there is provided a compound having structure (Ia'''), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000031.tif41128wherein, R a is H or C 1-6 alkyl; R 1 is H, F or CN; R 2 and R 5 are each independently H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 3 or R 4 one of which is OH and the other is H, halo, OH, CN, C 1-6 alkyl, C 1-6Haloalkyl, OC 1-6 alkyl or OC 1-6 is haloalkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl which may be substituted with one or more R 1-6 is; R 9' is OH, halo or C 3-5 cycloalkyl; R 10 and R 13 are each independently H or halo; R 11 and R 12 are each independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl; R 16 is H or CO 2 H; and n is 0, 1 or 2.

[0222] In another aspect, there is provided a compound having structure (Ia-1'''), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000032.tif41128wherein, R a is H or C 1-6 alkyl; R 1 is H, F or CN; R 2 and R 5 are each independently H or C 1-6 alkyl; R 3 or R 4 one of is OH and the other is H or C 1-6 alkyl; R 11 and R 12is, independently of each other, H, F or C 1-6 is alkyl; and n is 0, 1 or 2.

[0223] In another aspect, there is provided a compound having the structure (Ib'''), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000033.tif40128wherein R 1 is H, F or CN; R 2 and R 5 are, independently of each other, H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 3 or R 4 one of which is OH and the other is H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl which may be substituted with one or more R 1-6 ; R 9' is OH, halo or C 3-5 cycloalkyl; R 10 and R 13 are, independently of each other, H or halo; R 11 and R 12 are, independently of each other, H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl; R 16is H or CO 2 is H; and n is 0, 1 or 2.

[0224] In another aspect, a compound having the structure (Ib-1'''), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided: TIFF2025517702000034.tif40128 wherein, R 1 is H, F or CN; R 2 and R 5 are each independently H or C 1-6 alkyl; R 3 or R 4 one of which is OH and the other is H or C 1-6 alkyl; R 11 and R 12 are each independently H or C 1-6 alkyl; and n is 0, 1 or 2.

[0225] In another aspect, a compound having the structure (Ic'''), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided: TIFF2025517702000035.tif41128 wherein, R a and R b are each independently H or C 1-6 alkyl; R 1 is H, F or CN; R 2 and R 5 are each independently H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 3 or R 4One of them is OH, and the other is H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 8 is H or halo; R 9 is H, C 3-5 cycloalkyl, or C optionally substituted with one or more R 9' alkyl; 1-6 R 9' is OH, halo or C 3-5 cycloalkyl; R 10 and R 13 are each independently H or halo; R 11 and R 12 are each independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl; R 16 is H or CO 2 H; and n is 0, 1 or 2.

[0226] In another aspect, there is provided a compound having the structure (Ic-1'''), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000036.tif41128 wherein R a and R b are each independently H or C 1-6 alkyl; R 1 is H, F or CN; R 2 and R 5 are each independently H or C 1-6 alkyl; R 3 or R 4 ​One of them is OH, and the other is H or C 1-6 is alkyl; R 11 and R 12 are each independently H or C 1-6 is alkyl; and n is 0, 1, or 2.

[0227] In more specific embodiments of each of structures (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), and (Ic-1'''), if necessary, such structures include the following more specific embodiments.

[0228] In one embodiment, X is CR a R b is. In another embodiment, X is NR a is. In yet another embodiment, X is O.

[0229] In one embodiment, R 11 and R 12 one of them is H. In another embodiment, R 11 is C 1-6 alkyl, and R 12 is H. In another embodiment, R 11 is H, and R 12 is C 1-6 alkyl. In another embodiment, R 11 and R 12 are both H. In another embodiment, R 11 and R 12 are both not H. In some embodiments, R 11 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl, and R 12 is H. In some embodiments, R 11 is H, F, CN, methyl, CF 3 or OCH 3 and R 12 is H. In other embodiments, R 11 is H and R12 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl. In other embodiments, R 11 is H, and R 12 is H, F, CN, methyl, CF 3 or OCH 3 .

[0230] In one embodiment, R 1 is H. In another embodiment, R 1 is F. In another embodiment, R 1 is CN.

[0231] In one embodiment, R 2 and R 5 are each independently H, C 1-6 alkyl, F, Cl, CF 3 , or CN. In another embodiment, R 2 is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl, and R 5 is H. In another embodiment, R 2 is H, and R 5 is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl.

[0232] In one embodiment, R 2 is H. In another embodiment, R 2 is OH. In an additional embodiment, R 2 is C 1-6 haloalkyl. In some embodiments, R 2 is CF 3 . In an additional embodiment, R 2 is C 1-6 alkyl. In a specific embodiment, R 2 is methyl. In another embodiment, R 2is ethyl. In another embodiment, R 2 is isopropyl. In yet another embodiment, R 2 is CN. In one embodiment, R 2 is halo. In another embodiment, R 2 is F. In another embodiment, R 2 is Cl. In another embodiment, R 2 is Br. In another embodiment, R 2 is OC 1-6 haloalkyl. In some embodiments, R 2 is OCF 3 . In another embodiment, R 2 is OC 1-6 alkyl. In a specific embodiment, R 2 is OCH 3 .

[0233] In one embodiment, R 5 is H. In another embodiment, R 5 is OH. In another embodiment, R 5 is C 1-6 haloalkyl. In another embodiment, R 5 is CF 3 . In another embodiment, R 5 is C 1-6 alkyl. In another embodiment, R 5 is methyl. In another embodiment, R 5 is ethyl. In another embodiment, R 5 is isopropyl. In another embodiment, R 5 is CN. In one embodiment, R 5 is halo. In another embodiment, R 5 is F. In another embodiment, R 5 is Cl. In another embodiment, R 5 is Br. In another embodiment, R 5 is OC 1-6 haloalkyl. In another embodiment, R 5 is OCF 3 . In another embodiment, R 5 is OC 1-6 alkyl. In another embodiment, R 5 is OCH3 It is.

[0234] In one aspect, R 3 is OH, and R 4 is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl. In another aspect, R 4 is OH, and R 3 is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl. In yet another aspect, R 3 is OH, and R 4 is H or C 1-6 alkyl. In another aspect, R 4 is OH, and R 3 is H or C 1-6 alkyl.

[0235] In some aspects, R 3 is OH. In another aspect, R 3 is H. In another aspect, R 3 is C 1-6 haloalkyl. In one aspect, R 3 is CF 3 . In another aspect, R 3 is C 1-6 alkyl. In a specific aspect, R 3 is methyl. In another aspect, R 3 is ethyl. In a certain aspect, R 3 is isopropyl. In another aspect, R 3 is CN. In one aspect, R 3 is halo. In some aspects, R 3 is F. In another aspect, R 3 is Cl. In one aspect, R 3 is Br. In another aspect, R 3 is OC 1-6 haloalkyl. In another aspect,3 is OCF 3 In some embodiments, R 3 is OC 1-6 alkyl. In certain embodiments, R 3 is OCH 3 .

[0236] In one embodiment, R 4 is OH. In another embodiment, R 4 is H. In another embodiment, R 4 is C 1-6 haloalkyl. In yet other embodiments, R 4 is CF 3 . In another embodiment, R 4 is C 1-6 alkyl. In a specific embodiment, R 4 is methyl. In another embodiment, R 4 is ethyl. In certain embodiments, R 4 is isopropyl. In another embodiment, R 4 is CN. In one embodiment, R 4 is halo. In yet other embodiments, R 4 is F. In another embodiment, R 4 is Cl. In additional embodiments, R 4 is Br. In additional embodiments, R 4 is I. In another embodiment, R 4 is OC 1-6 haloalkyl. In another embodiment, R 4 is OCF 3 . In other embodiments, R 4 is OC 1-6 alkyl. In certain embodiments, R 4 is OCH 3 .

[0237] In one embodiment, R 8 is H. In another embodiment, R 8 is F. In another embodiment, R 8 is Cl. In yet other embodiments, R 8 is Br. In yet other embodiments, R 8is I.

[0238] In one aspect, R 9 is H. In another aspect, R 9 is not H. In some aspects, R 9 is C 1-6 alkyl. In a specific aspect, R 9 is methyl. In some aspects, R 9 is ethyl. In a certain aspect, R 9 is isopropyl. In some aspects, R 9 may be C 1-6 alkyl substituted with one or more Fs. In another aspect, R 9 is -CH 2 CH 2 F. In a certain aspect, R 9 is -CH 2 CHF 2 In another aspect, R 9 is -CH 2 CF 3 In one aspect, R 9 is C 3-5 cycloalkyl. In a specific aspect, R 9 is cyclopropyl. In another aspect, R 9 may be C 3-5 alkyl substituted with one or more C 1-6 cycloalkyls. In a certain aspect, R 9 is TIFF2025517702000037.tif9128. In another aspect, R 9 may be C 1-6 alkyl substituted with one or more OHs. In some aspects, R 9 is TIFF2025517702000038.tif5128.

[0239] In one aspect, R 9' is OH. In one aspect, R 9' is halo. In still other aspects, R 9'is F. In another aspect, R 9' is Cl. In an additional aspect, R 9' is Br. In an additional aspect, R 9' is I. In one aspect, R 9' is C 3-5 cycloalkyl. In a specific aspect, R 9' is cyclopropyl.

[0240] In one aspect, R 10 and R 13 are both H. In another aspect, R 10 and R 13 are both halo. In yet another aspect, R 10 is H and R 13 is halo. In another aspect, R 13 is H and R 10 is halo.

[0241] In one aspect, R 10 is H. In one aspect, R 10 is F. In another aspect, R 10 is Cl. In yet another aspect, R 10 is Br.

[0242] In one aspect, R 13 is H. In one aspect, R 13 is F. In another aspect, R 13 is Cl. In yet another aspect, R 13 is Br.

[0243] In one aspect, R 16 is H. In another aspect, R 16 is CO 2 H.

[0244] In one aspect, Ra is H. In another aspect, Ra is C 1-6 alkyl. In a particular aspect, Ra is methyl.

[0245] In one aspect, Rb is H. In another aspect, Rb is C 1-6 alkyl. In certain aspects, Rb is methyl.

[0246] In one aspect, n is from 0 to 2. In one aspect, n is 0 or 1. In other aspects, n is 1 or 2. In yet other aspects, n is 0 or 2. In some aspects, n is 0. In other aspects, n is 1. In other aspects, n is 2.

[0247] In one aspect, the compound is selected from one of the compounds listed in Table 2, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0248] (Table 2) Representative compounds having structure (I''') TIFF2025517702000039.tif186164TIFF2025517702000040.tif241164TIFF2025517702000041.tif224164TIFF2025517702000042.tif241164TIFF2025517702000043.tif235164TIFF2025517702000044.tif221164TIFF2025517702000045.tif233164

[0249] In another aspect, there is provided a compound having structure (II), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000046.tif39128wherein, R a is H or C 1-6 alkyl; each R 15 is independently halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl or C 3-5 cycloalkyl; R 9is H, C 3-5 cycloalkyl, or C substituted with one or more Rs 9' which may be optionally substituted with 1-6 alkyl; R 9' is OH, halo or C 3-5 cycloalkyl; each R 17 is independently halo or CO 2 H; R 11 and R 12 are each independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, or OC 1-6 alkyl; and n is from 0 to 2; m is from 0 to 3; and p is from 0 to 9.

[0250] In a more specific embodiment of Structure (II), optionally, such a structure includes the following more specific embodiments.

[0251] In one embodiment, one of R 11 and R 12 is H. In another embodiment, R 11 is C 1-6 alkyl and R 12 is H. In another embodiment, R 11 is H and R 12 is C 1-6 alkyl. In another embodiment, R 11 and R 12 are both H. In another embodiment, R 11 and R 12 are both not H. In some embodiments, R 11 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl and R 12 is H. In some embodiments, R 11 is H, F, CN, methyl, CF 3 or OCH3 and R 12 is H. In other embodiments, R 11 is H and R 12 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl. In other embodiments, R 11 is H and R 12 is H, F, CN, methyl, CF 3 or OCH 3 .

[0252] In one embodiment, R 11 is H. In another embodiment, R 11 is halo. In certain embodiments, R 11 is F. In other embodiments, R 11 is Cl. In certain embodiments, R 11 is Br. In specific embodiments, R 11 is I. In some embodiments, R 11 is C 1-6 alkyl. In one embodiment, R 11 is methyl. In other embodiments, R 11 is ethyl. In additional embodiments, R 11 is propyl. In additional embodiments, R 11 is propyl. In further embodiments, R 11 is isopropyl. In other embodiments, R 11 is n-butyl. In further embodiments, R 11 is sec-butyl. In some embodiments, R 11 is tert-butyl. In some embodiments, R 11 is CN. In some embodiments, R 11 is C 1-6 haloalkyl. In specific embodiments, R 11 is CF 3 . In some embodiments, R 11 is OC 1-6 alkyl. In specific embodiments, R 11 is OCH 3 .

[0253] In one aspect, R 12 is H. In another aspect, R 12 is halo. In certain aspects, R 12 is F. In other aspects, R 12 is Cl. In certain aspects, R 12 is Br. In specific aspects, R 12 is I. In some aspects, R 12 is C 1-6 alkyl. In one aspect, R 12 is methyl. In other aspects, R 12 is ethyl. In additional aspects, R 12 is propyl. In additional aspects, R 12 is propyl. In further aspects, R 12 is isopropyl. In other aspects, R 12 is n-butyl. In further aspects, R 12 is sec-butyl. In some aspects, R 12 is tert-butyl. In some aspects, R 12 is CN. In some aspects, R 12 is C 1-6 haloalkyl. In specific aspects, R 12 is CF 3 In some aspects, R 12 is OC 1-6 alkyl. In specific aspects, R 12 is OCH 3 In one aspect, R

[0254] is CN, halo, or C 15 haloalkyl. In one aspect, R 1-6 is CN, F, or CF 15 In one aspect, R 3 is halo. In certain aspects, R 15 is F. In other aspects, R 15 is Cl. In certain aspects, R 15 is Cl. In certain aspects, R 15is Br. In a specific embodiment, R 15 is I. In some embodiments, R 15 is CN. In other embodiments, R 15 is OH. In some embodiments, R 15 is C 1-6 alkyl. In one embodiment, R 15 is methyl. In other embodiments, R 15 is ethyl. In additional embodiments, R 15 is propyl. In additional embodiments, R 15 is propyl. In further embodiments, R 15 is isopropyl. In other embodiments, R 15 is n-butyl. In further embodiments, R 15 is sec-butyl. In some embodiments, R 15 is tert-butyl. In some embodiments, R 15 is C 1-6 haloalkyl. In a specific embodiment, R 15 is CF 3 In some embodiments, R 15 is OC 1-6 alkyl. In a specific embodiment, R 15 is OCH 3 In some embodiments, R 15 is OC 1-6 haloalkyl. In a specific embodiment, R 15 is OCF 3 In some embodiments, R 15 is C 3-5 cycloalkyl. In a specific embodiment, R 15 is cyclopropyl.

[0255] In one embodiment, R 9 is H. In another embodiment, R 9 is not H. In some embodiments, R 9 is C 1-6 alkyl. In a specific embodiment, R 9 is methyl. In some embodiments, R 9 is ethyl. In a particular embodiment, R9 is isopropyl. In some embodiments, R 9 may be C 1-6 alkyl substituted with one or more Fs. In another embodiment, R 9 is -CH 2 CH 2 F. In certain embodiments, R 9 is -CH 2 CHF 2 . In another embodiment, R 9 is -CH 2 CF 3 . In one embodiment, R 9 is C 3-5 cycloalkyl. In a specific embodiment, R 9 is cyclopropyl. In another embodiment, R 9 may be C 3-5 alkyl substituted with one or more C 1-6 cycloalkyls. In certain embodiments, R 9 is TIFF2025517702000047.tif9128. In another embodiment, R 9 may be C 1-6 alkyl substituted with one or more OHs. In some embodiments, R 9 is TIFF2025517702000048.tif5128.

[0256] In one embodiment, R 9' is OH. In one embodiment, R 9' is halo. In still other embodiments, R 9' is F. In another embodiment, R 9' is Cl. In additional embodiments, R 9' is Br. In additional embodiments, R 9' is I. In one embodiment, R 9' is C 3-5 cycloalkyl. In a specific embodiment, R 9' is cyclopropyl.

[0257] In one embodiment, R 17is a halo. In certain embodiments, R 17 is F. In other embodiments, R 17 is Cl. In certain embodiments, R 17 is Br. In specific embodiments, R 17 is I. In some embodiments, R 17 is CO 2 H.

[0258] In one embodiment, Ra is H. In another embodiment, Ra is C 1-6 alkyl. In certain embodiments, Ra is methyl.

[0259] In one embodiment, n is from 0 to 2. In one embodiment, n is 0 or 1. In other embodiments, n is 1 or 2. In still other embodiments, n is 0 or 2. In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2.

[0260] In one embodiment, m is from 0 to 3. In one embodiment, m is 0 or 1. In other embodiments, m is 1 or 2. In still other embodiments, m is 0 or 2. In some embodiments, m is 0. In other embodiments, m is 1. In other embodiments, m is 2. In other embodiments, m is 3.

[0261] In one embodiment, p is from 0 to 9. In one embodiment, p is from 0 to 3. In one embodiment, p is 0 or 1. In other embodiments, p is 1 or 2. In still other embodiments, p is 0 or 2. In some embodiments, p is 0. In other embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0262] In one embodiment, the compound is selected from one of the compounds listed in Table 3, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0263] (Table 3) Representative compounds having structure (II) TIFF2025517702000049.tif68164

[0264] In another aspect, there is provided a compound having structure (III), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof: TIFF2025517702000050.tif43128 wherein, R 1 is H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl or C 3-5 cycloalkyl; R 2 and R 5 are each independently H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 3 or R 4 is OH, and the other is H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 11 and R 12 are each independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl; each R 18 is halo, CO 2 H, aminyl, C 3-5 cycloalkyl, or C 1-6 alkyl, where C 1-6 alkyl may be substituted with one or more R 9' ; R 9' is OH, halo or C 3-5 cycloalkyl; n is 1 or 2; and p is from 1 to 9.

[0265] In a more specific embodiment of Structure (III), optionally, such a structure includes the following more specific embodiments.

[0266] In one embodiment, R 11 and R 12 one of them is H. In another embodiment, R 11 is C 1-6 alkyl, and R 12 is H. In another embodiment, R 11 is H, and R 12 is C 1-6 alkyl. In another embodiment, R 11 and R 12 are both H. In another embodiment, R 11 and R 12 are both not H. In some embodiments, R 11 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl, and R 12 is H. In some embodiments, R 11 is H, F, CN, methyl, CF 3 or OCH 3 and R 12 is H. In other embodiments, R 11 is H, and R 12 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl. In other embodiments, R 11 is H, and R 12 is H, F, CN, methyl, CF 3 or OCH 3 and R

[0267] In one embodiment, R 11 is H. In another embodiment, R 11 is halo. In a particular embodiment, R 11is F. In other embodiments, R 11 is Cl. In certain embodiments, R 11 is Br. In specific embodiments, R 11 is I. In some embodiments, R 11 is C 1-6 alkyl. In one embodiment, R 11 is methyl. In other embodiments, R 11 is ethyl. In additional embodiments, R 11 is propyl. In additional embodiments, R 11 is propyl. In further embodiments, R 11 is isopropyl. In other embodiments, R 11 is n-butyl. In further embodiments, R 11 is sec-butyl. In some embodiments, R 11 is tert-butyl. In some embodiments, R 11 is CN. In some embodiments, R 11 is C 1-6 haloalkyl. In specific embodiments, R 11 is CF 3 In some embodiments, R 11 is OC 1-6 alkyl. In specific embodiments, R 11 is OCH 3 In one embodiment, R

[0268] is H. In another embodiment, R 12 is halo. In certain embodiments, R 12 is F. In other embodiments, R 12 is Cl. In certain embodiments, R 12 is Br. In specific embodiments, R 12 is I. In some embodiments, R 12 is C 12 alkyl. In one embodiment, R 1-6 is methyl. In other embodiments, R 12 is ethyl. In additional embodiments, R 12 is propyl. In additional embodiments, R 12 is propyl. In further embodiments, R12 is propyl. In a further aspect, R 12 is isopropyl. In other aspects, R 12 is n-butyl. In a further aspect, R 12 is sec-butyl. In some aspects, R 12 is tert-butyl. In some aspects, R 12 is CN. In some aspects, R 12 is C 1-6 haloalkyl. In a specific aspect, R 12 is CF 3 In some aspects, R 12 is OC 1-6 alkyl. In a specific aspect, R 12 is OCH 3 In one aspect, R

[0269] In one aspect, R 1 is H or CN. In one aspect, R 1 is H. In one aspect, R 1 is halo. In a particular aspect, R 1 is F. In other aspects, R 1 is Cl. In a particular aspect, R 1 is Br. In a specific aspect, R 1 is I. In some aspects, R 1 is CN. In other aspects, R 1 is OH. In some aspects, R 1 is C 1-6 alkyl. In one aspect, R 1 is methyl. In other aspects, R 1 is ethyl. In additional aspects, R 1 is propyl. In additional aspects, R 1 is propyl. In a further aspect, R 1 is isopropyl. In other aspects, R 1 is n-butyl. In a further aspect, R 1 is sec-butyl. In some aspects, R 1is tert-butyl. In some embodiments, R 1 is C 1-6 haloalkyl. In a specific embodiment, R 1 is CF 3 In some embodiments, R 1 is OC 1-6 alkyl. In a specific embodiment, R 1 is OCH 3 In some embodiments, R 1 is OC 1-6 haloalkyl. In a specific embodiment, R 1 is OCF 3 In some embodiments, R 1 is C 3-5 cycloalkyl. In a specific embodiment, R 1 is cyclopropyl.

[0270] In one embodiment, R 2 and R 5 are each independently H, C 1-6 alkyl, F, Cl, CF 3 , or CN. In another embodiment, R 2 is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl, and R 5 is H. In another embodiment, R 2 is H and R 5 is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl.

[0271] In one embodiment, R 2 is H. In another embodiment, R 2 is OH. In an additional embodiment, R 2 is C 1-6 haloalkyl. In some embodiments, R 2 is CF 3 In an additional embodiment, R 2 is C1-6 is alkyl. In a specific embodiment, R 2 is methyl. In another embodiment, R 2 is ethyl. In another embodiment, R 2 is isopropyl. In yet another embodiment, R 2 is CN. In one embodiment, R 2 is halo. In another embodiment, R 2 is F. In another embodiment, R 2 is Cl. In another embodiment, R 2 is Br. In another embodiment, R 2 is OC 1-6 haloalkyl. In some embodiments, R 2 is OCF 3 In another embodiment, R 2 is OC 1-6 alkyl. In a specific embodiment, R 2 is OCH 3 In one embodiment, R

[0272] is H. In another embodiment, R 5 is OH. In another embodiment, R 5 is C 5 haloalkyl. In another embodiment, R 1-6 is CF 5 In another embodiment, R 3 is C 5 alkyl. In another embodiment, R 1-6 is methyl. In another embodiment, R 5 is ethyl. In another embodiment, R 5 is isopropyl. In another embodiment, R 5 is CN. In one embodiment, R 5 is halo. In another embodiment, R 5 is F. In another embodiment, R 5 is Cl. In another embodiment, R 5 is Br. In another embodiment, R 5 is CN. In another embodiment, R 5 is OC 1-6 haloalkyl. In another embodiment, R 5 is OCF 3It is. In another aspect, R 5 is OC 1-6 alkyl. In another aspect, R 5 is OCH 3 .

[0273] In one aspect, R 3 is OH, and R 4 is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl. In another aspect, R 4 is OH, and R 3 is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl. In yet another aspect, R 3 is OH, and R 4 is H or C 1-6 alkyl. In another aspect, R 4 is OH, and R 3 is H or C 1-6 alkyl.

[0274] In some aspects, R 3 is OH. In another aspect, R 3 is H. In another aspect, R 3 is C 1-6 haloalkyl. In one aspect, R 3 is CF 3 . In another aspect, R 3 is C 1-6 alkyl. In a specific aspect, R 3 is methyl. In another aspect, R 3 is ethyl. In a particular aspect, R 3 is isopropyl. In another aspect, R 3 is CN. In one aspect, R 3 is halo. In some aspects, R 3 is F. In another aspect, R 3 is Cl. In one aspect, R3 is Br. In another embodiment, R 3 is OC 1-6 haloalkyl. In another embodiment, R 3 is OCF 3 . In some embodiments, R 3 is OC 1-6 alkyl. In certain embodiments, R 3 is OCH 3 .

[0275] In one embodiment, R 4 is OH. In another embodiment, R 4 is H. In another embodiment, R 4 is C 1-6 haloalkyl. In yet other embodiments, R 4 is CF 3 . In another embodiment, R 4 is C 1-6 alkyl. In specific embodiments, R 4 is methyl. In another embodiment, R 4 is ethyl. In certain embodiments, R 4 is isopropyl. In another embodiment, R 4 is CN. In one embodiment, R 4 is halo. In yet other embodiments, R 4 is F. In another embodiment, R 4 is Cl. In additional embodiments, R 4 is Br. In another embodiment, R 4 is OC 1-6 haloalkyl. In another embodiment, R 4 is OCF 3 . In other embodiments, R 4 is OC 1-6 alkyl. In certain embodiments, R 4 is OCH 3 .

[0276] In one embodiment, R 18 is halo. In certain embodiments, R 18 is F. In other embodiments, R 18is Cl. In certain embodiments, R 18 is Br. In specific embodiments, R 18 is I. In some embodiments, R 18 is CO 2 H. In other embodiments, R 18 is aminyl. In certain embodiments, R 18 is N(CH 3 ) 2 . In certain embodiments, R 18 is NH(CH 3 ). In some embodiments, R 18 is C 3-5 cycloalkyl. In specific embodiments, R 18 is cyclopropyl. In some embodiments, R 18 is C 1-6 alkyl. In one embodiment, R 18 is methyl. In other embodiments, R 18 is ethyl. In additional embodiments, R 18 is propyl. In additional embodiments, R 18 is propyl. In further embodiments, R 18 is isopropyl. In other embodiments, R 18 is n-butyl. In further embodiments, R 18 is sec-butyl. In some embodiments, R 18 is tert-butyl. In some embodiments, R 18 is C 1-6 alkyl which may be substituted with one or more Fs. In another embodiment, R 18 is -CH 2 CH 2 F. In certain embodiments, R 18 is -CH 2 CHF 2 . In another embodiment, R 18 is -CH 2 CF 3 . In one embodiment, R 18 is C 3-5 cycloalkyl. In specific embodiments, R 18 is cyclopropyl. In another embodiment, R18 is a C which may be substituted with one or more C 3-5 alkyl optionally substituted with cycloalkyl 1-6 alkyl. In certain embodiments, R 18 is TIFF2025517702000051.tif9128. In another embodiment, R 18 is a C alkyl optionally substituted with one or more OH 1-6 alkyl. In some embodiments, R 18 is TIFF2025517702000052.tif5128.

[0277] In one embodiment, R 9' is OH. In one embodiment, R 9' is halo. In yet other embodiments, R 9' is F. In another embodiment, R 9' is Cl. In additional embodiments, R 9' is Br. In additional embodiments, R 9' is I. In one embodiment, R 9' is C 3-5 cycloalkyl. In a specific embodiment, R 9' is cyclopropyl.

[0278] In one embodiment, n is 1 or 2. In other embodiments, n is 1. In other embodiments, n is 2.

[0279] In one embodiment, p is from 1 to 9. In one embodiment, p is from 1 to 3. In other embodiments, p is 1 or 2. In yet other embodiments, p is 2 or 3. In yet other embodiments, p is 1 or 3. In other embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0280] In one embodiment, the compound is selected from one of the compounds listed in Table 4, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0281] (Table 4) Representative compounds having structure (III) TIFF2025517702000053.tif44164

[0282] In another aspect, a compound having structure (IV), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided: TIFF2025517702000054.tif42128 wherein, Ring A is C 3-8 cycloalkyl, TIFF2025517702000055.tif15128 or a saturated heterocyclic ring, wherein the heteroatom consists of 1 to 2 oxygen atoms; Each R a and R b is each independently H or C 1-6 alkyl; R 1 is H, halo, OH, CN, C 1-6 alkyl, OC 1-6 alkyl, OC 1-6 haloalkyl or C 3-5 cycloalkyl; R 2 and R 5 are each independently H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 3 or R 4 one of which is OH and the other is H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 9 is H, C 3-5 cycloalkyl, or C 9' alkyl optionally substituted with one or more R 1-6 ; R 11 and R12 is, independently of each other, H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl; R 18 is halo, CO 2 H, aminyl, C 3-5 cycloalkyl, or C 1-6 alkyl, where C 1-6 alkyl may be substituted with one or more R 9' ; R 9' is OH, halo or C 3-5 cycloalkyl; n is 0, 1 or 2; p is from 0 to 9; and q is from 1 to 3, provided that when R 1 is H and A is TIFF2025517702000056.tif15128, R 9 is not unsubstituted ethyl.

[0283] In a more specific embodiment of structure (IV), optionally, such a structure includes the following more specific embodiments.

[0284] In one embodiment, one of R 11 and R 12 is H. In another embodiment, R 11 is C 1-6 alkyl and R 12 is H. In another embodiment, R 11 is H and R 12 is C 1-6 alkyl. In another embodiment, R 11 and R 12 are both H. In another embodiment, R 11 and R 12 are both not H. In some embodiments, R 11 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6is alkyl, and R 12 is H. In some embodiments, R 11 is H, F, CN, methyl, CF 3 or OCH 3 and R 12 is H. In other embodiments, R 11 is H and R 12 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl. In other embodiments, R 11 is H and R 12 is H, F, CN, methyl, CF 3 or OCH 3 .

[0285] In one embodiment, R 11 is H. In another embodiment, R 11 is halo. In certain embodiments, R 11 is F. In other embodiments, R 11 is Cl. In certain embodiments, R 11 is Br. In specific embodiments, R 11 is I. In some embodiments, R 11 is C 1-6 alkyl. In one embodiment, R 11 is methyl. In other embodiments, R 11 is ethyl. In additional embodiments, R 11 is propyl. In additional embodiments, R 11 is propyl. In further embodiments, R 11 is isopropyl. In other embodiments, R 11 is n-butyl. In further embodiments, R 11 is sec-butyl. In some embodiments, R 11 is tert-butyl. In some embodiments, R 11 is CN. In some embodiments, R 11 is C 1-6 haloalkyl. In specific embodiments, R 11 is CF 3 and in some embodiments, R11 is OC 1-6 alkyl. In a specific embodiment, R 11 is OCH 3 is.

[0286] In one embodiment, R 12 is H. In another embodiment, R 12 is halo. In a certain specific embodiment, R 12 is F. In other embodiments, R 12 is Cl. In a certain specific embodiment, R 12 is Br. In a specific embodiment, R 12 is I. In some embodiments, R 12 is C 1-6 alkyl. In one embodiment, R 12 is methyl. In other embodiments, R 12 is ethyl. In additional embodiments, R 12 is propyl. In additional embodiments, R 12 is propyl. In further embodiments, R 12 is isopropyl. In other embodiments, R 12 is n-butyl. In further embodiments, R 12 is sec-butyl. In some embodiments, R 12 is tert-butyl. In some embodiments, R 12 is CN. In some embodiments, R 12 is C 1-6 haloalkyl. In a specific embodiment, R 12 is CF 3 is. In some embodiments, R 12 is OC 1-6 alkyl. In a specific embodiment, R 12 is OCH 3 is.

[0287] In one embodiment, R 1 is H. In one embodiment, R 1 is halo. In a certain specific embodiment, R 1 is F. In other embodiments, R 1 is Cl. In a certain specific embodiment, R1 is Br. In a specific embodiment, R 1 is I. In some embodiments, R 1 is CN. In other embodiments, R 1 is OH. In some embodiments, R 1 is C 1-6 alkyl. In one embodiment, R 1 is methyl. In other embodiments, R 1 is ethyl. In additional embodiments, R 1 is propyl. In additional embodiments, R 1 is propyl. In further embodiments, R 1 is isopropyl. In other embodiments, R 1 is n-butyl. In further embodiments, R 1 is sec-butyl. In some embodiments, R 1 is tert-butyl. In some embodiments, R 1 is OC 1-6 alkyl. In a specific embodiment, R 1 is OCH 3 . In some embodiments, R 1 is OC 1-6 haloalkyl. In a specific embodiment, R 1 is OCF 3 . In some embodiments, R 1 is C 3-5 cycloalkyl. In a specific embodiment, R 1 is cyclopropyl.

[0288] In one embodiment, R 2 and R 5 are each independently H, C 1-6 alkyl, F, Cl, CF 3 , or CN. In another embodiment, R 2 is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl, and R 5 is H. In another embodiment, R 2 is H, and R5 is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl.

[0289] In one embodiment, R 2 is H. In another embodiment, R 2 is OH. In an additional embodiment, R 2 is C 1-6 haloalkyl. In some embodiments, R 2 is CF 3 . In an additional embodiment, R 2 is C 1-6 alkyl. In a specific embodiment, R 2 is methyl. In another embodiment, R 2 is ethyl. In another embodiment, R 2 is isopropyl. In still another embodiment, R 2 is CN. In one embodiment, R 2 is halo. In another embodiment, R 2 is F. In another embodiment, R 2 is Cl. In another embodiment, R 2 is Br. In another embodiment, R 2 is OC 1-6 haloalkyl. In some embodiments, R 2 is OCF 3 . In another embodiment, R 2 is OC 1-6 alkyl. In a specific embodiment, R 2 is OCH 3 .

[0290] In one embodiment, R 5 is H. In another embodiment, R 5 is OH. In another embodiment, R 5 is C 1-6 haloalkyl. In another embodiment, R 5 is CF 3 . In another embodiment, R 5 is C 1-6 alkyl. In another embodiment, R5 is methyl. In another embodiment, R 5 is ethyl. In another embodiment, R 5 is isopropyl. In another embodiment, R 5 is CN. In one embodiment, R 5 is halo. In another embodiment, R 5 is F. In another embodiment, R 5 is Cl. In another embodiment, R 5 is Br. In another embodiment, R 5 is OC 1-6 haloalkyl. In another embodiment, R 5 is OCF 3 . In another embodiment, R 5 is OC 1-6 alkyl. In another embodiment, R 5 is OCH 3 .

[0291] In one embodiment, R 3 is OH, and R 4 is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl. In another embodiment, R 4 is OH, and R 3 is H, OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl. In yet another embodiment, R 3 is OH, and R 4 is H or C 1-6 alkyl. In another embodiment, R 4 is OH, and R 3 is H or C 1-6 alkyl.

[0292] In some embodiments, R 3 is OH. In another embodiment, R 3 is H. In another embodiment, R 3 is C 1-6It is a haloalkyl. In one aspect, R 3 is CF 3 . In another aspect, R 3 is C 1-6 alkyl. In a specific aspect, R 3 is methyl. In another aspect, R 3 is ethyl. In a certain aspect, R 3 is isopropyl. In another aspect, R 3 is CN. In one aspect, R 3 is halo. In some aspects, R 3 is F. In another aspect, R 3 is Cl. In one aspect, R 3 is Br. In another aspect, R 3 is OCF 1-6 haloalkyl. In another aspect, R 3 is OCF 3 . In some aspects, R 3 is OCF 1-6 alkyl. In a certain aspect, R 3 is OCH 3 .

[0293] In one aspect, R 4 is OH. In another aspect, R 4 is H. In another aspect, R 4 is C 1-6 haloalkyl. In still other aspects, R 4 is CF 3 . In another aspect, R 4 is C 1-6 alkyl. In a specific aspect, R 4 is methyl. In another aspect, R 4 is ethyl. In a certain aspect, R 4 is isopropyl. In another aspect, R 4 is CN. In one aspect, R 4 is halo. In still other aspects, R 4 is F. In another aspect, R 4 is Cl. In an additional aspect, R 4is Br. In another embodiment, R 4 is OC 1-6 haloalkyl. In another embodiment, R 4 is OCF 3 In other embodiments, R 4 is OC 1-6 alkyl. In certain embodiments, R 4 is OCH 3 In one embodiment, R

[0294] In one embodiment, R 9 is H. In another embodiment, R 9 is not H. In some embodiments, R 9 is C 1-6 alkyl. In a specific embodiment, R 9 is methyl. In some embodiments, R 9 is ethyl. In certain embodiments, R 9 is isopropyl. In some embodiments, R 9 is C 1-6 alkyl optionally substituted with one or more Fs. In another embodiment, R 9 is -CH 2 CH 2 F. In certain embodiments, R 9 is -CH 2 CHF 2 In another embodiment, R 9 is -CH 2 CF 3 In one embodiment, R 9 is C 3-5 cycloalkyl. In a specific embodiment, R 9 is cyclopropyl. In another embodiment, R 9 is C 3-5 alkyl optionally substituted with one or more C 1-6 cycloalkyls. In certain embodiments, R 9 is TIFF2025517702000057.tif9128. In another embodiment, R 9 is C 1-6 alkyl optionally substituted with one or more OHs. In some embodiments, R9 is TIFF2025517702000058.tif5128.

[0295] In one aspect, R 9' is OH. In one aspect, R 9' is halo. In yet another aspect, R 9' is F. In another aspect, R 9' is Cl. In an additional aspect, R 9' is Br. In an additional aspect, R 9' is I. In one aspect, R 9' is C 3-5 cycloalkyl. In a specific aspect, R 9' is cyclopropyl.

[0296] In one aspect, R 18 is halo. In a particular aspect, R 18 is F. In another aspect, R 18 is Cl. In a particular aspect, R 18 is Br. In a specific aspect, R 18 is I. In some aspects, R 18 is CO 2 H. In another aspect, R 18 is aminyl. In a particular aspect, R 18 is N(CH 3 ) 2 . In a particular aspect, R 18 is NH(CH 3 ). In some aspects, R 18 is C 3-5 cycloalkyl. In a specific aspect, R 18 is cyclopropyl. In some aspects, R 18 is C 1-6 alkyl. In one aspect, R 18 is methyl. In another aspect, R 18 is ethyl. In an additional aspect, R 18 is propyl. In an additional aspect, R 18 is propyl. In a further aspect, R18 is isopropyl. In other embodiments, R 18 is n-butyl. In further embodiments, R 18 is sec-butyl. In some embodiments, R 18 is tert-butyl. In some embodiments, R 18 is C alkyl optionally substituted with one or more Fs 1-6 . In another embodiment, R 18 is -CH 2 CH 2 F. In certain embodiments, R 18 is -CH 2 CHF 2 . In another embodiment, R 18 is -CH 2 CF 3 . In one embodiment, R 18 is C 3-5 cycloalkyl. In a specific embodiment, R 18 is cyclopropyl. In another embodiment, R 18 is C alkyl optionally substituted with one or more C 3-5 cycloalkyls 1-6 . In certain embodiments, R 18 is TIFF2025517702000059.tif9128. In another embodiment, R 18 is C alkyl optionally substituted with one or more OHs 1-6 . In some embodiments, R 18 is TIFF2025517702000060.tif5128.

[0297] In one embodiment, Ra is H. In another embodiment, Ra is C 1-6 alkyl. In certain embodiments, Ra is methyl.

[0298] In one embodiment, Rb is H. In another embodiment, Rb is C 1-6 alkyl. In certain embodiments, Rb is methyl.

[0299] In one embodiment, n is from 0 to 2. In one embodiment, n is 0 or 1. In other embodiments, n is 1 or 2. In still other embodiments, n is 0 or 2. In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2.

[0300] In one embodiment, p is from 0 to 9. In one embodiment, p is from 0 to 3. In one embodiment, p is 0 or 1. In other embodiments, p is 1 or 2. In still other embodiments, p is 0 or 2. In some embodiments, p is 0. In other embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0301] In one embodiment, q is from 1 to 3. In other embodiments, q is 1 or 2. In still other embodiments, q is 1 or 3. In some embodiments, q is 2 or 3. In other embodiments, q is 1. In other embodiments, q is 2. In other embodiments, q is 3.

[0302] In one embodiment, the compound is selected from one of the compounds listed in Table 5, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0303] (Table 5) Representative compounds having structure (IV) TIFF2025517702000061.tif227164

[0304] In another embodiment, a compound having structure (V), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof is provided: TIFF2025517702000062.tif41128 wherein, R a is H or C 1-6 alkyl; each R c and R d are each independently H or C 1-6 alkyl, or R cand R d are joined together to form an oxo; R 1 is H, halo, OH, CN, C 1-6 alkyl, OC 1-6 alkyl, OC 1-6 haloalkyl or C 3-5 cycloalkyl; R 2 and R 5 are each independently H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 3 or R 4 is OH and the other is H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 11 and R 12 are each independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl; R 18 is C 1-3 alkyl, where C 1-3 alkyl may be substituted with one or more R 9' ; R 9' is OH, halo or C 3-5 cycloalkyl; and q is from 1 to 3.

[0305] In a more specific embodiment of structure (V), optionally, such a structure includes the following more specific embodiments.

[0306] In one embodiment, one of R 11 and R 12 is H. In another embodiment, R 11 is C1-6 is alkyl, and R 12 is H. In another embodiment, R 11 is H, and R 12 is C 1-6 alkyl. In another embodiment, R 11 and R 12 are both H. In another embodiment, R 11 and R 12 are both not H. In some embodiments, R 11 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl, and R 12 is H. In some embodiments, R 11 is H, F, CN, methyl, CF 3 or OCH 3 and R 12 is H. In other embodiments, R 11 is H, and R 12 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl or OC 1-6 alkyl. In other embodiments, R 11 is H, and R 12 is H, F, CN, methyl, CF 3 or OCH 3 and R

[0307] In one embodiment, R 11 is H. In another embodiment, R 11 is halo. In a particular embodiment, R 11 is F. In other embodiments, R 11 is Cl. In a particular embodiment, R 11 is Br. In a specific embodiment, R 11 is I. In some embodiments, R 11 is C 1-6 alkyl. In one embodiment, R 11 is methyl. In other embodiments, R 11 is ethyl. In additional embodiments, R 11 is propyl. In additional embodiments, R11 is propyl. In a further aspect, R 11 is isopropyl. In other aspects, R 11 is n-butyl. In a further aspect, R 11 is sec-butyl. In some aspects, R 11 is tert-butyl. In some aspects, R 11 is CN. In some aspects, R 11 is C 1-6 haloalkyl. In a specific aspect, R 11 is CF 3 In some aspects, R 11 is OC 1-6 alkyl. In a specific aspect, R 11 is OCH 3 In one aspect, R

[0308] is H. In another aspect, R 12 is halo. In a particular aspect, R 12 is F. In other aspects, R 12 is Cl. In a particular aspect, R 12 is Br. In a specific aspect, R 12 is I. In some aspects, R 12 is C 12 alkyl. In one aspect, R 1-6 is methyl. In other aspects, R 12 is ethyl. In additional aspects, R 12 is propyl. In additional aspects, R 12 is propyl. In a further aspect, R 12 is propyl. In a further aspect, R 12 is isopropyl. In other aspects, R 12 is n-butyl. In a further aspect, R 12 is sec-butyl. In some aspects, R 12 is tert-butyl. In some aspects, R 12 is CN. In some aspects, R 12 is C 1-6It is a haloalkyl. In a specific embodiment, R 12 is CF 3 . In some embodiments, R 12 is OC 1-6 alkyl. In a specific embodiment, R 12 is OCH 3 .

[0309] In one embodiment, R 1 is H. In one embodiment, R 1 is halo. In a particular embodiment, R 1 is F. In other embodiments, R 1 is Cl. In a particular embodiment, R 1 is Br. In a specific embodiment, R 1 is I. In some embodiments, R 1 is CN. In other embodiments, R 1 is OH. In some embodiments, R 1 is C 1-6 alkyl. In one embodiment, R 1 is methyl. In other embodiments, R 1 is ethyl. In additional embodiments, R 1 is propyl. In additional embodiments, R 1 is propyl. In further embodiments, R 1 is isopropyl. In other embodiments, R 1 is n-butyl. In further embodiments, R 1 is sec-butyl. In some embodiments, R 1 is tert-butyl. In some embodiments, R 1 is OCF 1-6 alkyl. In a specific embodiment, R 1 is OCH 3 . In some embodiments, R 1 is OCF 1-6 haloalkyl. In a specific embodiment, R 1 is OCF 3 . In some embodiments, R 1 is C 3-5 cycloalkyl. In a specific embodiment, R 1is cyclopropyl.

[0310] In one aspect, R 2 and R 5 are each independently H, C 1-6 alkyl, F, Cl, CF 3 , or CN. In another aspect, R 2 is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl, and R 5 is H. In another aspect, R 2 is H and R 5 is OH, CF 3 , C 1-6 alkyl, CN, halo, OCF 3 or OC 1-6 alkyl.

[0311] In one aspect, R 2 is H. In another aspect, R 2 is OH. In an additional aspect, R 2 is C 1-6 haloalkyl. In some aspects, R 2 is CF 3 . In an additional aspect, R 2 is C 1-6 alkyl. In a specific aspect, R 2 is methyl. In another aspect, R 2 is ethyl. In another aspect, R 2 is isopropyl. In yet another aspect, R 2 is CN. In one aspect, R 2 is halo. In another aspect, R 2 is F. In another aspect, R 2 is Cl. In another aspect, R 2 is Br. In another aspect, R 2 is OC 1-6 haloalkyl. In some aspects, R 2 is OCF 3 . In another aspect, R 2is OC 1-6 is alkyl. In a specific embodiment, R 2 is OCH 3 is.

[0312] In one embodiment, R 5 is H. In another embodiment, R 5 is OH. In another embodiment, R 5 is C 1-6 haloalkyl. In another embodiment, R 5 is CF 3 is. In another embodiment, R 5 is C 1-6 alkyl. In another embodiment, R 5 is methyl. In another embodiment, R 5 is ethyl. In another embodiment, R 5 is isopropyl. In another embodiment, R 5 is CN. In one embodiment, R 5 is halo. In another embodiment, R 5 is F. In another embodiment, R 5 is Cl. In another embodiment, R 5 is Br. In another embodiment, R 5 is OCF 1-6 haloalkyl. In another embodiment, R 5 is OCF 3 is. In another embodiment, R 5 is OCF 1-6 alkyl. In another embodiment, R 5 is OCH 3 is.

[0313] In one embodiment, R 3 is OH, and R 4 is H, OH, CF 3 C 1-6 alkyl, CN, halo, OCF 3 or OCF 1-6 alkyl. In another embodiment, R 4 is OH, and R 3 is H, OH, CF 3 C 1-6 alkyl, CN, halo, OCF 3 or OCF1-6 is alkyl. In yet other embodiments, R 3 is OH, and R 4 is H or C 1-6 alkyl. In another embodiment, R 4 is OH, and R 3 is H or C 1-6 alkyl.

[0314] In some embodiments, R 3 is OH. In another embodiment, R 3 is H. In another embodiment, R 3 is C 1-6 haloalkyl. In one embodiment, R 3 is CF 3 In another embodiment, R 3 is C 1-6 alkyl. In a specific embodiment, R 3 is methyl. In another embodiment, R 3 is ethyl. In a particular embodiment, R 3 is isopropyl. In another embodiment, R 3 is CN. In one embodiment, R 3 is halo. In some embodiments, R 3 is F. In another embodiment, R 3 is Cl. In one embodiment, R 3 is Br. In another embodiment, R 3 is OC 1-6 haloalkyl. In another embodiment, R 3 is OCF 3 In some embodiments, R 3 is OC 1-6 alkyl. In a particular embodiment, R 3 is OCH 3 In one embodiment, R

[0315] is OH. In another embodiment, R 4 is H. In another embodiment, R 4 is C 4 haloalkyl. In yet other embodiments, R 1-6 is CF 4 ​3 is. In another embodiment, R 4 is C 1-6 alkyl. In a specific embodiment, R 4 is methyl. In another embodiment, R 4 is ethyl. In a certain embodiment, R 4 is isopropyl. In another embodiment, R 4 is CN. In one embodiment, R 4 is halo. In yet another embodiment, R 4 is F. In another embodiment, R 4 is Cl. In an additional embodiment, R 4 is Br. In another embodiment, R 4 is OC 1-6 haloalkyl. In another embodiment, R 4 is OCF 3 is. In other embodiments, R 4 is OC 1-6 alkyl. In a certain embodiment, R 4 is OCH 3 is.

[0316] In one embodiment, Ra is H. In another embodiment, Ra is C 1-6 alkyl. In a certain embodiment, Ra is methyl.

[0317] In one embodiment, Rc is H. In another embodiment, Rc is C 1-6 alkyl. In a certain embodiment, Rc is methyl.

[0318] In one embodiment, Rd is H. In another embodiment, Rd is C 1-6 alkyl. In a certain embodiment, Rd is methyl.

[0319] In one embodiment, Rc and Rd are connected together to form an oxo.

[0320] In some embodiments, R 19 is C 1-6 alkyl. In a specific embodiment, R 19is methyl. In some embodiments, R 19 is ethyl. In certain embodiments, R 19 is isopropyl. In some embodiments, R 19 is C 1-6 alkyl which may be substituted with one or more Fs. In another embodiment, R 19 is -CH 2 CH 2 F. In certain embodiments, R 19 is -CH 2 CHF 2 . In another embodiment, R 19 is -CH 2 CF 3 . In one embodiment, R 19 is C 3-5 cycloalkyl. In a specific embodiment, R 19 is cyclopropyl. In another embodiment, R 19 is C 3-5 alkyl which may be substituted with one or more C 1-6 cycloalkyls. In certain embodiments, R 19 is TIFF2025517702000063.tif9128. In another embodiment, R 19 is C 1-6 alkyl which may be substituted with one or more OHs. In some embodiments, R 19 is TIFF2025517702000064.tif5128.

[0321] In one embodiment, R 9' is OH. In one embodiment, R 9' is halo. In still other embodiments, R 9' is F. In another embodiment, R 9' is Cl. In additional embodiments, R 9' is Br. In additional embodiments, R 9' is I. In one embodiment, R 9' is C 3-5 cycloalkyl. In a specific embodiment, R 9' is cyclopropyl.

[0322] In one embodiment, q is from 1 to 3. In other embodiments, q is 1 or 2. In still other embodiments, q is 1 or 3. In some embodiments, q is 2 or 3. In other embodiments, q is 1. In other embodiments, q is 2. In other embodiments, q is 3.

[0323] In one embodiment, the compound is selected from one of the compounds listed in Table 6, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0324] (Table 6) Representative compounds having structure (V) TIFF2025517702000065.tif40164

[0325] Pharmaceutical composition In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of structure (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), (Ic-1'''), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient. For example, the active compound is usually admixed with the carrier, diluted by the carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper or other container. When the active compound is admixed with the carrier or the carrier serves as a diluent, the carrier can be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active compound. The active compound can be adsorbed onto a granular solid carrier, for example, contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, clay, 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, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with wax.

[0326] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes or salts thereof, formulated with a pharmaceutically acceptable carrier (which can also include other additives) and manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of diseases in mammals. Pharmaceutical compositions can be formulated, for example, in unit dosage forms for oral administration (e.g., tablets, capsules, caplets, gelcaps, or syrups); for topical administration (e.g., as creams, gels, lotions, or ointments); for intravenous administration (e.g., as a sterile solution free of microparticulate emboli in a solvent system suitable for intravenous use); 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, troches, oral thin strips, orally disintegrating tablets, orally disintegrating strips, and sprinkle oral powders or granules); or in any other formulation described herein. Conventional procedures and components for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), and The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0327] In some embodiments, a pharmaceutical composition comprising a compound of structure (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), (Ic-1'''), (II), (III), (IV) or (V), 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 substance.

[0328] 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 compound or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes or salts, and having non-toxic and non-inflammatory properties in a patient. Excipients can include, for example: anti-adhesion agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavoring agents, fragrances, fluidizing agents (fluidity enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or water of hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methyl cellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, corn starch, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0329] The formulation can be mixed with adjuvants that do not react detrimentally 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, sweetening agents, or flavoring agents. If desired, the composition can also be sterilized.

[0330] In another aspect, provided is a method of making a composition of a compound described herein, which includes formulating the compound of the present invention with a pharmaceutically acceptable carrier or diluent. In some aspects, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such aspects, the method can further include formulating the composition into tablets or capsules. In other aspects, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such aspects, the method further includes lyophilizing the composition to form a lyophilized preparation. In some aspects, the composition is formulated into a pediatric dosage form suitable for treating pediatric subjects.

[0331] In certain aspects, the present invention provides a compound having structure (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), (Ic-1'''), (II), (III), (IV) or (V), 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, the compounds of the present invention can be synthesized using appropriately modified synthetic procedures shown in the following examples and reaction schemes.

[0332] For this purpose, the reactions, processes and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to those having appropriate skills in the art. For example, the reactions may be carried out in any suitable solvent or other reagents for carrying out the required transformations. Generally, suitable solvents are protic or aprotic solvents that are substantially non-reactive with the reactants, intermediates or products at the temperature at which the reaction is carried out (i.e., a temperature that can range from the freezing temperature to the boiling temperature). A given reaction may be carried out in one solvent or a mixture of two or more solvents. Depending on the individual reaction, a solvent suitable for the individual work-up after the reaction may be used.

[0333] All reagents not described as synthesized in the experimental section are either commercially available, or 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 present invention may need to be purified. The purification of organic compounds is well known to those skilled in the art, and there may be several methods for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, impurities may be removed by stirring using a suitable solvent. In some cases, the compound may be purified by chromatography, especially flash column chromatography, using a silica gel cartridge prepared or prepacked for the purpose and a solvent gradient of eluents such as heptane, ether, ethyl acetate, acetonitrile, ethanol, etc. In some cases, the compound may be purified by preparative HPLC using the methods as described.

[0334] Purification methods as described herein can provide compounds of the present invention having sufficiently basic or acidic functionality in the form of salts, for example, trifluoroacetic acid or formate salts in the case of compounds of the present invention that are sufficiently basic, or ammonium salts in the case of compounds of the present invention that are sufficiently acidic. This type of salt can either be converted into its free base or free acid form, respectively, by various methods known to those skilled in the art, or can be used as a salt in subsequent biological assays. It should be understood that the specific forms of the compounds of the present invention as isolated and described herein are not necessarily the only forms in which the compounds can be applied to biological assays to quantify a particular biological activity.

[0335] The names of the chemical substances were generated by PerkinElmer Informatics, Inc. using ChemDraw naming software (Version 17.0.0.206). In some cases, the commonly recognized names of commercially available reagents were used instead of the names generated by the naming software.

[0336] Method of treatment In some aspects, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies, where "treatment" refers to an intervention that improves the signs or symptoms of a disease or pathological condition. As used herein, the terms "treatment," "treating," and "treatment" in relation to a disease, pathological condition, or symptom also refer to any observable beneficial effect of that treatment. Beneficial effects can be evidenced, for example, by a delay in the onset of clinical symptoms of a disease in a susceptible subject, a decrease in the severity of some or all of the clinical symptoms of the disease, a delay in the progression of the disease, a decrease in the number of recurrences of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art specific to a particular disease. Preventive treatment is a treatment administered to a subject who does not show signs of a disease or shows only initial signs, for the purpose of reducing the risk of developing the disease state. Therapeutic treatment is a treatment administered to a subject after the signs and symptoms of a disease have appeared.

[0337] In some aspects, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies 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 can be a subject diagnosed with an NLRP3 inflammasome-dependent pathology such as an 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 mental disease, or a blood disease.

[0338] Diagnosis can be performed by any method or technique known in the art. One of ordinary skill in the art will understand that the subject to be treated in accordance with the present disclosure may be undergoing standard tests or may alternatively be identified as being at risk due to the presence of one or more risk factors associated with a disease or medical condition, without undergoing testing. The term "patient" may be used interchangeably with the term "subject". The subject may refer to an adult or pediatric subject.

[0339] The route of administration can be any route that effectively transports the active compounds of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal, or parenteral including intravenous, subcutaneous and / or intramuscular. In one aspect, the route of administration is oral. In another aspect, the route of administration is topical.

[0340] Dosage forms can be administered once a day or more than once a day, for example, two or three times a day. Alternatively, the dosage form can be administered less frequently than daily, for example, every other day or once a week, if determined to be desirable from the prescribing physician or drug prescribing information. The dosing regimen can include, for example, titrating the dose to the extent necessary or useful for the indication to be treated, such that the patient's body can adapt to the treatment to minimize or avoid unwanted side effects associated with the treatment and / or to maximize the therapeutic effect of the compound. Other dosage forms include slow or controlled release forms. Suitable dosing 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.

[0341] In one aspect, the present invention provides an oral pharmaceutical composition comprising a compound of structure (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), (Ic-1'''), (II), (III), (IV) or (V), 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 aspect, the present invention provides a topical pharmaceutical composition comprising a compound of structure (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), (Ic-1'''), (II), (III), (IV) or (V), 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 aspect, the present invention provides a parenteral pharmaceutical composition comprising a compound of structure (I), (I'), (I''), (Ia), (Ia'), (Ib), (Ib'), (Ic), (Ic'), (I'''), (Ia'''), (Ia-1'''), (Ib'''), (Ib-1'''), (Ic'''), (Ic-1'''), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, together with at least one pharmaceutically acceptable parenteral carrier, diluent or excipient.

[0342] In some aspects, the present invention provides a method for treating an NLRP3 inflammasome-dependent disorder in a patient or subject, wherein modulating NLRP3 provides a medical benefit to the patient or subject.

[0343] In some aspects, NLRP3 inflammasome-dependent pathologies are inflammation, inflammatory diseases, immune diseases, cancer, infectious diseases including viral infections; central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, eye diseases, skin diseases, mental diseases or blood diseases.

[0344] In one aspect, the NLRP3 inflammasome-dependent pathology is a neuroinflammation-related disorder or a neurodegenerative disease.

[0345] In one aspect, the present invention provides a method for inhibiting the NLRP3 inflammasome using an effective amount of a pharmaceutical composition as described herein. In one aspect, the pharmaceutical composition is selective for modulating NLRP3 inflammasome activity rather than hERG activity. In certain aspects, the selectivity for NLRP3 inflammasome activity is ≧1,000-fold greater than hERG activity. In certain aspects, the selectivity for NLRP3 inflammasome activity is ≧10-fold greater than hERG activity. In certain aspects, the selectivity for NLRP3 inflammasome activity is ≧100-fold greater than hERG activity.

[0346] In another aspect, the present invention provides a method for treating an NLRP3 inflammasome-dependent pathology by administering to a subject in need thereof an effective amount of a pharmaceutical composition as described herein. In certain aspects, the NLRP3 inflammasome-dependent pathology is a neuroinflammation-related disorder or a neurodegenerative disease.

[0347] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies including inflammation resulting from an inflammatory disorder (e.g., an autoinflammatory disease), inflammation occurring as a symptom of a non-inflammatory disorder, inflammation resulting from an 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 the following: (a) Skin diseases, such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic eczema, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (b) Arthropathies, such as osteoarthritis, systemic juvenile idiopathic arthritis, adult 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) Myopathic 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 antibody syndrome, or food-related allergies that can have effects remote from the gastrointestinal tract (e.g., migraine, rhinitis or eczema); (e) Respiratory conditions, such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic or dust asthma, especially chronic or habitual asthma such as late-onset asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis such as 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) Immunopathologies, such as autoimmune pathologies, such as systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic scleroderma, 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) Infections or infection-related conditions, such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infections, acute or chronic parasitic infections, acute or chronic viral infections, acute or chronic fungal infections, meningitis, hepatitis (A, B, or C, or other viral hepatitis), peritonitis, pneumonia, laryngotracheitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis, Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis / epididymitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (k) Kidney conditions, such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia, or nephrotic syndrome; (l) Lymphatic conditions, such as Castleman disease; (m) Conditions of the immune system, or conditions in which it is involved, such as hyper IgE syndrome, lepromatous leprosy, familial hemophagocytic syndrome, or graft-versus-host disease; (n) Liver conditions, such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH) or primary biliary cirrhosis; (o) Cancers, including those listed hereinbelow; (p) Burns, wounds, trauma, bleeding or stroke; (q) Radiation exposure; and / or (r) Obesity; (s) Pain, such as inflammatory hyperalgesia; and / or (t) Neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

[0348] In another aspect, the present invention provides a method of treating NLRP3 inflammasome-dependent pathologies such as inflammatory diseases. For example, inflammatory disorders such as autoinflammatory diseases such as cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multisystem inflammatory disease (NOMID), Magid syndrome, pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), adult Still's disease (AOSD), A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-related antibody deficiency immunodeficiency disorder (PLAID), PLCG2-related autoinflammatory, antibody deficiency immunodeficiency disorder (APLAID), or inflammation resulting from B cell immunodeficiency, periodic fever and developmental delay with sideroblastic anemia (SIFD).

[0349] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as immune diseases. For example, autoimmune diseases such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti-synthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyendocrine insufficiency, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, lupus erythematosus including systemic lupus erythematosus (SLE), primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS) including multiple sclerosis (MS), myasthenia gravis, opsoclonus-myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, 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, systemic scleroderma, systemic connective tissue disorder, Takayasu arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Behçet's disease, Chagas disease, autonomic neuropathy, 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.

[0350] In another aspect, the present invention provides a method of treating NLRP3 inflammasome-dependent pathologies 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, gastrointestinal cancer, myelodysplastic syndromes (MDS), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), leukemia including promyelocytic leukemia (APML, or APL), adrenal cancer, anal cancer, basal cell carcinoma of the skin, 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 family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumors, lymphomas including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal and paranasal cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, sublingual gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymus cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms tumor.

[0351] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as infectious diseases including viral infections. For example, viral infections (e.g., influenza virus, human immunodeficiency virus (HIV), alphavirus (such as chikungunya and Ross River virus), flavivirus (such as dengue virus and Zika virus), herpesvirus (such as Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxvirus (such as vaccinia virus (modified vaccinia virus Ankara) and myxoma virus), adenovirus (such as adenovirus 5), or papillomavirus), bacterial infections (e.g., Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordetella pertussis, Burkholderia pseudomallei, Corynebacterium diphtheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Haemophilus influenzae, Pasteurella multocida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi or Yersinia pestis), fungal infections (e.g., by Candida or Aspergillus species), protozoal infections (e.g., by malaria, Babesia, Giardia, Entamoeba, Leishmania or Trypanosoma), helminth infections (e.g., by Schistosoma, nematodes, tapeworms or flukes), and prion infections.

[0352] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as central nervous system diseases. For example, Parkinson's disease, Alzheimer's disease, frontotemporal dementia, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain injury due to pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis.

[0353] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as neuroinflammation-related diseases. For example, multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Parkinson's disease or Alzheimer's disease.

[0354] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as neurodegenerative diseases. For example, Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

[0355] In one aspect, the neurodegenerative disease is characterized by a deep involvement of the cell-mediated neuroinflammatory process.

[0356] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as metabolic diseases. For example, type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout.

[0357] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as cardiovascular diseases. For example, hypertension, ischemia, reperfusion injury including post-MI ischemic reperfusion injury, attacks including ischemic attacks, transient ischemic attacks, 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's syndrome.

[0358] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as respiratory diseases. For example, chronic obstructive pulmonary disease (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis.

[0359] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as liver diseases. For example, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) including progressive fibrosis stages F3 and F4, alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH).

[0360] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as kidney diseases. For example, acute kidney disease, hyperoxaluria, chronic kidney disease, nephrolithiasis, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy;

[0361] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as eye diseases. For example, diseases of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet forms), uveitis, corneal infections, diabetic retinopathy, optic neuropathy, dry eye, and glaucoma.

[0362] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as skin diseases. For example, dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-induced skin diseases, and acne conglobata.

[0363] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as mental diseases. For example, depression, and mental stress.

[0364] In another aspect, the present invention provides a method for treating NLRP3 inflammasome-dependent pathologies such as blood diseases. For example, sickle cell anemia.

Example

[0365] General method 1 The 1H NMR (400 MHz) spectrum was obtained in a solution of deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) or dimethyl sulfoxide-d 6 (DMSO). The HPLC retention time, purity and mass spectrum (LCMS) were obtained using a Shimadzu LCMS 2010 operating in the ES(+) ionization mode (Shim-pack XR-ODS 3.0*30mm 2.2μm). Flow rate: 0.8 mL / min, acquisition time: 3 min, wavelength: UV220, oven temperature: 50 °C.

[0366] The following additional abbreviations are used: ethyl acetate (EtOAc), N,N-diisopropylethylamine (DIEA), water (H 2 O), hydrochloric acid (HCl), methanol (MeOH), dimethyl sulfoxide (DMSO), silica gel (SiO 2 ), trifluoroacetic acid (TFA), 1-methyl-2-pyrrolidinone (NMP), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 4 ), palladium on carbon (Pd / C), 9-borabicyclo[3.3.1]nonane (9-BBN), sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ), sodium sulfate (Na 2 SO 4 ), cesium carbonate (Cs 2 CO 3 ), ammonia (NH 3 ), tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile (MeCN or ACN), dimethoxyethane (DME), boron tribromide (BBr​3 ) retention time (RT), molecular weight (MW), room temperature (rt), time (h), volume / volume (v / v), proton nuclear magnetic resonance ( 1 HNMR), sodium hydride (NaH), formaldehyde (HCHO), acetic acid (AcOH), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhosPdG3), degrees Celsius (°C), milligram (mg), gram (g), millimole (mmol), milliliter (mL), polyethylene (PE), molar concentration (M), sodium bicarbonate (NaHCO 3 ), hydrogen ion exponent (pH), sodium cyanoborohydride (NaBH 3 CN), preparative high performance liquid chromatography (preparative HPLC), normal phase (N).

[0367] Example 1 General synthetic route A General scheme 1 TIFF2025517702000066.tif53130

[0368] Synthesis of 2-[4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]pyridazin-3-yl]phenol (Compound No. 2) TIFF2025517702000067.tif27156

[0369] Synthesis of (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazine-3-amine TIFF2025517702000068.tif15128To a solution of 3,6-dichloro-4-methyl-pyridazine (8.56 g, 52.5 mmol) in NMP (50 mL) was added (3R)-1-methylpiperidin-3-amine (5.0 g, 43.8 mmol) and DIEA (11 mL, 65.7 mmol). The resulting mixture was stirred at 110 °C for 14 h under a nitrogen atmosphere. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layers were combined and anhydrous Na2 SO 4 It was dried over SO and concentrated under reduced pressure to give a crude residue. The crude material was purified by silica gel column chromatography (4.6% MeOH in DCM) to give the desired product (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazine-3-amine (5.30 g) as a yellow solid.

[0370] Synthesis of 2-[4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]pyridazin-3-yl]phenol (Compound No. 2) TIFF2025517702000069.tifTo a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (110 mg, 0.498 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL), (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazine-3-amine (100 mg, 0.415 mmol), Na 2 CO 3 (110 mg, 1.04 mmol) and Pd(dppf)Cl 2 ·DCM (17 mg, 0.021 mmol) were added. The resulting mixture was stirred at 120 °C for 4 h under a nitrogen atmosphere. The mixture was then diluted with water (30 mL), acidified to pH ca. 7 - 8 with 2N aqueous HCl, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (0.05% NH 3 ·H 2 O as an additive) to give the desired product 2-[4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]pyridazin-3-yl]phenol (Compound No. 2, 43 mg, 33% yield) as a white solid.

[0371] Example 2 General Synthetic Route B General Scheme 2 TIFF2025517702000070.tif90131

[0372] (Synthesis of (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound No. 73)) TIFF2025517702000071.tif47150

[0373] (Synthesis of tert-butyl (R)-3-((6-chloro-5-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate) TIFF2025517702000072.tif12128To a mixture of (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (1.00 g, 4.97 mmol) in THF (10 mL) was added NaH (230 mg, 5.85 mmol, 60% in mineral oil) portionwise at 0 °C. The mixture was stirred at 20 °C for 2 h under a nitrogen atmosphere. Then, 3,6-dichloro-4-methylpyridazine (830 mg, 5.07 mmol) was added and the resulting mixture was stirred at 20 °C for an additional 14 h. The mixture was poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (30% EtOAc in PE) to give the desired product tert-butyl (R)-3-((6-chloro-5-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate (1.27 g, 78% yield) as a yellow solid.

[0374] (Synthesis of (R)-3-chloro-4-methyl-6-(piperidin-3-yloxy)pyridazine) TIFF2025517702000073.tif13128To a mixture of tert-butyl (R)-3-((6-chloro-5-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate (11.6 g, 35.4 mmol) in DCM (110 mL) was added 4 M HCl in dioxane (100 mL). The mixture was stirred at 20 °C for 2 h. Then, saturated NaHCO 3An aqueous solution was added to adjust the pH to about 8 - 9. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the crude product (R)-3-chloro-4-methyl-6-(piperidin-3-yloxy)pyridazine as an off-white solid, which was used without further purification.

[0375] Synthesis of (R)-3-chloro-4-methyl-6-((1-methylpiperidin-3-yl)oxy)pyridazine To a mixture of (R)-3-chloro-4-methyl-6-(piperidin-3-yloxy)pyridazine (6.95 g) in THF (50 mL) and water (5 mL), HCHO (2.48 g, 30.5 mmol) (37% in water), NaBH 3 CN (2.88 g, 45.8 mmol) and AcOH (1.83 g, 30.5 mmol) were added. The mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. Then the mixture was poured into water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the crude product (R)-3-chloro-4-methyl-6-((1-methylpiperidin-3-yl)oxy)pyridazine as a brown oil, which was used without further purification.

[0376] Synthesis of (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound No. 73) A mixture of (R)-3-chloro-4-methyl-6-((1-methylpiperidin-3-yl)oxy)pyridazine (300 mg) in dioxane (3 mL) and water (0.3 mL) was added to [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (307 mg, 1.49 mmol), XPhosPdG3 (53 mg, 0.06 mmol) and Cs 2 CO 3 (1.20 g, 3.72 mmol). The mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was then poured into water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a crude residue. The crude residue was purified by preparative HPLC (0.05% NH 3 ·H 2 O as an additive) to give the desired product (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound No. 73, 42 mg, 9% yield) as an off-white solid.

[0377] Example 3 General synthetic route C General scheme 3 TIFF2025517702000076.tif88161

[0378] Synthesis of (S)-5-fluoro-2-(4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (Compound No. 36) and (R)-5-fluoro-2-(4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (Compound No. 106) TIFF2025517702000077.tif118133

[0379] Synthesis of 3-(2-(benzyloxy)-4-fluorophenyl)-6-chloro-4-methylpyridazine TIFF2025517702000078.tif 17128 DME (7 mL) and H 2 A solution of 6-chloro-4-methylpyridazin-3-yl trifluoromethanesulfonate (562 mg, 2.03 mmol) and (2-(benzyloxy)-4-fluorophenyl)boronic acid (500 mg, 2.03 mmol) in H 3 ) 4 (352 mg, 0.305 mmol) and Na 2 CO 3 (843 mg, 6.10 mmol) was added. The resulting mixture was stirred at 90 °C for 16 h under a nitrogen atmosphere. Then, the mixture was 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 Na 2 SO 4 and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 3:1) to give the desired product 3-(2-(benzyloxy)-4-fluorophenyl)-6-chloro-4-methylpyridazine (340 mg, 50% yield) as a white solid.

[0380] Synthesis of tert-butyl 3-((6-(2-(benzyloxy)-4-fluorophenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate TIFF2025517702000079.tif A solution of tert-butyl 3-methylenepiperidine-1-carboxylate (300 mg, 1.52 mmol) in THF (10 mL) was added to a solution of 1 M 9-BBN in THF (1.52 mL, 1.52 mmol). The mixture was stirred at 65 °C for 12 h under a nitrogen atmosphere. Then, to the mixture at room temperature, 3-(2-(benzyloxy)-4-fluorophenyl)-6-chloro-4-methylpyridazine (250 mg, 0.760 mmol), Pd(dppf)Cl 2 (111 mg, 0.152 mmol), K 2 CO 3 (315 mg, 2.28 mmol) and H 2O (2 mL) was added. The resulting mixture was stirred at 65 °C for 12 h under a nitrogen atmosphere. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 2:1) to give the desired product tert-butyl 3-((6-(2-(benzyloxy)-4-fluorophenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate (90 mg, 24% yield) as a yellow oil.

[0381] Synthesis of 3-(2-(benzyloxy)-4-fluorophenyl)-4-methyl-6-(piperidin-3-ylmethyl)pyridazine TIFF2025517702000080.tif17128To a solution of tert-butyl 3-((6-(2-(benzyloxy)-4-fluorophenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate (90 mg, 0.18 mmol) in DCM (1 mL) was added a solution of 4 M HCl in 1,4-dioxane (10 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to give the crude product 3-(2-(benzyloxy)-4-fluorophenyl)-4-methyl-6-(piperidin-3-ylmethyl)pyridazine (90 mg) as a yellow oil. The crude product was used in the next step without further purification.

[0382] Synthesis of 3-(2-(benzyloxy)-4-fluorophenyl)-4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazine TIFF2025517702000081.tif19128To a solution of 3-(2-(benzyloxy)-4-fluorophenyl)-4-methyl-6-(piperidin-3-ylmethyl)pyridazine (90 mg) in THF (3 mL) and H 2 O (0.3 mL) was added aqueous 37% formaldehyde solution (20 mg, 0.25 mmol), NaBH3 CN (20 mg, 0.32 mmol) and AcOH (13 mg, 0.21 mmol) were added. The resulting mixture was stirred at 50 °C for 2 hours. Then, a saturated aqueous solution of NaHCO 3 was added to adjust the pH to about 7 - 8, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the crude product 3-(2-(benzyloxy)-4-fluorophenyl)-4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazine (40 mg) as a yellow oil. The crude product was used in the next step without further purification.

[0383] (S)-5-Fluoro-2-(4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (Compound No. 36) and (R)-5-fluoro-2-(4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (Compound No. 106) Synthesis To a solution of 3-(2-(benzyloxy)-4-fluorophenyl)-4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazine (40 mg) in MeOH (1 mL), Pd / C (10 mg) was added. The mixture was stirred at 30 °C for 14 hours under a hydrogen atmosphere (15 psi). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product 5-fluoro-2-(4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (20 mg) as a racemic mixture. Then, the crude product was separated by preparative supercritical fluid chromatography (preparative SFC) (DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2O EtOH]; B %: 30% to 30%, purified by (points), to give the desired product (R)-5-fluoro-2-(4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (Compound No. 106, 5.6 mg, yield 43%) and (S)-5-fluoro-2-(4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (Compound No. 36, 8.9 mg, yield 27%) as white solids.

[0384] Example 4 General synthetic route D General scheme 4 TIFF2025517702000083.tif90148

[0385] (R)-3-Methyl-2-(6-(methyl(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound No. 21) synthesis TIFF2025517702000084.tif86154

[0386] Synthesis of tert-butyl (R)-3-((6-chloropyridazin-3-yl)(methyl)amino)piperidine-1-carboxylate A solution of 3,6-dichloropyridazine (1.00 g, 6.71 mmol) and (R)-tert-butyl 3-(methylamino)piperidine-1-carboxylate (1.51 g, 7.05 mmol) in 17128 NMP (8 mL) was added with DIEA (2.6 g, 20 mmol). The resulting mixture was stirred at 140 °C for 16 h under a nitrogen atmosphere. Then, the mixture was poured into water (100 mL) and extracted with 6:1 DCM:MeOH (3 × 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (30% EtOAc in PE) to give the desired product tert-butyl (R)-3-((6-chloropyridazin-3-yl)(methyl)amino)piperidine-1-carboxylate (1.88 g, 70% yield) as a yellow solid.

[0387] Synthesis of (R)-6-chloro-N-methyl-N-(piperidin-3-yl)pyridazin-3-amine A solution of tert-butyl (R)-3-((6-chloropyridazin-3-yl)(methyl)amino)piperidine-1-carboxylate (1.83 g, 5.61 mmol) in 19128 DCM (2 mL) was added with a solution of 4 M HCl in 1,4-dioxane (15 mL). The resulting mixture was stirred at room temperature for 2 h. Then, a saturated aqueous solution of NaHCO 3 was added to adjust the pH to about 7 - 8, and the mixture was extracted with 5:1 DCM:MeOH (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the crude product (R)-6-chloro-N-methyl-N-(piperidin-3-yl)pyridazin-3-amine (1.40 g) as a yellow solid. The crude product was used in the next step without further purification.

[0388] Synthesis of (R)-6-chloro-N-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine To a solution of (R)-6-chloro-N-methyl-N-(piperidin-3-yl)pyridazin-3-amine (1.40 g, 6.17 mmol) in THF (3 mL) and water (0.3 mL), 37% aqueous formaldehyde solution (0.60 g, 7.41 mmol), NaBH 3 CN (0.58 g, 9.26 mmol) and AcOH (0.37 g, 6.17 mmol) were added. The resulting mixture was stirred at 50 °C for 2 h. Then, saturated aqueous solution of NaHCO 3 was added to adjust the pH to about 7 - 8, and the mixture was extracted with 5:1 DCM:MeOH (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude residue. The crude residue was purified by silica gel column chromatography (15% MeOH in DCM) to give the desired product (R)-6-chloro-N-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (445 mg, 30% yield) as a yellow solid.

[0389] Synthesis of (R)-6-(2-methoxy-6-methylphenyl)-N-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine To a solution of (R)-6-chloro-N-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (100 mg, 0.415 mmol) and 2-(2-methoxy-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (113 mg, 0.457 mmol) in 1,4-dioxane (4 mL) and water (1 mL), Xphos-pd-G3 (53 mg, 0.062 mmol) and Cs 2 CO 3 (406 mg, 1.25 mmol) were added. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. Then, 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), and dried over anhydrous Na 2 SO 4It was dried and concentrated under reduced pressure to give a crude residue. The crude residue was purified by silica gel column chromatography (15% MeOH in DCM) to give the desired product (R)-6-(2-methoxy-6-methylphenyl)-N-methyl-N-(1-methylpiperidin-3-yl)pyridazine-3-amine (96 mg, 71% yield) as an off-white solid.

[0390] (R)-3-Methyl-2-(6-(methyl(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound No. 21) Synthesis To a solution of (R)-6-(2-methoxy-6-methylphenyl)-N-methyl-N-(1-methylpiperidin-3-yl)pyridazine-3-amine (86 mg, 0.26 mmol) in anhydrous DCM (3 mL) was added BBr 3 (0.25 mL, 2.6 mmol) slowly at -78 °C. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. Then, a saturated aqueous solution of NaHCO 3 was added to adjust the pH to about 7 - 8, and the mixture was extracted with 5:1 DCM:MeOH (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a crude residue. The crude residue was purified by preparative HPLC (0.05% NH 4 HCO 3 ) as an additive to give the desired product (R)-3-methyl-2-(6-(methyl(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound No. 21, 21.3 mg, 26% yield) as an off-white solid.

[0391] Example 5 Synthesis of Representative Compounds The compounds listed in Table 7 below were prepared by procedures similar to those described in the representative schemes found in the examples, with appropriate changes to the reactants, amounts of reagents, protection and deprotection, solvents, and reaction conditions. Also, the characteristic data of the compounds are summarized in Table 7 of this specification.

[0392] (Table 7) TIFF2025517702000090.tif116128TIFF2025517702000091.tif215115TIFF2025517702000092.tif215115TIFF2025517702000093.tif215115TIFF2025517702000094.tif205115TIFF2025517702000095.tif236115TIFF2025517702000096.tif196115TIFF2025517702000097.tif214115TIFF2025517702000098.tif222115TIFF2025517702000099.tif207115TIFF2025517702000100.tif202115TIFF2025517702000101.tif223115TIFF2025517702000102.tif208115TIFF2025517702000103.tif223115TIFF2025517702000104.tif227115TIFF2025517702000105.tif207115TIFF2025517702000106.tif232115TIFF2025517702000107.tif198115TIFF2025517702000108.tif237115TIFF2025517702000109.tif210115TIFF2025517702000110.tif207115TIFF2025517702000111.tif213115TIFF2025517702000112.tif235115TIFF2025517702000113.tif202115TIFF2025517702000114.tif232115TIFF2025517702000115.tif213115TIFF2025517702000116.tif132128

[0393] Example 6 Evaluation of NLRP3 inflammasome activation and cell viability in THP1 macrophages THP1-human acute monocytic leukemia cells (ATCC, cat # TIB-202) were cultured in Gibco RPMI-1640 medium (ThermoFisher cat # 72400054) supplemented with 10% heat-inactivated FBS at a density of 3 - 8×10 5 viable cells / ml. Then, when the cell concentration reached 8×10 5 cells / mL, the cells were passaged (every 2 - 3 days).

[0394] To determine the IC 50 of the compound, 1.75×10 4 cells / well were plated in a CELLSTAR 384-well plate (Greiner cat # 781091) in 50 μl / well of DMEM (ThermoFisher, cat # 10393021), 10% FBS, 1×GlutaMax (ThermoFisher, cat # 35050038) + 20 nM PMA (Sigma, cat # P1585), and only the inner 224 wells of the 384-well plate were used. The parameter wells were filled with 50 μl PBS and incubated at 37°C, 5% CO 2 for 48 hours.

[0395] After 48 hours of incubation, the PMA-containing medium was removed and replaced with 40 μl / well of fresh DMEM, 10% FBS, 1×GlutMax, and incubated at 37°C, 5% CO 2 for 24 hours.

[0396] The next day, the cells were primed with 20 ng / ml of LPS (E. coli) (Sigma, cat # L3129) in DMEM, 10% FBS, 1×GlutMax at 37°C, 5% CO 2 for 3 hours.

[0397] Following the LPS priming step, cells were treated with the compound at a maximum final concentration of 10 uM, dilution factor of 1:4, for 8 times (10 uM, 2.5 uM, 0.625 uM, 0.156 uM, 0.039 uM, 0.0097 uM, 0.0024 uM, 0.0006 uM). DMSO was used as a vehicle control, and 1 uM of MCC950 (InvivGen, cat # inh-mcc) was used as a positive control, and incubated at 37 °C, 5% CO 2 for 1 hour.

[0398] Following the 1-hour compound incubation, cells were treated with nigericin (InvivoGen, cat # tlrl-nig) at a final concentration of 6.7 uM at 37 °C, 5% CO 2 for 3 hours to perform the NLRP3 inflammasome activation step.

[0399] Thereafter, 30 ul of cell supernatant samples were collected for cytokine analysis, and cytokine analysis was performed using Hu IL-1β AlphaLISA (Perkin Elemer, cat # AL220C) and Hu IL-6 AlphaLISA (Perkin Elemer, cat # AL220C). Cell viability was evaluated by performing the CellTiter-Glo Luminescent Assay (Promega, cat #G7572) according to the manufacturer's protocol.

[0400] The evaluation of cell viability for the selected NLRP3 inflammasome modulators is shown in Tables 8 and 9.

[0401] For Table 8, the activity ranges are as follows: "++++++" represents IL-1β activity ≤ 1 nM; "+++++" represents IL-1β activity > 1 nM and ≤ 10 nM; "++++" represents IL-1β activity > 10 nM and ≤ 100 nM; "+++" represents IL-1β activity > 100 nM and ≤ 500 nM; "++" represents IL-1β activity > 500 nM and ≤ 1,000 nM; "+" represents IL-1β activity > 1,000 nM; "*" represents not yet tested.

[0402] Regarding Table 4, the activity range is as follows: "++++" represents IL-6 activity ≤ 1 μM; "+++" represents IL-6 activity > 1 μM and ≤ 5 μM; "++" represents IL-6 activity > 5 μM and ≤ 10 μM; "+" represents IL-6 activity > 10 μM; "*" represents not yet tested.

[0403] (Table 8) TIFF2025517702000117.tif222149TIFF2025517702000118.tif222149TIFF2025517702000119.tif222149TIFF2025517702000120.tif222149TIFF2025517702000121.tif222149TIFF2025517702000122.tif79128

[0404] (Table 9) TIFF2025517702000123.tif79144TIFF2025517702000124.tif222144TIFF2025517702000125.tif222144TIFF2025517702000126.tif222144TIFF2025517702000127.tif222144TIFF2025517702000128.tif222144

[0405] Example 7 hERG Assay Protocol in CHO-hERG Cells CHO-hERG cells stored in liquid nitrogen (subcultured and frozen at Sophion Biosciences (Ballerup, Denmark) and WuXi AppTec (Suzhou) Co., Ltd.) were tested to confirm the absence of mycoplasma contamination. Cells after passage 30 were not used. The CHO-hERG cells were cultured at 37 °C (±2 °C) in a humidified incubator with 5% CO2 (4% - 8%) in air. The cells were recovered in recovery medium (F12 medium containing 10% fetal bovine serum), subcultured in complete medium (F12 medium supplemented with 10% fetal bovine serum, 1% geneticin (registered trademark) selection antibiotic (G418), 89 μg / mL hygromycin B (HB)), and the culture medium was switched to recovery medium in the final subculture prior to the patch clamp experiment.

[0406] IC of the compound 50 To determine the, the selected compound ("test substance") was dissolved in DMSO and then diluted with ECS to obtain standard solutions (working solutions). Five concentrations of 0.3, 1, 3, 10, and 30 μM were tested. Cells were tested in duplicate for each concentration.

[0407] Exponentially growing CHO-hERG cells were harvested and suspended in extracellular solution for use. hERG currents were recorded at physiological temperature (33.0 °C to 37.0 °C) using the whole-cell patch-clamp method. The output signal from the patch-clamp amplifier was digitized and passed through a low-pass filter at 2.9 KHz. The recording was controlled with Patchmaster Pro software. The recording chamber containing the seeded cells was placed on an inverted microscope stage. Cells within the recording chamber were randomly selected for testing. The cells were continuously perfused from the perfusion system. A micropipette filled with ICS was used as the recording electrode in manual patch-clamp studies. The micropipette was prepared on the day of the patch-clamp experiment using a glass capillary (BF150-117-10, SUTTER INSTRUMENT USA). The pipette resistance (Rp) was within 2 - 5 MΩ when filled with ICS. The voltage was raised from a holding potential of -80 mV to +60 mV in 850 ms to open the hERG channel. Subsequently, the voltage was lowered to -50 mV in 1275 ms to elicit a "rebound" or tail current, the peak tail current was measured and collected for data analysis. Finally, the voltage was lowered back to the holding potential (-80 mV). This command voltage protocol was continuously repeated every 15 seconds during the application of the test substance.

[0408] During the initial recording period using the vehicle control standard solution, the peak tail current amplitude was monitored for at least 3 sweeps until it became stable. Subsequently, the cells were perfused with the test substance / positive control standard solution until the peak tail current amplitude reached a steady state. When three consecutive and superimposable peak tail currents were collected, it was considered that a steady state had been reached. At this point, the cells were perfused again with the test substance at the next concentration. One or more test substances / positive controls or different concentrations of the same test substance were tested on each cell, and the vehicle control washout was performed until the current amplitude returned to at least 80% of the measured value before the application of the test substance. 100 nM cisapride was tested as a positive control to evaluate the reliability of the test system. Cells were tested with at least 2 replicates for each concentration. According to scientific literature, 100 nM cisapride inhibits more than 50% of the hERG current (Milnes, J.T., et al.).

[0409] Seal criterion: Once the whole-cell configuration was achieved, a holding potential (e.g., -80 mV) was applied and at the same time the membrane parameters (Cm, Rm and Rs) were collected. A "good" whole-cell recording was generally defined as follows: the series resistance (Rs) was less than 10 MΩ; the membrane resistance (Rm) was more than 500 MΩ and the membrane capacitance (Cm) was less than 100 pF. Current amplitude: The peak current amplitude should be between 400 pA and 5000 pA before the application of the test substance / positive control; otherwise the cells were discarded. Leak criterion: At a holding potential of -80 mV, the absolute leak current value should be less than 200 pA. The current amplitude was adjusted with the leak current at -80 mV. Sweeps with an absolute leak current value greater than 200 pA were not used for data analysis.

[0410] The activity evaluation for the selected compounds is shown in Table 10.

[0411] For Table 10, the activity ranges are as follows: "++++++" represents hERG activity ≤ 1 μM; "+++++" represents hERG activity > 1 μM and ≤ 3 μM; "++++" represents hERG activity > 3 μM and ≤ 10 μM; "+++" represents hERG activity > 10 μM and ≤ 20 μM; "++" represents hERG activity > 20 μM and ≤ 30 μM; "+" represents hERG activity > 30 μM; "*" represents not yet tested.

[0412] (Table 10) TIFF2025517702000129.tif222144TIFF2025517702000130.tif222144TIFF2025517702000131.tif222144TIFF2025517702000132.tif222144TIFF2025517702000133.tif222144TIFF2025517702000134.tif79128

[0413] Example 8 Comparative assay data Inhibition of hERG channels associated with NLRP3 inflammasome modulators and QT prolongation in related electrocardiogram recording methods (ECG) are recognized human cardiovascular safety risks (Hancox et al., Molecular Pharmacology 2008, 73:1592 - 1595, incorporated herein by reference). QT prolongation can lead to ventricular tachycardia and torsades de pointes (TdP) arrhythmias that can result in sudden death. Therefore, there is a need for NLRP3 inflammasome modulators that overcome safety impairments of hERG.

[0414] NLRP3 modulators are provided that have surprising and unexpected technical advantages with respect to cardiac ion channel (e.g., hERG) activity. For example, Compounds 2, 21, 22, and 51 (and their analogous analogs) of the present invention exhibit strong IL-1β and IL-6 activity while having unexpectedly low hERG inhibition. In comparison, Compounds A, B, C, D, and Compounds 3 and 15 as shown in Table 6 below have high hERG inhibition while showing strong IL-1β activity. These data show that the chemical nature of the functional group attached at the R 1 position has a significant impact on whether the compound exhibits advantageous properties in humans. Without wishing to be bound by theory, the R 1 position functional group that exhibits a small steric dimension with electron-withdrawing properties confers strong IL-1β activity and low hERG inhibition. Thus, Compounds 2, 21, 22, and 51 (and their analogous analogs) show surprisingly advantageous data for human application.

[0415] Evaluate the comparison of IL-1β, IL-6 and hERG activities for the compounds selected in Table 11.

[0416] For Table 11, the activity ranges are as described above for IL-1β, IL-6 and hERG (see Tables 3, 4 and 5 respectively).

[0417] (Table 11) TIFF2025517702000135.tif122158TIFF2025517702000136.tif228158TIFF2025517702000137.tif62158

[0418] Summarize the characteristic data of Compounds A, B, C, and D in Table 12 below.

[0419] (Table 12) TIFF2025517702000138.tif164128

[0420] The various aspects described above can be combined to provide further aspects. U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications that are referenced herein and / or listed on the application data sheet, including U.S. Provisional Patent Application No. 63 / 341,975, filed May 13, 2022, are hereby incorporated by reference in their entirety. Aspects of the various aspects can be modified, as necessary, to utilize concepts from various patents, applications, and publications to provide still further aspects.

[0421] These and other modifications can be added to the aspects 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 aspects disclosed in the specification and the claims, but should be construed to include all possible aspects together with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited to the disclosure.

Claims

[Claim 1] Compounds having structure (I'''), or their pharmaceutically acceptable salts, isomers, hydrates, solvates, or isotopes: During the ceremony, X is CR a R b , NR a or O; R a and R b These are, independently, H or C 1-6 It is alkyl; R 1 is H, F, or CN; R 2 and R 5 are each independently H, halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl or OC 1-6 haloalkyl; R 3 or R 4 One side is OH, and the other side is H, halo, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, OC 1-6 Alkyl or OC 1-6 It is a haloalkyl; R 8 is H or halo; R 9 H, C 3-5 Cycloalkyl, or one or more R 9' Even if replaced by C 1-6 It is alkyl; R 9' is OH, halo, or C 3-5 It is cycloalkyl; R 10 and R 13 These are, independently, H or halo; R 11 and R 12 These are H, Haro, CN, and C, each independent of the others. 1-6 Alkyl, C 1-6 Haloalkyl or OC 1-6 It is alkyl; R 16 is H or CO 2 H is; and n is 0, 1, or 2.

Images