Modulators of NLRP3 inflammasomes and related products and methods

Abstract

Provided herein are compounds, the method comprises the following steps of: contacting the NLRP3 inflammasome with an effective amount of a compound with the following structure (I) or a pharmaceutically acceptable salt, an isomer, a hydrate, a solvate or an isotope compound, or applying an effective amount of a compound with the following structure (I) or a pharmaceutically acceptable salt, an isomer, a hydrate and a solvate to an individual in need of the NLRP3 inflammasome, or isotope compounds, for use in the modulation of NLRP3 inflammasome in general, or more particularly in the treatment of NLRP3 inflammasome dependent disorders, where X, R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R13 and n are as defined herein. Also provided are pharmaceutical compositions containing such compounds, as well as the compounds themselves. # imgabs0 #

Description

background Technical Field

[0001] The present invention relates to regulators of NLRP3 inflammasome, products containing regulators of NLRP3 inflammasome, and methods for using and preparing the same.

[0002] Related technical description

[0003] NOD-like receptor protein 3 (NLRP3) is a key protein that interacts with apoptosis-associated speck-like protein (ASC) and procaspase-1 to form the NLRP3 inflammasome. Activation of the NLRP3 inflammasome produces inflammatory mediators such as interleukin-1β (IL-1β) and interleukin-18 (IL-18), which helps activate the innate immune system. Dysregulation of innate immunity can lead to various diseases.

[0004] The innate immune response protects the host from microbial invasion. The formation of the NLRP3 inflammasome activates caspase-1, leading to the maturation and secretion of IL-1β and IL-18, the cleavage of gasdermin-D, and ultimately cell death through pyroptosis. This system alerts the presence of invading microorganisms by releasing cytokines and eliminates inflammation by eliminating infected cells.

[0005] However, non-microbial compounds, both endogenous and exogenous, are also potent inducers of NLRP3 inflammasomes, allergic responses, or other forms of inflammation. For example, NLRP3 may be implicated in Parkinson's and / or Alzheimer's disease, suggesting that misfolded proteins form aggregates that lead to activation of the NLRP3 inflammasome. Inhaled environmental particles such as asbestos and silica also activate the NLRP3 inflammasome, and high levels of IL-1β have been implicated in the development of asbestosis and silicosis, both progressive lung diseases that lead to fibrosis.

[0006] Emerging studies have shown that the increased production of IL-1β and IL-18 involved in the NLRP3 inflammasome contributes to the development and progression of various diseases, such as neuroinflammation-related disorders, such as brain infection, acute injury, multiple sclerosis (amyotrophic lateral sclerosis), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other neurodegenerative diseases; cardiovascular disease, cardiovascular risk reduction, atherosclerosis, type I and type II diabetes and related complications, inflammatory skin diseases, acne, suppurative hidradenitis, asthma, age-related macular degeneration or cancer-related diseases. Diseases that are immune or inflammatory in nature are often difficult to diagnose or treat effectively.

[0007] Therefore, there is a need in the art for compounds that modulate the NLRP3 inflammasome for use in treating diseases in which blocking the NLRP3 inflammasome would be beneficial.

[0008] Additionally, there is a need for compounds that modulate the NLRP3 inflammasome with 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 repolarization of the cardiac action potential, and reduced hERG function can lengthen the ventricular action potential, prolong the QT interval in the electrocardiogram, and increase the risk of potentially fatal ventricular arrhythmias. In order to reduce the risk of investing resources in drug candidates that fail preclinical safety studies due to QT prolongation, it is important to screen compounds for off-target activity of the hERG channel early in the lead compound optimization process. Therefore, it would be advantageous to develop compounds that modulate the NLRP3 inflammasome while exhibiting little hERG activity, thereby reducing the potential for cardiotoxicity.

[0009] The present invention satisfies these needs and provides other advantages that will become apparent from the description below. SUMMARY OF THE INVENTION

[0011] In one embodiment, there is provided a compound having structure (I):

[0012]

[0013] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , R11 , R 12 , R 13 and n are as defined herein.

[0014] In another embodiment, a pharmaceutical composition is provided, comprising a carrier or excipient, and a compound having structure (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0015] In another embodiment, a method of treating a NLRP3 inflammasome-dependent disorder is provided by administering 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 to an individual in need thereof. In some embodiments, the NLRP3 inflammasome-dependent disorder is a neuroinflammatory-related disorder or a neurodegenerative disease. In some embodiments, the NLRP3 inflammasome is modulated so that there is no risk of cardiotoxicity at physiologically relevant exposures of NLRP modulation. DETAILED DESCRIPTION OF THE INVENTION

[0017] definition

[0018] As used herein, the following terms have the meanings defined below, unless the context indicates otherwise.

[0019] "Modulating" the NLRP3 inflammasome means that the compound interacts with NLRP3 in a manner that impedes its ATPase function and the formation of the downstream NLRP3 inflammasome complex. In the above case, the compound acts to inhibit or impede the activation of the NLRP3 inflammasome, and the compound may also be described as an inhibitor.

[0020] NLRP3 refers to NOD-like receptor protein 3. NLRP3 is a gene encoding a protein and an example sequence can be found at https: / / www.uniprot.org / uniprot / Q96P20. NLRP3 functions as an ATPase that is self-inhibited under normal conditions. NLRP3, unlike other inflammasomes, requires a two-step activation process that can be triggered by a variety of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The first step is to activate the NLRP3 inflammasome by recognizing PAMPs, DAMPs, or pathological species through pattern recognition receptors (PRRs) such as Toll-like receptors. Activation increases the expression of NLRP3, IL1β precursor (pro-IL1β), and IL18 precursor (pro-IL18). NLRP3 activation is mediated by second signals such as ATP, K +The efflux of IL-1β and IL-18 is triggered by other cellular stresses or pathological species, leading to ATP hydrolysis and enzyme activation. This activation leads to oligomerization of the inflammasome complex, which results in the self-cleavage and activation of caspase-1. Active caspase-1 then cleaves pro-IL1β and pro-IL18. Active IL11β and IL18 are then released from the cell through the gasdermin D pore, and the release of these cytokines triggers downstream inflammatory responses and leads to cell death via pyroptosis.

[0021] “hERG” refers to human ether-a-go-go related gene (hERG), which encodes a rapidly activating delayed rectifier potassium channel (I Kr ), which is important for cardiac repolarization. Reduced hERG function prolongs the ventricular action potential, prolongs the QT interval on the electrocardiogram, and increases the risk of potentially fatal ventricular arrhythmias

[0022] "Effective amount" refers to the amount of a specific active agent sufficient to achieve a desired effect in an individual treated with the agent. Ideally, an effective amount of an active agent is an amount sufficient to inhibit or treat a disease without causing substantial toxicity to the individual. The effective amount of an active agent depends on the individual being treated, the severity of the affliction, and the mode of administration of the pharmaceutical composition. Those skilled in the art will appreciate methods of determining an effective amount of a disclosed compound sufficient to achieve a desired effect in an individual based on the present disclosure.

[0023] "Alkyl" refers to a saturated or unsaturated straight 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. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl.

[0024] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0025] "Hydroxyl" refers to -OH.

[0026] "Cyano" refers to -CN.

[0027] "Carboxylic acid" or "carboxyl" refers to -CO2H.

[0028] "Oxo" refers to a =0 substituent.

[0029] "Haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by halogen. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2CF3, -CH2CHF2, and the like.

[0030] "Alkoxy" refers to an alkyl group as defined above attached through an oxygen atom (ie, -O-alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.

[0031] "Haloalkoxy" refers to a haloalkyl group as defined above attached through an oxygen atom (ie, -O-haloalkyl). Examples of haloalkoxy include, but are not limited to, -OCF3 and the like.

[0032] "Aminyl" refers to -NH2, -NHalkyl or N(alkyl), wherein alkyl is as defined above. Examples of amino or aminyl include, but are not limited to, -NH2, -NHCH3, -N(CH3)2, and the like.

[0033] "Cycloalkyl" refers to a non-aromatic ring structure containing 3 or more ring members. In some embodiments, the cycloalkyl includes 3 to 8 ring members. In some embodiments, the cycloalkyl includes 3 to 5 ring members. For example, cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0034] "Heterocycle" refers to aromatic and non-aromatic ring structures containing 3 or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, S, or P. In some embodiments, heterocyclyl includes 3 to 20 ring members, while other schemes have 3 to 15 ring members. At least one ring contains heteroatoms, but it is not necessary for each ring in the polycyclic system to contain heteroatoms. For example, both dioxolanyl rings and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are heterocyclyls within the meaning of this article. For example, heterocycles include dioxane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, etc.

[0035] Heterocyclic radicals also include fused ring types including those with fused aromatic and non-aromatic groups.Heterocyclic radicals also include polycyclic ring systems containing heteroatoms, such as but not limited to quinuclidine radicals, and also include heterocyclic radicals with substituents, including but not limited to alkyl, halogen, amino, hydroxyl, cyano, carboxyl, nitro, thiol (thio) or alkoxy, which are bonded to one of the ring members.Heterocyclic radicals as defined herein can be heteroaryl or partially or completely saturated cyclic groups including at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thienyl, benzothienyl, benzofuranyl, dihydrobenzofuranyl, indolyl, indolinyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl.

[0036] As used herein, "isomers" encompass all chiral, diastereoisomer, or racemic forms (also referred to as stereoisomers, which are in contrast to structural or positional isomers) of a structure unless a particular stereochemistry or isomeric form has been specifically indicated. Such compounds may be enriched or resolved to any degree of enrichment for optical isomers at any or all asymmetric atoms as apparent from the description. Racemic and diastereomeric mixtures as well as individual optical isomers may be synthesized substantially free of their enantiomer or diastereomeric partners, and these are within the scope of certain embodiments of the present invention. Isomers resulting from the presence of a chiral center include a pair of non-superimposable isomers, referred to as "enantiomers". Single enantiomers of a pure compound are optically active (i.e., they are able to rotate the plane of plane polarized light and are designated as R or S).

[0037] "Isolated optical isomers" refers to compounds that have been substantially purified from the corresponding optical isomers of the same chemical formula. For example, the purity of the isolated isomers can be at least about 80%, at least 80%, or at least 85% by weight. In other embodiments, the isolated isomers are at least 90% pure, or at least 98% pure, or at least 99% pure (by weight).

[0038] "Substantially enantiomerically or diastereomerically" pure means that the level of enantiomeric or diastereomeric enrichment of one enantiomer relative to the other enantiomer or diastereomer is at least about 80%, more specifically greater than 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

[0039] The terms "racemate" and "racemic mixture" refer to a mixture of equal amounts of two enantiomers. A racemate is labeled "(±)" because it is optically inactive (i.e., does not rotate plane-polarized light in either direction because its constituent enantiomers cancel each other). All compounds bearing an asterisk (*) near a tertiary or quaternary carbon atom are optically active isomers and may be purified from the corresponding racemate and / or synthesized by appropriate chiral synthesis.

[0040] A "hydrate" is a compound that exists in association with water molecules. The combination may include a stoichiometric amount of water, such as a monohydrate or a dihydrate, or may include a random amount of water. As used herein, the term "hydrate" refers to the solid form; that is, a compound in aqueous solution may be hydrated but is not a hydrate as that term is used herein.

[0041] "Solvates" are similar to hydrates, 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. The term "solvate" as used herein refers to a solid form; that is, a compound in a solvent solution may be solvated but is not a solvate as used herein.

[0042] "Isotopes" refer to atoms having the same number of protons but a different number of neutrons, and isotopic compounds 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 six protons and six neutrons, while carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). Although fluorine has multiple isotopes, fluorine-19 has the longest lifespan. Thus, isotopic compounds of compounds having structures (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, structures (I), (I'), (I"), (Ia), (Ia'), (Ib'), (Ic), (Ic'), (I"'), (Ia"'), (Ia-1"'), (Ib"'), (Ib-1"'), (Ic"'), (Ic-1"'), (II), (III), (IV) or (V). , (Ib), (Ib'), (Ic), (Ic'), (I"'), (Ia"'), (Ia-1"'), (Ib"'), (Ib-1"'), (Ic"'), (Ic-1"'), (II), (III), (IV) or (V) wherein one or more carbon-12 atoms are replaced by carbon-13 and / or carbon-14 atoms, wherein one or more hydrogen atoms are replaced by deuterium and / or tritium, and / or wherein one or more fluorine atoms are replaced by fluorine-19.

[0043] "Salt" generally refers to an organic compound in ionic form, such as a carboxylic acid or an amine, together with a counterion. For example, a salt formed by an acid in anionic form and a cation is called an "acid addition salt." Conversely, a salt formed by a base in cationic form and an anion is called a "base addition salt."

[0044] The term "pharmaceutically acceptable" refers to substances that have been approved for human use and are generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to non-toxic inorganic or organic acid and / or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated herein by reference).

[0045] Pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, metal salts, including alkali metal, alkaline earth metal and transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts prepared from basic amines, such as N, N'dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[0046] 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 aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic and sulfonic acid classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic / pamoic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, p-aminobenzenesulfonic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactonic and galacturonic acid.

[0047] 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 embodiments thereof) or pharmaceutically acceptable salts thereof may contain one or more centers of geometric asymmetry and may thus give rise to enantiomers, diastereomers and other stereoisomeric forms defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. Accordingly, the embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or can be resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also included.

[0048] Although pharmaceutically unacceptable salts are not generally useful as pharmaceuticals, such salts may be useful, for example, as intermediates in the synthesis of 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), for example, in their purification by recrystallization.

[0049] As used herein, "NLRP3 inflammasome-dependent disease" refers to a disorder in which modulation of NLRP3 provides a medical benefit to the patient or individual.

[0050] In some embodiments, the NLRP3 inflammasome-dependent disease is inflammation, inflammatory disease, immune disease, cancer, infection including viral infection; central nervous system disease, metabolic disease, cardiovascular disease, respiratory disease, liver disease, kidney disease, eye disease, skin disease, psychological disease or blood disease.

[0051] In one embodiment, the NLRP3 inflammasome-dependent disorder is a neuroinflammation-related disorder or a neurodegenerative disease.

[0052] In one embodiment, the invention provides a method of inhibiting the NLRP3 inflammasome using an effective amount of a pharmaceutical composition described herein. In one embodiment, the pharmaceutical composition is selective for modulating NLRP3 inflammasome activity relative to hERG activity. In certain embodiments, the selectivity for NLRP3 inflammasome activity relative to hERG activity is greater than or equal to 1,000 times. In certain embodiments, the selectivity for NLRP3 inflammasome activity relative to hERG activity is greater than or equal to 10 times. In certain embodiments, the selectivity for NLRP3 inflammasome activity relative to hERG activity is greater than or equal to 100 times.

[0053] In another embodiment, the present invention provides a method of treating a NLRP3 inflammasome-dependent disorder by administering an effective amount of a pharmaceutical composition described herein to an individual in need thereof. In certain embodiments, the NLRP3 inflammasome-dependent disorder is one or more neuroinflammation-related disorders or neurodegenerative diseases.

[0054] As used herein, the phrase "inflammation" refers to inflammation, including inflammation that occurs due to an inflammatory disorder (e.g., an autoinflammatory disease), inflammation that occurs as a symptom of a non-inflammatory disorder, inflammation that occurs due to infection, or inflammation secondary to trauma, injury, or autoimmunity. Examples of inflammation that can be treated or prevented include inflammatory responses associated with or caused by the following diseases:

[0055] (a) skin disorders, such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia;

[0056] (b) joint disorders, such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, crystal induced arthropathy (e.g., pseudogout, gout), or seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis or Reiter's disease);

[0057] (c) muscle disorders, such as polymyositis or myasthenia gravis;

[0058] (d) gastrointestinal disorders, such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer, celiac disease, proctitis, pancreatitis, eosinopilic gastro-enteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that can produce effects distal to the intestine (e.g., migraine, rhinitis, or eczema);

[0059] (e) respiratory disorders, such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, in particular chronic or intractable asthma, such as late asthma and airways hyper-responsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, rhinitis caseosa, hypertrophic rhinitis, rhinitis pumlenta, dry rhinitis, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis 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;

[0060] (f) vascular disorders, such as atherosclerosis, Behcet's disease, vasculitis, or Wegener's granulomatosis;

[0061] (g) immune disorders, such as autoimmune disorders, for example, systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenia purpura, or Graves' disease;

[0062] (h) eye disorders, such as uveitis, allergic conjunctivitis or vernal conjunctivitis;

[0063] (i) neurological disorders, such as multiple sclerosis or encephalomyelitis;

[0064] (j) infectious or infection-related conditions, such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (type A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis, Mycobacterium aviumintracellulare, Pneumocystis cariniipneumonia, orchitis / epididymitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus, viral encephalitis, encephalitis / aseptic meningitis, or pelvic inflammatory disease;

[0065] (k) renal disorders, such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia or nephritic syndrome;

[0066] (l) Lymphatic system disorders, such as Castleman's disease;

[0067] (m) immune system disorders or disorders involving the immune system, such as hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis or graft-versus-host disease;

[0068] (n) liver disorders, such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), or primary biliary cirrhosis;

[0069] (o) cancer, including those listed below;

[0070] (p) burns, wounds, trauma, hemorrhage or stroke;

[0071] (q) radiation exposure; and / or

[0072] (r) obesity;

[0073] (s) pain, such as inflammatory hyperalgesia; and / or

[0074] (t) Neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

[0075] As used herein, the phrase "inflammatory disease" refers to inflammation that occurs due to an inflammatory disorder, such as an autoinflammatory disease, such as cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), adult-onset Still's disease (AOSD), haploinsufficiency of A20 (HA20), pediatric granulomatous arthritis (PGA), and inflammatory bowel disease (AGS). sideroblastic anaemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD).

[0076] As used herein, the phrase "immune disease" refers to, for example, an autoimmune disease, 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 polyglandular failure, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease), idiopathic thrombocytopenic purpura, Kawasaki disease, lupus erythematosus including systemic lupus erythematosus (SLE), multiple sclerosis (MS) (including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS)), myasthenia gravis, opsoclonus myoclonus syndrome (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 sclerosis, systemic connective tissue disorders, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Beliefs disease, Chagas' disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome syndrome), giant cell arteritis, leukoplakia, or vulvodynia.

[0077] As used herein, the phrase "cancer" refers to, for example, lung cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), Langerhans cell histiocytosis (LCH), myeloproliferative neoplasm (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndrome (MDS), leukemia (including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), promyelocytic leukemia (APML or APL)), adrenal cancer, anal cancer, basal cell skin cancer and squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CML), leukaemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing family of 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 tumor, lymphoma (including cutaneous T-cell lymphoma), malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal cavity and paranasal sinuses cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity and oropharyngeal cancer cancer), osteosarcoma, ovarian cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary 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, Waldenstrom macroglobulinemia, and Wilms tumor.

[0078] As used herein, the phrase "infection, including viral infection" refers to, for example, viral infection (e.g., from influenza virus, human immunodeficiency virus (HIV), alphavirus (e.g., Chikungunya virus and Ross River virus), flavivirus (e.g., Dengue virus and Zika virus), herpesvirus (e.g., Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxvirus (e.g., vaccinia virus (Modified vaccinia virus Ankara) and myxoma virus), adenovirus (e.g., adenovirus 5) or papillomavirus), bacterial infection (e.g.,From Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella pertussis, Burkholderia pseudomallei, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteurella multicida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae leprae), Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibriocholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi burgdorferi), or Yersinia pestis), fungal infections (e.g.from Candida or Aspergillus species), protozoan infections (e.g., from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania, or Trypanosomes), helminthic infections (e.g., from schistosoma, roundworms, tapeworms, or flukes), and prion infections.

[0079] As used herein, the phrase "central nervous system disease" refers to, for example, Parkinson's disease, Alzheimer's disease, frontotemporal dementia, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain damage caused by pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis.

[0080] As used herein, the phrase "neuroinflammation-related disease" refers to, for example, multiple sclerosis, brain infection, acute injury, neurodegenerative disease, Parkinson's disease, or Alzheimer's disease.

[0081] As used herein, the phrase "neurodegenerative disease" refers to, for example, Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

[0082] In one embodiment, the neurodegenerative disease is characterized by profound involvement of a cell-mediated neuroinflammatory process.

[0083] As used herein, the phrase "metabolic disease" refers to, for example, type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout.

[0084] As used herein, the phrase "cardiovascular disease" refers to, for example, hypertension, ischemia-reperfusion injury (including ischemic-reperfusion injury after MI), stroke (including ischemic stroke), transient ischemic attack, myocardial infarction (including recurrent myocardial infarction), heart failure (including congestive heart failure and heart failure with preserved ejection fraction), embolism, aneurysm (including abdominal aortic aneurysm), cardiovascular risk reduction (CvRR), and pericarditis (including Dressler's syndrome).

[0085] As used herein, the phrase "respiratory disease" refers to, for example, chronic obstructive pulmonary disease (COPD), asthma (eg, allergic asthma and steroid-resistant asthma), asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis.

[0086] As used herein, the phrase "liver disease" refers to, for example, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) (including advanced fibrosis stages F3 and F4), alcoholic fatty liver disease (AFLD) and alcoholic steatohepatitis (ASH).

[0087] As used herein, the phrase "kidney disease" refers to, for example, acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy;

[0088] As used herein, the phrase "ocular disease" refers to, for example, diseases of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma.

[0089] As used herein, the phrase "skin disease" refers to, for example, dermatitis (e.g., contact dermatitis and atopic dermatitis), contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-causing skin diseases, and acne conglobate.

[0090] As used herein, the phrase "psychological illness" refers to, for example, depression and psychological stress.

[0091] As used herein, the phrase "blood disorder" refers to, for example, sickle cell disease.

[0092] As used herein, the term "administering" refers to providing a compound described herein or a pharmaceutical composition comprising the compound. The compound or composition can be administered to an individual by another person or by the individual himself. Non-limiting examples of routes of administration include oral, parenteral (e.g., intravenous), or topical.

[0093] As used herein, the term "treatment" refers to an intervention that improves the signs or symptoms of a disease or pathological condition. As used herein, the terms "treatment" and "treatment" in relation to a disease, pathological condition or symptom also refer to any observable beneficial effect of the treatment. The beneficial effect can be demonstrated by, for example, a delay in the onset of clinical symptoms of the disease in susceptible individuals, a reduction in the severity of some or all of the clinical symptoms of the disease, a slowing of disease progression, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the individual, or by other parameters specific to a particular disease as known in the art. Preventive treatment is a treatment administered to an individual who does not show signs of the disease or only shows early signs, with the goal of reducing the risk of developing a lesion. Therapeutic treatment is a treatment administered to an individual after the signs and symptoms of the disease appear.

[0094] As used herein, the term "subject" refers to an animal (e.g., a mammal, such as a human). The individual to be treated according to the methods described herein can be an individual who has been diagnosed with an NLRP3 inflammasome-dependent disorder, such as inflammation, inflammatory disease, immune disease, cancer, infection, including viral infection; central nervous system disease, metabolic disease, cardiovascular disease, respiratory disease, liver disease, kidney disease, eye disease, skin disease, psychological disease or blood disease.

[0095] Diagnosis can be performed by any method or technique known in the art. It will be appreciated by those skilled in the art that individuals to be treated according to the present disclosure may have been subjected to standard testing, or may have been identified as being at risk due to the presence of one or more risk factors associated with a disease or condition without examination. The term "patient" may be used interchangeably with the term "individual". An individual may refer to an adult individual or a child individual.

[0096] Compound

[0097] As described in detail above, the present disclosure provides compounds that exhibit significant activity as NLRP3 inflammasome antagonists (i.e., as NLRP3 inflammasome inhibitors). Accordingly, one embodiment provides a compound having structure (I):

[0098]

[0099] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0100] (1) When X is CR a R b hour;

[0101] Where R a and Rb Each independently is H or C 1-6 alkyl;

[0102] R 1 It is H, OH, CF3, C 1-6 Alkyl, C 3-5 Cycloalkyl, CN, halogen, OC 1-6 Alkyl or OCF3;

[0103] R 2 and R 5 are independently H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0104] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0105] R 8 is H or halogen;

[0106] R 9 It is H, C 3-5 Cycloalkyl or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0107] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0108] R 10 and R 13 are independently H or halogen;

[0109] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 alkyl;

[0110] n is 0, 1 or 2; or

[0111] (2) When X is NR a or O;

[0112] Where R a and R b Each independently is H or C 1-6 alkyl;

[0113] R 1 It is H, OH, CF3, C1-6 Alkyl, C 3-5 Cycloalkyl, CN, halogen, OC 1-6 Alkyl or OCF3;

[0114] R 2 and R 5 are independently H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0115] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0116] R 8 is H or halogen;

[0117] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0118] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0119] R 10 and R 13 are independently H or halogen;

[0120] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 alkyl;

[0121] n is 0, 1, or 2; and

[0122] If X is NR a or O, and R 1 is Cl, CH3, CF3, OCF3 or methyl, then R 2 and R 5 One of them is not H.

[0123] In another embodiment, a compound having the following structure (I) is provided:

[0124]

[0125] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0126] (1) When X is CR a R b hour;

[0127] Where R a and R b Each independently is H or C 1-6 alkyl;

[0128] R 1 It is H, OH, CF3, C 1-6 Alkyl, C 3-5 Cycloalkyl, CN, halogen, OC 1-6 Alkyl or OCF3;

[0129] R 2 and R 5 are independently H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0130] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0131] R 8 is H or halogen;

[0132] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0133] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0134] R 10 and R 13 are independently H or halogen;

[0135] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 alkyl;

[0136] n is 0, 1 or 2; or

[0137] (2) When X is NR a or O;

[0138] Where Ra and R b Each independently is H or C 1-6 Alkyl;

[0139] (A)R 1 It is H, OH, C 2-6 Alkyl, C 3-5 Cycloalkyl, CN, F, Br or OC 1-6 alkyl;

[0140] R 2 and R 5 are independently H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0141] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0142] R 8 is H or halogen;

[0143] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0144] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0145] R 10 and R 13 are independently H or halogen;

[0146] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 Alkyl; and

[0147] n is 0, 1 or 2; or

[0148] (B)R 1 is CF3, methyl, Cl or OCF3;

[0149] R 2 and R 5 One of them is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6alkyl, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0150] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0151] R 8 is H or halogen;

[0152] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0153] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0154] R 10 and R 13 are independently H or halogen;

[0155] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 Alkyl; and

[0156] n is 0, 1 or 2.

[0157] In one embodiment, a compound having the following structure (I') is provided:

[0158]

[0159] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0160] X is CR a R b NR a or O;

[0161] Where R a and R b Each independently is H or C 1-6 alkyl;

[0162] R 1 It is H, OH, C 2-6 Alkyl, C 3-5Cycloalkyl, CN, F, Br or OC 1-6 alkyl;

[0163] R 2 and R 5 Each independently is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0164] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0165] R 8 is H or halogen;

[0166] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0167] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0168] R 10 and R 13 are independently H or halogen;

[0169] R 11 and R 12 are independently H, halogen, CF3, 1-6 Alkyl, CN or OC 1-6 Alkyl; and

[0170] n is 0, 1 or 2.

[0171] In one embodiment, a compound having the following structure (I") is provided:

[0172]

[0173] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0174] X is CR a R b , R a or O;

[0175] Where R a and R b Each independently is H or C 1-6alkyl;

[0176] R 1 It is H, F, CN, C 2-6 Alkyl or C 3-5 Cycloalkyl;

[0177] R 2 and R 5 Each independently is H or C 1-6 alkyl;

[0178] R 3 or R 4 One of them is OH, and the other is H, OH or C 1-6 alkyl;

[0179] R 11 and R 12 are independently H, F or C 1-6 Alkyl; and

[0180] n is 0, 1 or 2.

[0181] In one embodiment, a compound having the following structure (Ia) is provided:

[0182]

[0183] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0184] R a Is H or C 1-6 alkyl; and wherein

[0185] (A)R 1 It is H, OH, C 2-6 Alkyl, C 3-5 Cycloalkyl, CN, F, Br or OC 1-6 alkyl;

[0186] R 2 and R 5 are independently H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0187] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0188] R 8 is H or halogen;

[0189] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0190] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0191] R 10 and R 13 are independently H or halogen;

[0192] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 Alkyl; and

[0193] n is 0, 1 or 2; or

[0194] (B)R 1 is CF3, methyl, Cl or OCF3;

[0195] R 2 and R 5 One of them is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0196] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0197] R 8 is H or halogen;

[0198] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0199] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0200] R 10 and R 13 are independently H or halogen;

[0201] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 Alkyl; and

[0202] n is 0, 1 or 2.

[0203] In one embodiment, a compound having the following structure (Ia) is provided:

[0204]

[0205] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0206] R a Is H or C 1-6 alkyl;

[0207] R 1 It is H, OH, C 2-6 Alkyl, C 3-5 Cycloalkyl, CN, F, Br or OC 1-6 alkyl;

[0208] R 2 and R 5 are independently H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0209] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0210] R 8 is H or halogen;

[0211] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0212] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0213] R 10 and R 13 are independently H or halogen;

[0214] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 Alkyl; and

[0215] n is 0, 1 or 2.

[0216] In one embodiment, a compound having the following structure (Ia') is provided:

[0217]

[0218] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0219] R a Is H or C 1-6 alkyl;

[0220] R 1 It is H, F, CN, C 2-6 Alkyl or C 3-5 Cycloalkyl;

[0221] R 2 and R 5 Each independently is H or C 1-6 alkyl;

[0222] R 3 or R 4 One of them is OH, and the other is H, OH or C 1-6 alkyl;

[0223] R 11 and R 12 are independently H, F or C 1-6 Alkyl; and

[0224] n is 0, 1 or 2.

[0225] In one embodiment, a compound having the following structure (Ib) is provided:

[0226]

[0227] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0228] (A)R 1 It is H, OH, C 2-6 Alkyl, C 3-5 Cycloalkyl, CN, F, Br or OC 1-6 alkyl;

[0229] R 2 and R 5 are independently H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0230] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0231] R 8 is H or halogen;

[0232] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0233] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0234] R 10 and R 13 are independently H or halogen;

[0235] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 Alkyl; and

[0236] n is 0, 1 or 2; or

[0237] (B)R 1 is CF3, methyl, Cl or OCF3;

[0238] R 2 and R 5 One of them is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0239] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6alkyl;

[0240] R 8 is H or halogen;

[0241] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0242] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0243] R 10 and R 13 are independently H or halogen;

[0244] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 Alkyl; and

[0245] n is 0, 1 or 2.

[0246] In one embodiment, a compound having the following structure (Ib) is provided:

[0247]

[0248] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0249] R 1 It is H, OH, C 2-6 Alkyl, C 3-5 Cycloalkyl, CN, F, Br or OC 1-6 alkyl;

[0250] R 2 and R 5 are independently H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0251] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0252] R 8 is H or halogen;

[0253] R9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0254] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0255] R 10 and R 13 are independently H or halogen;

[0256] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 Alkyl; and

[0257] n is 0, 1 or 2.

[0258] In one embodiment, a compound having the following structure (Ib') is provided:

[0259]

[0260] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0261] R 1 It is H, F, C 2-6 Alkyl or C 3-5 Cycloalkyl;

[0262] R 2 and R 5 Each independently is H or C 1-6 alkyl;

[0263] R 3 or R 4 One of them is OH, and the other is H, OH or C 1-6 alkyl;

[0264] R 11 and R 12 Each independently is H or C 1-6 Alkyl; and

[0265] n is 0, 1 or 2.

[0266] In one embodiment, a compound having the following structure (Ic) is provided:

[0267]

[0268] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0269] R a and R b Each independently is H or C 1-6 alkyl;

[0270] R 1 It is H, OH, CF3, C 1-6 Alkyl, C 3-5 Cycloalkyl, CN, halogen, OC 1-6 Alkyl or OCF3;

[0271] R 2 and R 5 are independently H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0272] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0273] R 8 is H or halogen;

[0274] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0275] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0276] R 10 and R 13 are independently H or halogen;

[0277] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 Alkyl; and

[0278] n is 0, 1 or 2.

[0279] In one embodiment, a compound having the following structure (Ic) is provided:

[0280]

[0281] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0282] R a and R b Each independently is H or C 1-6 alkyl;

[0283] R 1 It is H, OH, C 2-6 Alkyl, C 3-5 Cycloalkyl, CN, F, Br or OC 1-6 alkyl;

[0284] R 2 and R 5 are independently H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0285] R 3 or R 4 One of them is OH, and the other is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl;

[0286] R 8 is H or halogen;

[0287] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0288] R 9’ is OH, F or C 3-5 Cycloalkyl;

[0289] R 10 and R 13 are independently H or halogen;

[0290] R 11 and R 12 are independently H, halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 Alkyl; and

[0291] n is 0, 1 or 2.

[0292] In one embodiment, a compound having the following structure (Ic') is provided:

[0293]

[0294] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0295] R a and R b Each independently is H or C 1-6 alkyl;

[0296] R 1 It is H, F, C 2-6 Alkyl or C 3-5 Cycloalkyl;

[0297] R 2 and R 5 Each independently is H or C 1-6 alkyl;

[0298] R 3 or R 4 One of them is OH, and the other is H, OH or C 1-6 alkyl;

[0299] R 11 and R 12 Each independently is H or C 1-6 Alkyl; and

[0300] n is 0, 1 or 2.

[0301] In more specific embodiments of each of Structures (I), (I'), (I"), (Ia), (Ia'), (Ib), (Ib'), (Ic) and (Ic'), such structures include the following more specific embodiments, where appropriate.

[0302] In one embodiment, X is CR a R b .

[0303] In another embodiment, X is NR a .

[0304] In yet another embodiment, X is O.

[0305] In one embodiment, R 11 and R 12 Not H.

[0306] In some embodiments, R 11 Halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 Alkyl, and R 12 It's H.

[0307] In other embodiments, R 11is H, and R 12 Halogen, CF3, C 1-6 Alkyl, CN or OC 1-6 alkyl.

[0308] In yet another embodiment, R 11 and R 12 All are H.

[0309] In some embodiments, R 11 and R 12 None of them is H.

[0310] In one embodiment, R 1 It's H.

[0311] In another embodiment, R 1 It's OH.

[0312] In other embodiments, R 1 It's CF3.

[0313] In yet another embodiment, R 1 It's F.

[0314] In one embodiment, R 1 It is Cl.

[0315] In another embodiment, R 1 It's Br.

[0316] In another embodiment, R 1 It's I.

[0317] In some embodiments, R 1 It's OCF3.

[0318] In one embodiment, R 1 It is CN.

[0319] In some embodiments, R 1 It is C 1-6 alkyl.

[0320] In certain embodiments, R 1 It's methyl.

[0321] In other embodiments, R 1 It is C 2-6 alkyl.

[0322] In certain embodiments, R 1 It is ethyl.

[0323] In certain embodiments, R 1 It is isopropyl.

[0324] In one embodiment, R 1 It's OC 1-6 alkyl.

[0325] In certain embodiments, R 1 It is OCH3.

[0326] In one embodiment, R 1 It is C 3-5 Cycloalkyl.

[0327] In certain embodiments, R 1 It is cyclopropyl.

[0328] In certain embodiments, R 1 It is cyclobutyl.

[0329] In one embodiment, R 2 and R 5 Independently H, C 1-6 Alkyl, F, Cl, CF3 or CN.

[0330] In another embodiment, R 2 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 Alkyl, and R 5 It's H.

[0331] In some embodiments, R 2 is H, and R 5 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl.

[0332] In one embodiment, R 2 It's H.

[0333] In another embodiment, R 2 It's OH.

[0334] In some embodiments, R 2 It's CF3.

[0335] In other embodiments, R 2 It is C 1-6 alkyl.

[0336] In certain embodiments, R 2 It's methyl.

[0337] In other embodiments, R 2 It is ethyl.

[0338] In yet another embodiment, R2 It is isopropyl.

[0339] In another embodiment, R 2 It is CN.

[0340] In some embodiments, R 2 It's F.

[0341] In yet another embodiment, R 2 It is Cl.

[0342] In some embodiments, R 2 It's Br.

[0343] In another embodiment, R 2 It's I.

[0344] In one embodiment, R 2 It's OCF3.

[0345] In yet another embodiment, R 2 It's OC 1-6 alkyl.

[0346] In one embodiment, R 2 It is OCH3.

[0347] In some embodiments, R 5 It's H.

[0348] In one embodiment, R 5 It's OH.

[0349] In some embodiments, R 5 It's CF3.

[0350] In other embodiments, R 5 It is C 1-6 alkyl.

[0351] In yet another embodiment, R 5 It's methyl.

[0352] In certain embodiments, R 5 It is ethyl.

[0353] In other embodiments, R 5 It is isopropyl.

[0354] In yet another embodiment, R 5 It is CN.

[0355] In one embodiment, R 5 It's F.

[0356] In some embodiments, R5 It is Cl.

[0357] In another embodiment, R 5 It is Cl.

[0358] In other embodiments, R 5 It's Br.

[0359] In another embodiment, R 5 It's I.

[0360] In one embodiment, R 5 It's OCF3.

[0361] In yet another embodiment, R 5 It's OC 1-6 alkyl.

[0362] In one embodiment, R 5 It is OCH3.

[0363] In some embodiments, R 3 is OH, and R 4 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl.

[0364] In other embodiments, R 4 is OH, and R 3 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl.

[0365] In one embodiment, R 3 is OH, and R 4 Is H or C 1-6 alkyl.

[0366] In another embodiment, R 4 is OH, and R 3 Is H or C 1-6 alkyl.

[0367] In one embodiment, R 3 It's OH.

[0368] In other embodiments, R 3 It's H.

[0369] In another embodiment, R 3 It's CF3.

[0370] In some embodiments, R 3 It is C1-6 alkyl.

[0371] In other embodiments, R 3 It's methyl.

[0372] In certain embodiments, R 3 It is ethyl.

[0373] In some embodiments, R 3 It is isopropyl.

[0374] In other embodiments, R 3 It is CN.

[0375] In yet another embodiment, R 3 It's F.

[0376] In one embodiment, R 3 It is Cl.

[0377] In some embodiments, R 3 It's Br.

[0378] In another embodiment, R 3 It's I.

[0379] In another embodiment, R 3 It's OCF3.

[0380] In yet another embodiment, R 3 It's OC 1-6 alkyl.

[0381] In one embodiment, R 3 It is OCH3.

[0382] In some embodiments, R 4 It's OH.

[0383] In one embodiment, R 4 It's H.

[0384] In another embodiment, R 4 It's CF3.

[0385] In yet another embodiment, R 4 It is C 1-6 alkyl.

[0386] In some embodiments, R 4 It's methyl.

[0387] In other embodiments, R 4 It is ethyl.

[0388] In some embodiments, R4 It is isopropyl.

[0389] In one embodiment, R 4 It is CN.

[0390] In another embodiment, R 4 It's F.

[0391] In yet another embodiment, R 4 It is Cl.

[0392] In yet another embodiment, R 4 It's Br.

[0393] In another embodiment, R 4 It's I.

[0394] In another embodiment, R 4 It's OCF3.

[0395] In yet another embodiment, R 4 It's OC 1-6 alkyl.

[0396] In some embodiments, R 4 It is OCH3.

[0397] In one embodiment, R 8 It's H.

[0398] In another embodiment, R 8 It's F.

[0399] In yet another embodiment, R 8 It is Cl.

[0400] In another embodiment, R 8 It's Br.

[0401] In another embodiment, R 8 It's I.

[0402] In some embodiments, R 9 It's H.

[0403] In one embodiment, R 9 Not H.

[0404] In another embodiment, R 9 It is C 1-6 alkyl.

[0405] In some embodiments, R 9 It's methyl.

[0406] In other embodiments, R9 It is ethyl.

[0407] In yet another embodiment, R 9 It is isopropyl.

[0408] In one embodiment, R 9 is C optionally substituted with one or more F 1-6 alkyl.

[0409] In certain embodiments, R 9 It is -CH2CH2F.

[0410] In yet another embodiment, R 9 It is -CH2CHF2.

[0411] In some embodiments, R 9 It is -CH2CF3.

[0412] In one embodiment, R 9 It is C 3-5 Cycloalkyl.

[0413] In certain embodiments, R 9 It is cyclopropyl.

[0414] In one embodiment, R 9 is optionally replaced by one or more C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0415] In certain embodiments, R 9 yes

[0416] In some embodiments, R 9 is C optionally substituted by one or more OH 1-6 alkyl.

[0417] In other embodiments, R 9 yes

[0418] In another embodiment, R 10 and R 13 All are H.

[0419] In one embodiment, R 10 and R 13 All are halogens.

[0420] In certain embodiments, R 10 and R 13 All are F.

[0421] In another embodiment, R10 is H, and R 13 It's a halogen.

[0422] In yet another embodiment, R 10 is H, and R 13 It's F.

[0423] In one embodiment, R 10 It's H.

[0424] In another embodiment, R 10 It's F.

[0425] In certain embodiments, R 10 It is Cl.

[0426] In other embodiments, R 10 It's Br.

[0427] In another embodiment, R 10 It's I.

[0428] In one embodiment, R 13 It's H.

[0429] In some embodiments, R 13 It's F.

[0430] In other embodiments, R 13 It is Cl.

[0431] In yet another embodiment, R 13 It's Br.

[0432] In another embodiment, R 13 It's I.

[0433] In some embodiments, n is 0.

[0434] In other embodiments, n is 1.

[0435] In other embodiments, n is 2.

[0436] In one embodiment, the compound is selected from a compound listed in Table 1, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0437] Table 1

[0438] Representative compounds having structure (I)

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451] In one embodiment, a compound having structure (I'") is provided:

[0452]

[0453] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0454] X is CR a R b NR a or O;

[0455] R a and R b Each independently is H or C 1-6 alkyl;

[0456] R 1 is H, F or CN;

[0457] R 2 and R 5 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0458] R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0459] R 8 is H or halogen;

[0460] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0461] R 9’ is OH, halogen or C 3-5 Cycloalkyl;

[0462] R 10 and R 13 are each independently H or halogen;

[0463] R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl;

[0464] R 16 is H or CO2H; and

[0465] n is 0, 1 or 2.

[0466] In another embodiment, provided is a compound having structure (Ia'"):

[0467]

[0468] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0469] R a Is H or C 1-6 alkyl;

[0470] R 1 is H, F or CN;

[0471] R 2 and R 5 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0472] R 3 or R 4One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0473] R 8 is H or halogen;

[0474] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0475] R 9’ is OH, halogen or C 3-5 Cycloalkyl;

[0476] R 10 and R 13 are each independently H or halogen;

[0477] R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl;

[0478] R 16 is H or CO2H; and

[0479] n is 0, 1 or 2.

[0480] In another embodiment, a compound having structure (Ia-1'") is provided:

[0481]

[0482] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0483] R a Is H or C 1-6 alkyl;

[0484] R 1 is H, F or CN;

[0485] R 2 and R 5 Each independently is H or C 1-6 alkyl;

[0486] R 3 or R 4One of them is OH and the other is H or C 1-6 alkyl;

[0487] R 11 and R 12 are independently H, F or C 1-6 Alkyl; and

[0488] n is 0, 1 or 2.

[0489] In another embodiment, provided is a compound having structure (Ib'"):

[0490]

[0491] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0492] R 1 is H, F or CN;

[0493] R 2 and R 5 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0494] R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0495] R 8 is H or halogen;

[0496] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0497] R 9’ is OH, halogen or C 3-5 Cycloalkyl;

[0498] R 10 and R 13 are each independently H or halogen;

[0499] R 11 and R 12are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl;

[0500] R 16 is H or CO2H; and

[0501] n is 0, 1 or 2.

[0502] In another embodiment, a compound having structure (Ib-1'") is provided:

[0503]

[0504] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0505] R 1 is H, F or CN;

[0506] R 2 and R 5 Each independently is H or C 1-6 alkyl;

[0507] R 3 or R 4 One of them is OH and the other is H or C 1-6 alkyl;

[0508] R 11 and R 12 Each independently is H or C 1-6 Alkyl; and

[0509] n is 0, 1 or 2.

[0510] In another embodiment, provided is a compound having structure (Ic'"):

[0511]

[0512] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0513] R a and R b Each independently is H or C 1-6 alkyl;

[0514] R 1 is H, F or CN;

[0515] R 2 and R 5 are independently H, halogen, OH, CN, C1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0516] R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0517] R 8 is H or halogen;

[0518] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0519] R 9’ is OH, halogen or C 3-5 Cycloalkyl;

[0520] R 10 and R 13 are each independently H or halogen;

[0521] R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl;

[0522] R 16 is H or CO2H; and

[0523] n is 0, 1 or 2.

[0524] In another embodiment, a compound having structure (Ic-1'") is provided:

[0525]

[0526] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0527] R a and R b Each independently is H or C 1-6 alkyl;

[0528] R 1 is H, F or CN;

[0529] R 2 and R 5 Each independently is H or C 1-6 alkyl;

[0530] R 3 or R 4 One of them is OH and the other is H or C 1-6 alkyl;

[0531] R 11 and R 12 Each independently is H or C 1-6 Alkyl; and

[0532] n is 0, 1 or 2.

[0533] In more specific embodiments of each of structures (I"'), (Ia"'), (Ia-1"'), (Ib"'), (Ib-1"'), (Ic"') and (Ic-1"'), when appropriate, such structures include the following more specific embodiments.

[0534] In one embodiment, X is CR a R b In another embodiment, X is NR a In yet another embodiment, X is O.

[0535] In one embodiment, R 11 and R 12 In another embodiment, one of R 11 It is C 1-6 Alkyl and R 12 is H. In another embodiment, R 11 is H and R 12 It is C 1-6 In another embodiment, R 11 and R 12 are H. In another embodiment, R 11 and R 12 In some embodiments, R 11 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl, and R 12 is H. In some embodiments, R 11 is H, F, CN, methyl, CF3 or OCH3, and R 12 is H. In other embodiments, R 11 is H, and R 12H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 In other embodiments, R 11 is H, and R 12 is H, F, CN, methyl, CF3 or OCH3.

[0536] In one embodiment, wherein R 1 is H. In another embodiment, wherein R 1 is F. In another embodiment, R 1 It is CN.

[0537] In one embodiment, R 2 and R 5 Each independently is H, C 1-6 In another embodiment, R 2 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 Alkyl, and R 5 is H. In another embodiment, R 2 is H and R 5 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl.

[0538] In one embodiment, R 2 is H. In another embodiment, R 2 is OH. In another embodiment, R 2 It is C 1-6 In some embodiments, R 2 is CF3. In another embodiment, R 2 It is C 1-6 In a specific embodiment, R 2 In another embodiment, R 2 In another embodiment, R 2 In yet another embodiment, R 2 In one embodiment, R 2 In another embodiment, R 2 is F. In another embodiment, R 2 In another embodiment, R 2 is Br. In another embodiment, R 2 It's OC 1-6In some embodiments, R 2 is OCF3. In another embodiment, R 2 It's OC 1-6 In a specific embodiment, R 2 It is OCH3.

[0539] In one embodiment, R 5 is H. In another embodiment, R 5 In another embodiment, R 5 It is C 1-6 In another embodiment, R 5 In another embodiment, R 5 It is C 1-6 In another embodiment, R 5 In another embodiment, R 5 In another embodiment, R 5 In another embodiment, R 5 In one embodiment, R 5 In another embodiment, R 5 is F. In another embodiment, R 5 In another embodiment, R 5 is Br. In another embodiment, R 5 It's OC 1-6 In another embodiment, R 5 is OCF3. In another embodiment, R 5 It's OC 1-6 In another embodiment, R 5 It is OCH3.

[0540] In one embodiment, R 3 is OH, and R 4 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 In another embodiment, R 4 is OH, and R 3 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 In yet another embodiment, R 3 is OH, and R 4 Is H or C 1-6 In another embodiment, R 4 is OH, and R3 Is H or C 1-6 alkyl.

[0541] In some embodiments, R 3 In another embodiment, R 3 is H. In another embodiment, R 3 It is C 1-6 In one embodiment, R 3 In another embodiment, R 3 It is C 1-6 In a specific embodiment, R 3 In another embodiment, R 3 In certain embodiments, R 3 In another embodiment, R 3 In one embodiment, R 3 is halogen. In some embodiments, R 3 is F. In another embodiment, R 3 In one embodiment, R 3 is Br. In another embodiment, R 3 It's OC 1-6 In another embodiment, R 3 is OCF3. In some embodiments, R 3 It's OC 1-6 In certain embodiments, R 3 It is OCH3.

[0542] In one embodiment, R 4 In another embodiment, R 4 is H. In another embodiment, R 4 It is C 1-6 In yet another embodiment, R 4 In another embodiment, R 4 It is C 1-6 In certain embodiments, R 4 In another embodiment, R 4 In certain embodiments, R 4 In another embodiment, R 4 In one embodiment, R 4 In yet another embodiment, R 4 is F. In another embodiment, R 4 In another embodiment, R4 is Br. In another embodiment, R 4 is 1. In another embodiment, R 4 It's OC 1-6 In another embodiment, R 4 is OCF3. In other embodiments, R 4 It's OC 1-6 In certain embodiments, R 4 It is OCH3.

[0543] In one embodiment, R 8 is H. In another embodiment, R 8 is F. In another embodiment, R 8 In yet another embodiment, R 8 is Br. In yet another embodiment, R 8 It's I.

[0544] In one embodiment, R 9 is H. In another embodiment, R 9 is not H. In some embodiments, R 9 It is C 1-6 In a specific embodiment, R 9 In some embodiments, R 9 In certain embodiments, R 9 In some embodiments, R 9 is C optionally substituted with one or more F 1-6 In another embodiment, R 9 is -CH2CH2F. In certain embodiments, R 9 is -CH2CHF2. In another embodiment, R 9 is -CH2CF3. In one embodiment, R 9 It is C 3-5 In a specific embodiment, R 9 In another embodiment, R 9 is optionally replaced by one or more C 3-5 Cycloalkyl substituted C 1-6 In certain embodiments, R 9 yes In another embodiment, R 9 is C optionally substituted by one or more OH 1-6 In some embodiments, R 9 yes

[0545] In one embodiment, R 9’ In one embodiment, R 9’ In yet another embodiment, R 9’ is F. In another embodiment, R 9’ In another embodiment, R 9’ is Br. In another embodiment, R 9’ is I. In one embodiment, R 9’ It is C 3-5 In a specific embodiment, R 9’ It is cyclopropyl.

[0546] In one embodiment, R 10 and R 13 are H. In another embodiment, R 10 and R 13 In yet another embodiment, R 10 is H, and R 13 is halogen. In other embodiments, R 13 is H, and R 10 It's a halogen.

[0547] In one embodiment, R 10 is H. In one embodiment, R 10 is F. In another embodiment, R 10 In yet another embodiment, R 10 It's Br.

[0548] In one embodiment, R 13 is H. In one embodiment, R 13 is F. In another embodiment, R 13 In yet another embodiment, R 13 It's Br.

[0549] In one embodiment, R 16 is H. In another embodiment, R 16 It is CO2H.

[0550] In one embodiment, Ra is H. In another embodiment, Ra is C 1-6 In certain embodiments, Ra is methyl.

[0551] In one embodiment, Rb is H. In another embodiment, Rb is C 1-6 In certain embodiments, Rb is methyl.

[0552] In one embodiment, n is 0-2. In one embodiment, n is 0 or 1. In other embodiments, n is 1 or 2. In yet another embodiment, n is 0 or 2. In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2.

[0553] In one embodiment, the compound is selected from a compound listed in Table 2, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0554] Table 2

[0555] Representative compounds having structure (I''):

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563] In another embodiment, a compound having structure (II) is provided:

[0564]

[0565] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0566] R a Is H or C 1-6 alkyl;

[0567] Each R 15 are independently halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl or C 3-5 Cycloalkyl;

[0568] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0569] R 9’ is OH, halogen or C 3-5 Cycloalkyl;

[0570] Each R 17 are independently halogen or CO2H;

[0571] R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, or OC 1-6 Alkyl; and

[0572] n is 0-2;

[0573] m is 0-3; and

[0574] p is 0-9.

[0575] In more specific embodiments of structure (II), such structures include the following more specific embodiments, where applicable.

[0576] In one embodiment, R 11 and R 12 In another embodiment, one of R 11 It is C 1-6 Alkyl, and R 12 is H. In another embodiment, R 11 is H, and R 12 It is C 1-6 In another embodiment, R 11 and R 12 are H. In another embodiment, R 11 and R 12 In some embodiments, R 11 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl, and R 12 is H. In some embodiments, R 11 is H, F, CN, methyl, CF3 or OCH3, and R 12 is H. In other embodiments, R 11 is H, and R 12 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 In other embodiments, R 11 is H, and R 12is H, F, CN, methyl, CF3 or OCH3.

[0577] In one embodiment, R 11 is H. In another embodiment, R 11 In certain embodiments, R 11 is F. In other embodiments, R 11 is Cl. In certain embodiments, R 11 is Br. In a specific embodiment, R 11 is 1. In some embodiments, R 11 It is C 1-6 In one embodiment, R 11 In other embodiments, R 11 In another embodiment, R 11 In another embodiment, R 11 In another embodiment, R 11 In other embodiments, R 11 In another embodiment, R 11 In some embodiments, R 11 In some embodiments, R 11 is CN. In some embodiments, R 11 It is C 1-6 In certain embodiments, R 11 is CF3. In some embodiments, R 11 It's OC 1-6 In certain embodiments, R 11 It is OCH3.

[0578] In one embodiment, R 12 is H. In another embodiment, R 12 In certain embodiments, R 12 is F. In other embodiments, R 12 is Cl. In certain embodiments, R 12 is Br. In certain embodiments, R 12 is 1. In some embodiments, R 12 It is C 1-6 In one embodiment, R 12 In other embodiments, R 12 In another embodiment, R 12 In another embodiment, R 12 In another embodiment, R 12In other embodiments, R 12 In another embodiment, R 12 In some embodiments, R 12 In some embodiments, R 12 is CN. In some embodiments, R 12 It is C 1-6 In certain embodiments, R 12 is CF3. In some embodiments, R 12 It's OC 1-6 In certain embodiments, R 12 It is OCH3.

[0579] In one embodiment, R 15 is CN, halogen, or C 1-6 In one embodiment, R 15 is CN, F, or CF3. In one embodiment, R 15 In certain embodiments, R 15 is F. In other embodiments, R 15 is Cl. In certain embodiments, R 15 is Br. In a specific embodiment, R 15 is 1. In some embodiments, R 15 is CN. In other embodiments, R 15 is OH. In some embodiments, R 15 It is C 1-6 In one embodiment, R 15 In other embodiments, R 15 In another embodiment, R 15 In another embodiment, R 15 In another embodiment, R 15 In other embodiments, R 15 In another embodiment, R 15 In some embodiments, R 15 In some embodiments, R 15 It is C 1-6 In certain embodiments, R 15 is CF3. In some embodiments, R 15 It's OC 1-6 In certain embodiments, R 15 is OCH3. In some embodiments, R 15 It's OC 1-6In certain embodiments, R 15 is OCF3. In some embodiments, R 15 It is C 3-5 In certain embodiments, R 15 It is cyclopropyl.

[0580] In one embodiment, R 9 is H. In another embodiment, R 9 is not H. In some embodiments, R 9 It is C 1-6 In a specific embodiment, R 9 In some embodiments, R 9 In certain embodiments, R 9 In some embodiments, R 9 is C optionally substituted with one or more F 1-6 In another embodiment, R 9 is -CH2CH2F. In certain embodiments, R 9 is -CH2CHF2. In another embodiment, R 9 is -CH2CF3. In one embodiment, R 9 It is C 3-5 In a specific embodiment, R 9 In another embodiment, R 9 is optionally replaced by one or more C 3-5 Cycloalkyl substituted C 1-6 In certain embodiments, R 9 yes In another embodiment, R 9 is C optionally substituted by one or more OH 1-6 In some embodiments, R 9 yes

[0581] In one embodiment, R 9’ In one embodiment, R 9’ In yet another embodiment, R 9’ is F. In another embodiment, R 9’ In another embodiment, R 9’ is Br. In another embodiment, R 9’ is I. In one embodiment, R 9’ It is C 3-5 In a specific embodiment, R 9’ It is cyclopropyl.

[0582] In one embodiment, R 17 In certain embodiments, R 17 is F. In other embodiments, R 17 is Cl. In certain embodiments, R 17 is Br. In a specific embodiment, R 17 is 1. In some embodiments, R 17 It is CO2H.

[0583] In one embodiment, Ra is H. In another embodiment, Ra is C 1-6 In certain embodiments, Ra is methyl.

[0584] In one embodiment, n is 0-2. In one embodiment, n is 0 or 1. In other embodiments, n is 1 or 2. In yet another embodiment, n is 0 or 2. In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2.

[0585] In one embodiment, m is 0-3. In one embodiment, m is 0 or 1. In other embodiments, m is 1 or 2. In yet another embodiment, 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.

[0586] In one embodiment, p is 0-9. In one embodiment, p is 0-3. In one embodiment, p is 0 or 1. In other embodiments, p is 1 or 2. In yet another embodiment, 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.

[0587] In one embodiment, the compound is selected from a compound listed in Table 3, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0588] Table 3 Representative compounds with structure (II)

[0589]

[0590] In another embodiment, a compound having structure (III) is provided:

[0591]

[0592] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0593] R 1 H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl or C 3-5 Cycloalkyl;

[0594] R 2 and R 5 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0595] R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0596] R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl;

[0597] R 18 Each is a halogen, CO2H, amine, C 3-5 Cycloalkyl, or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more R 9’ replace;

[0598] R 9’ is OH, halogen or C 3-5 Cycloalkyl;

[0599] n is 1 or 2; and

[0600] p is 1-9.

[0601] In more specific embodiments of structure (III), such structures include the following more specific embodiments, where appropriate.

[0602] In one embodiment, R 11 and R 12In another embodiment, one of R 11 It is C 1-6 Alkyl, and R 12 is H. In another embodiment, R 11 is H, and R 12 It is C 1-6 In another embodiment, R 11 and R 12 are H. In another embodiment, R 11 and R 12 In some embodiments, R 11 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl, and R 12 is H. In some embodiments, R 11 is H, F, CN, methyl, CF3 or OCH3, and R 12 is H. In other embodiments, R 11 is H, and R 12 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 In other embodiments, R 11 is H, and R 12 is H, F, CN, methyl, CF3 or OCH3.

[0603] In one embodiment, R 11 is H. In another embodiment, R 11 In certain embodiments, R 11 is F. In other embodiments, R 11 is Cl. In certain embodiments, R 11 is Br. In a specific embodiment, R 11 is 1. In some embodiments, R 11 It is C 1-6 In one embodiment, R 11 In other embodiments, R 11 In another embodiment, R 11 In another embodiment, R 11 In another embodiment, R 11 In other embodiments, R 11 In another embodiment, R 11 In some embodiments, R 11In some embodiments, R 11 is CN. In some embodiments, R 11 It is C 1-6 In certain embodiments, R 11 is CF3. In some embodiments, R 11 It's OC 1-6 In certain embodiments, R 11 It is OCH3.

[0604] In one embodiment, R 12 is H. In another embodiment, R 12 In certain embodiments, R 12 is F. In other embodiments, R 12 is Cl. In certain embodiments, R 12 is Br. In certain embodiments, R 12 is 1. In some embodiments, R 12 It is C 1-6 In one embodiment, R 12 In other embodiments, R 12 In another embodiment, R 12 In another embodiment, R 12 In another embodiment, R 12 In other embodiments, R 12 In another embodiment, R 12 In some embodiments, R 12 In some embodiments, R 12 is CN. In some embodiments, R 12 It is C 1-6 In certain embodiments, R 12 is CF3. In some embodiments, R 12 It's OC 1-6 In certain embodiments, R 12 It is OCH3.

[0605] In one embodiment, R 1 is H or CN. In one embodiment, R 1 is H. In one embodiment, R 1 In certain embodiments, R 1 is F. In other embodiments, R 1 is Cl. In certain embodiments, R 1 is Br. In a specific embodiment, R1 is 1. In some embodiments, R 1 is CN. In other embodiments, R 1 is OH. In some embodiments, R 1 It is C 1-6 In one embodiment, R 1 In other embodiments, R 1 In another embodiment, R 1 In another embodiment, R 1 In another embodiment, R 1 In other embodiments, R 1 In another embodiment, R 1 In some embodiments, R 1 In some embodiments, R 1 It is C 1-6 In certain embodiments, R 1 is CF3. In some embodiments, R 1 It's OC 1-6 In certain embodiments, R 1 is OCH3. In some embodiments, R 1 It's OC 1-6 In certain embodiments, R 1 is OCF3. In some embodiments, R 1 It is C 3-5 In certain embodiments, R 1 It is cyclopropyl.

[0606] In one embodiment, R 2 and R 5 Each independently is H, C 1-6 In another embodiment, R 2 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 Alkyl, and R 5 is H. In another embodiment, R 2 is H, and R 5 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl.

[0607] In one embodiment, R 2 is H. In another embodiment, R 2is OH. In another embodiment, R 2 It is C 1-6 In some embodiments, R 2 is CF3. In another embodiment, R 2 It is C 1-6 In a specific embodiment, R 2 In another embodiment, R 2 In another embodiment, R 2 In yet another embodiment, R 2 In one embodiment, R 2 In another embodiment, R 2 is F. In another embodiment, R 2 In another embodiment, R 2 is Br. In another embodiment, R 2 It's OC 1-6 In some embodiments, R 2 is OCF3. In another embodiment, R 2 It's OC 1-6 In a specific embodiment, R 2 It is OCH3.

[0608] In one embodiment, R 5 is H. In another embodiment, R 5 In another embodiment, R 5 It is C 1-6 In another embodiment, R 5 In another embodiment, R 5 It is C 1-6 In another embodiment, R 5 In another embodiment, R 5 In another embodiment, R 5 In another embodiment, R 5 In one embodiment, R 5 In another embodiment, R 5 is F. In another embodiment, R 5 In another embodiment, R 5 is Br. In another embodiment, R 5 It's OC 1-6 In another embodiment, R 5 is OCF3. In another embodiment, R5 It's OC 1-6 In another embodiment, R 5 It is OCH3.

[0609] In one embodiment, R 3 is OH, and R 4 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 In another embodiment, R 4 is OH, and R 3 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 In yet another embodiment, R 3 is OH, and R 4 Is H or C 1-6 In another embodiment, R 4 is OH, and R 3 Is H or C 1-6 alkyl.

[0610] In some embodiments, R 3 In another embodiment, R 3 is H. In another embodiment, R 3 It is C 1-6 In one embodiment, R 3 In another embodiment, R 3 It is C 1-6 In a specific embodiment, R 3 In another embodiment, R 3 In certain embodiments, R 3 In another embodiment, R 3 In one embodiment, R 3 is halogen. In some embodiments, R 3 is F. In another embodiment, R 3 In one embodiment, R 3 is Br. In another embodiment, R 3 It's OC 1-6 In another embodiment, R 3 is OCF3. In some embodiments, R 3 It's OC 1-6 In certain embodiments, R 3 It is OCH3.

[0611] In one embodiment, R 4 In another embodiment, R 4 is H. In another embodiment, R 4 It is C 1-6 In yet another embodiment, R 4 In another embodiment, R 4 It is C 1-6 In certain embodiments, R 4 In another embodiment, R 4 In certain embodiments, R 4 In another embodiment, R 4 In one embodiment, R 4 In yet another embodiment, R 4 is F. In another embodiment, R 4 In another embodiment, R 4 is Br. In another embodiment, R 4 It's OC 1-6 In another embodiment, R 4 is OCF3. In other embodiments, R 4 It's OC 1-6 In certain embodiments, R 4 It is OCH3.

[0612] In one embodiment, R 18 In certain embodiments, R 18 is F. In other embodiments, R 18 is Cl. In certain embodiments, R 18 is Br. In a specific embodiment, R 18 is 1. In some embodiments, R 18 is CO2H. In other embodiments, R 18 In certain embodiments, R 18 is N(CH3)2. In certain embodiments, R 18 is NH(CH3). In some embodiments, R 18 It is C 3-5 In certain embodiments, R 18 In some embodiments, R 18 It is C 1-6 In one embodiment, R 18 In other embodiments, R 18 In another embodiment, R18 In another embodiment, R 18 In another embodiment, R 18 In other embodiments, R 18 In another embodiment, R 18 In some embodiments, R 18 In some embodiments, R 18 is C optionally substituted with one or more F 1-6 In another embodiment, R 18 is -CH2CH2F. In certain embodiments, R 18 is -CH2CHF2. In another embodiment, R 18 is -CH2CF3. In one embodiment, R 18 It is C 3-5 In a specific embodiment, R 18 In another embodiment, R 18 is optionally replaced by one or more C 3-5 Cycloalkyl substituted C 1-6 In certain embodiments, R 18 yes In another embodiment, R 18 is C optionally substituted by one or more OH 1-6 In some embodiments, R 18 yes

[0613] In one embodiment, R 9’ In one embodiment, R 9’ In yet another embodiment, R 9’ is F. In another embodiment, R 9’ In another embodiment, R 9’ is Br. In another embodiment, R 9’ is I. In one embodiment, R 9’ It is C 3-5 In a specific embodiment, R 9’ It is cyclopropyl.

[0614] In one embodiment, n is 1 or 2. In other embodiments, n is 1. In other embodiments, n is 2.

[0615] In one embodiment, p is 1-9. In one embodiment, p is 1-3. In other embodiments, p is 1 or 2. In yet another embodiment, p is 2 or 3. In yet another embodiment, p is 1 or 3. In other embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0616] In one embodiment, the compound is selected from a compound listed in Table 4, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0617] Table 4 Representative compounds having structure (III)

[0618]

[0619] In another embodiment, a compound having structure (IV) is provided:

[0620]

[0621] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0622] Ring A is C 3-8 Cycloalkyl, or a saturated heterocyclic ring, wherein the heteroatom of the saturated heterocyclic ring consists of 1-2 oxygen atoms;

[0623] Each R a and R b Each independently is H or C 1-6 alkyl;

[0624] R 1 H, halogen, OH, CN, C 1-6 Alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl or C 3-5 Cycloalkyl;

[0625] R 2 and R 5 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0626] R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC1-6 Alkyl or OC 1-6 Haloalkyl;

[0627] R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl;

[0628] R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl;

[0629] R 18 It is halogen, CO2H, amine, C 3-5 Cycloalkyl, or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more R 9’ replace;

[0630] R 9’ is OH, halogen or C 3-5 Cycloalkyl;

[0631] n is 0, 1, or 2;

[0632] p is 0-9; and

[0633] q is 1-3.

[0634] The condition is that when R 1 is H and A is When R 9 Not an unsubstituted ethyl group.

[0635] In more specific embodiments of structure (IV), such structures include the following more specific embodiments, where applicable.

[0636] In one embodiment, R 11 and R 12 In another embodiment, one of R 11 It is C 1-6 Alkyl and R 12 is H. In another embodiment, R 11 is H and R 12 It is C 1-6 In another embodiment, R 11 and R 12 are H. In another embodiment, R 11 and R 12In some embodiments, R 11 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl, and R 12 is H. In some embodiments, R 11 is H, F, CN, methyl, CF3 or OCH3, and R 12 is H. In other embodiments, R 11 is H, and R 12 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 In other embodiments, R 11 is H, and R 12 is H, F, CN, methyl, CF3 or OCH3.

[0637] In one embodiment, R 11 is H. In another embodiment, R 11 In certain embodiments, R 11 is F. In other embodiments, R 11 is Cl. In certain embodiments, R 11 is Br. In a specific embodiment, R 11 is 1. In some embodiments, R 11 It is C 1-6 In one embodiment, R 11 In other embodiments, R 11 In another embodiment, R 11 In another embodiment, R 11 In another embodiment, R 11 In other embodiments, R 11 In another embodiment, R 11 In some embodiments, R 11 In some embodiments, R 11 is CN. In some embodiments, R 11 It is C 1-6 In certain embodiments, R 11 is CF3. In some embodiments, R 11 It's OC 1-6 In certain embodiments, R 11 It is OCH3.

[0638] In one embodiment, R12 is H. In another embodiment, R 12 In certain embodiments, R 12 is F. In other embodiments, R 12 is Cl. In certain embodiments, R 12 is Br. In certain embodiments, R 12 is 1. In some embodiments, R 12 It is C 1-6 In one embodiment, R 12 In other embodiments, R 12 In another embodiment, R 12 In another embodiment, R 12 In another embodiment, R 12 In other embodiments, R 12 In another embodiment, R 12 In some embodiments, R 12 In some embodiments, R 12 is CN. In some embodiments, R 12 It is C 1-6 In certain embodiments, R 12 is CF3. In some embodiments, R 12 It's OC 1-6 In certain embodiments, R 12 It is OCH3.

[0639] In one embodiment, R 1 is H. In one embodiment, R 1 In certain embodiments, R 1 is F. In other embodiments, R 1 is Cl. In certain embodiments, R 1 is Br. In a specific embodiment, R 1 is 1. In some embodiments, R 1 is CN. In other embodiments, R 1 is OH. In some embodiments, R 1 It is C 1-6 In one embodiment, R 1 In other embodiments, R 1 In another embodiment, R 1 In another embodiment, R 1 In another embodiment, R 1In other embodiments, R 1 In another embodiment, R 1 In some embodiments, R 1 In some embodiments, R 1 It's OC 1-6 In certain embodiments, R 1 is OCH3. In some embodiments, R 1 It's OC 1-6 In certain embodiments, R 1 is OCF3. In some embodiments, R 1 It is C 3-5 In certain embodiments, R 1 It is cyclopropyl.

[0640] In one embodiment, R 2 and R 5 Each independently is H, C 1-6 In another embodiment, R 2 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 Alkyl, and R 5 is H. In another embodiment, R 2 is H, and R 5 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl.

[0641] In one embodiment, R 2 is H. In another embodiment, R 2 is OH. In another embodiment, R 2 It is C 1-6 In some embodiments, R 2 is CF3. In another embodiment, R 2 It is C 1-6 In a specific embodiment, R 2 In another embodiment, R 2 In another embodiment, R 2 In yet another embodiment, R 2 In one embodiment, R 2 In another embodiment, R 2 is F. In another embodiment, R 2 In another embodiment, R2 is Br. In another embodiment, R 2 It's OC 1-6 In some embodiments, R 2 is OCF3. In another embodiment, R 2 It's OC 1-6 In a specific embodiment, R 2 It is OCH3.

[0642] In one embodiment, R 5 is H. In another embodiment, R 5 In another embodiment, R 5 It is C 1-6 In another embodiment, R 5 In another embodiment, R 5 It is C 1-6 In another embodiment, R 5 In another embodiment, R 5 In another embodiment, R 5 In another embodiment, R 5 In one embodiment, R 5 In another embodiment, R 5 is F. In another embodiment, R 5 In another embodiment, R 5 is Br. In another embodiment, R 5 It's OC 1-6 In another embodiment, R 5 is OCF3. In another embodiment, R 5 It's OC 1-6 In another embodiment, R 5 It is OCH3.

[0643] In one embodiment, R 3 is OH, and R 4 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 In another embodiment, R 4 is OH, and R 3 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 In yet another embodiment, R 3 is OH, and R 4Is H or C 1-6 In another embodiment, R 4 is OH, and R 3 Is H or C 1-6 alkyl.

[0644] In some embodiments, R 3 In another embodiment, R 3 is H. In another embodiment, R 3 It is C 1-6 In one embodiment, R 3 In another embodiment, R 3 It is C 1-6 In a specific embodiment, R 3 In another embodiment, R 3 In certain embodiments, R 3 In another embodiment, R 3 In one embodiment, R 3 is halogen. In some embodiments, R 3 is F. In another embodiment, R 3 In one embodiment, R 3 is Br. In another embodiment, R 3 It's OC 1-6 In another embodiment, R 3 is OCF3. In some embodiments, R 3 It's OC 1-6 In certain embodiments, R 3 It is OCH3.

[0645] In one embodiment, R 4 In another embodiment, R 4 is H. In another embodiment, R 4 It is C 1-6 In yet another embodiment, R 4 In another embodiment, R 4 It is C 1-6 In certain embodiments, R 4 In another embodiment, R 4 In certain embodiments, R 4 In another embodiment, R 4 In one embodiment, R 4 In yet another embodiment, R 4is F. In another embodiment, R 4 In another embodiment, R 4 is Br. In another embodiment, R 4 It's OC 1-6 In another embodiment, R 4 is OCF3. In other embodiments, R 4 It's OC 1-6 In certain embodiments, R 4 It is OCH3.

[0646] In one embodiment, R 9 is H. In another embodiment, R 9 is not H. In some embodiments, R 9 It is C 1-6 In a specific embodiment, R 9 In some embodiments, R 9 In certain embodiments, R 9 In some embodiments, R 9 It is C 1-6 Alkyl is optionally substituted with one or more F. In another embodiment, R 9 is -CH2CH2F. In certain embodiments, R 9 is -CH2CHF2. In another embodiment, R 9 is -CH2CF3. In one embodiment, R 9 It is C 3-5 In a specific embodiment, R 9 In another embodiment, R 9 is optionally replaced by one or more C 3-5 Cycloalkyl substituted C 1-6 In certain embodiments, R 9 yes In another embodiment, R 9 is C optionally substituted by one or more OH 1-6 In some embodiments, R 9 yes

[0647] In one embodiment, R 9’ In one embodiment, R 9’ In yet another embodiment, R 9’ is F. In another embodiment, R 9’ In another embodiment, R 9’is Br. In another embodiment, R 9’ is I. In one embodiment, R 9’ It is C 3-5 In a specific embodiment, R 9’ It is cyclopropyl.

[0648] In one embodiment, R 18 In certain embodiments, R 18 is F. In other embodiments, R 18 is Cl. In certain embodiments, R 18 is Br. In a specific embodiment, R 18 is 1. In some embodiments, R 18 is CO2H. In other embodiments, R 18 In certain embodiments, R 18 is N(CH3)2. In certain embodiments, R 18 is NH(CH3). In some embodiments, R 18 It is C 3-5 In certain embodiments, R 18 In some embodiments, R 18 It is C 1-6 In one embodiment, R 18 In other embodiments, R 18 In another embodiment, R 18 In another embodiment, R 18 In another embodiment, R 18 In other embodiments, R 18 In another embodiment, R 18 In some embodiments, R 18 In some embodiments, R 18 is C optionally substituted with one or more F 1-6 In another embodiment, R 18 is -CH2CH2F. In certain embodiments, R 18 is -CH2CHF2. In another embodiment, R 18 is -CH2CF3. In one embodiment, R 18 It is C 3-5 In a specific embodiment, R 18 In another embodiment, R 18 is optionally replaced by one or more C 3-5 Cycloalkyl substituted C1-6 In certain embodiments, R 18 yes In another embodiment, R 18 is C optionally substituted by one or more OH 1-6 In some embodiments, R 18 yes

[0649] In one embodiment, Ra is H. In another embodiment, Ra is C 1-6 In certain embodiments, Ra is methyl.

[0650] In one embodiment, Rb is H. In another embodiment, Rb is C 1-6 In certain embodiments, Rb is methyl.

[0651] In one embodiment, n is 0-2. In one embodiment, n is 0 or 1. In other embodiments, n is 1 or 2. In yet another embodiment, n is 0 or 2. In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2.

[0652] In one embodiment, p is 0-9. In one embodiment, p is 0-3. In one embodiment, p is 0 or 1. In other embodiments, p is 1 or 2. In yet another embodiment, 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.

[0653] In one embodiment, q is 1-3. In other embodiments, q is 1 or 2. In yet another embodiment, 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.

[0654] In one embodiment, the compound is selected from a compound listed in Table 5, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0655] Table 5

[0656] Representative compounds having structure (IV)

[0657]

[0658] In another embodiment, a compound having structure (V) is provided:

[0659]

[0660] or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein:

[0661] R a Is H or C 1-6 alkyl;

[0662] Each R c and R d Each independently is H or C 1-6 Alkyl, or R c and R d Linked together to form oxo;

[0663] R 1 H, halogen, OH, CN, C 1-6 Alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl or C 3-5 Cycloalkyl;

[0664] R 2 and R 5 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0665] R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl;

[0666] R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl;

[0667] R 18 It is C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more R 9’ replace;

[0668] R 9’ is OH, halogen or C 3-5 cycloalkyl; and

[0669] q is 1-3.

[0670] In more specific embodiments of Structure (V), such structures include the following more specific embodiments, where applicable.

[0671] In one embodiment, R 11 and R 12 In another embodiment, one of R 11 It is C 1-6 Alkyl and R 12 is H. In another embodiment, R 11 is H, and R 12 It is C 1-6 In another embodiment, R 11 and R 12 are H. In another embodiment, R 11 and R 12 In some embodiments, R 11 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 Alkyl, and R 12 is H. In some embodiments, R 11 is H, F, CN, methyl, CF3 or OCH3, and R 12 is H. In other embodiments, R 11 is H, and R 12 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 In other embodiments, R 11 is H, and R 12 is H, F, CN, methyl, CF3 or OCH3.

[0672] In one embodiment, R 11 is H. In another embodiment, R 11 In certain embodiments, R 11 is F. In other embodiments, R 11 is Cl. In certain embodiments, R 11 is Br. In a specific embodiment, R 11 is 1. In some embodiments, R 11 It is C 1-6 In one embodiment, R 11 In other embodiments, R 11 In another embodiment, R 11In another embodiment, R 11 In another embodiment, R 11 In other embodiments, R 11 In another embodiment, R 11 In some embodiments, R 11 In some embodiments, R 11 is CN. In some embodiments, R 11 It is C 1-6 In certain embodiments, R 11 is CF3. In some embodiments, R 11 It's OC 1-6 In certain embodiments, R 11 It is OCH3.

[0673] In one embodiment, R 12 is H. In another embodiment, R 12 In certain embodiments, R 12 is F. In other embodiments, R 12 is Cl. In certain embodiments, R 12 is Br. In certain embodiments, R 12 is 1. In some embodiments, R 12 It is C 1-6 In one embodiment, R 12 In other embodiments, R 12 In another embodiment, R 12 In another embodiment, R 12 In another embodiment, R 12 In other embodiments, R 12 In another embodiment, R 12 In some embodiments, R 12 In some embodiments, R 12 is CN. In some embodiments, R 12 It is C 1-6 In certain embodiments, R 12 is CF3. In some embodiments, R 12 It's OC 1-6 In certain embodiments, R 12 It is OCH3.

[0674] In one embodiment, R 1 is H. In one embodiment, R1 In certain embodiments, R 1 is F. In other embodiments, R 1 is Cl. In certain embodiments, R 1 is Br. In a specific embodiment, R 1 is 1. In some embodiments, R 1 is CN. In other embodiments, R 1 is OH. In some embodiments, R 1 It is C 1-6 In one embodiment, R 1 In other embodiments, R 1 In another embodiment, R 1 In another embodiment, R 1 In another embodiment, R 1 In other embodiments, R 1 In another embodiment, R 1 In some embodiments, R 1 In some embodiments, R 1 It's OC 1-6 In certain embodiments, R 1 is OCH3. In some embodiments, R 1 It's OC 1-6 In certain embodiments, R 1 is OCF3. In some embodiments, R 1 It is C 3-5 In certain embodiments, R 1 It is cyclopropyl.

[0675] In one embodiment, R 2 and R 5 Each independently is H, C 1-6 In another embodiment, R 2 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 Alkyl, and R 5 is H. In another embodiment, R 2 is H, and R 5 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl.

[0676] In one embodiment, R 2is H. In another embodiment, R 2 is OH. In another embodiment, R 2 It is C 1-6 In some embodiments, R 2 is CF3. In another embodiment, R 2 It is C 1-6 In a specific embodiment, R 2 In another embodiment, R 2 In another embodiment, R 2 In yet another embodiment, R 2 In one embodiment, R 2 In another embodiment, R 2 is F. In another embodiment, R 2 In another embodiment, R 2 is Br. In another embodiment, R 2 It's OC 1-6 In some embodiments, R 2 is OCF3. In another embodiment, R 2 It's OC 1-6 In a specific embodiment, R 2 It is OCH3.

[0677] In one embodiment, R 5 is H. In another embodiment, R 5 In another embodiment, R 5 It is C 1-6 In another embodiment, R 5 In another embodiment, R 5 It is C 1-6 In another embodiment, R 5 In another embodiment, R 5 In another embodiment, R 5 In another embodiment, R 5 In one embodiment, R 5 In another embodiment, R 5 is F. In another embodiment, R 5 In another embodiment, R 5 is Br. In another embodiment, R 5 It's OC 1-6 In another embodiment, R 5is OCF3. In another embodiment, R 5 It's OC 1-6 In another embodiment, R 5 It is OCH3.

[0678] In one embodiment, R 3 is OH, and R 4 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 In another embodiment, R 4 is OH, and R 3 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 In yet another embodiment, R 3 is OH, and R 4 Is H or C 1-6 In another embodiment, R 4 is OH, and R 3 Is H or C 1-6 alkyl.

[0679] In some embodiments, R 3 In another embodiment, R 3 is H. In another embodiment, R 3 It is C 1-6 In one embodiment, R 3 In another embodiment, R 3 It is C 1-6 In a specific embodiment, R 3 In another embodiment, R 3 In certain embodiments, R 3 In another embodiment, R 3 In one embodiment, R 3 is halogen. In some embodiments, R 3 is F. In another embodiment, R 3 In one embodiment, R 3 is Br. In another embodiment, R 3 It's OC 1-6 In another embodiment, R 3 is OCF3. In some embodiments, R 3 It's OC 1-6 In certain embodiments, R 3 It is OCH3.

[0680] In one embodiment, R 4 In another embodiment, R 4 is H. In another embodiment, R 4 It is C 1-6 In yet another embodiment, R 4 In another embodiment, R 4 It is C 1-6 In certain embodiments, R 4 In another embodiment, R 4 In certain embodiments, R 4 In another embodiment, R 4 In one embodiment, R 4 In yet another embodiment, R 4 is F. In another embodiment, R 4 In another embodiment, R 4 is Br. In another embodiment, R 4 It's OC 1-6 In another embodiment, R 4 is OCF3. In other embodiments, R 4 It's OC 1-6 In certain embodiments, R 4 It is OCH3.

[0681] In one embodiment, Ra is H. In another embodiment, Ra is C 1-6 In certain embodiments, Ra is methyl.

[0682] In one embodiment, Rc is H. In another embodiment, Rc is C 1-6 In certain embodiments, Rc is methyl.

[0683] In one embodiment, Rd is H. In another embodiment, Rd is C 1-6 In certain embodiments, Rd is methyl.

[0684] In one embodiment, Rc and Rd are linked together to form oxo.

[0685] In some embodiments, R 19 It is C 1-6 In a specific embodiment, R 19 In some embodiments, R 19 In certain embodiments, R19 In some embodiments, R 19 is C optionally substituted with one or more F 1-6 In another embodiment, R 19 is -CH2CH2F. In certain embodiments, R 19 is -CH2CHF2. In another embodiment, R 19 is -CH2CF3. In one embodiment, R 19 It is C 3-5 In a specific embodiment, R 19 In another embodiment, R 19 is optionally replaced by one or more C 3-5 Cycloalkyl substituted C 1-6 In certain embodiments, R 19 yes In another embodiment, R 19 is C optionally substituted by one or more OH 1-6 In some embodiments, R 19 yes

[0686] In one embodiment, R 9’ In one embodiment, R 9’ In yet another embodiment, R 9’ is F. In another embodiment, R 9’ In another embodiment, R 9’ is Br. In another embodiment, R 9’ is I. In one embodiment, R 9’ It is C 3-5 In a specific embodiment, R 9’ It is cyclopropyl.

[0687] In one embodiment, q is 1-3. In other embodiments, q is 1 or 2. In yet another embodiment, 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.

[0688] In one embodiment, the compound is selected from a compound listed in Table 6, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0689] Table 6 Representative compounds having structure (V)

[0690]

[0691] Pharmaceutical composition

[0692] 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, and at least one pharmaceutically acceptable carrier, diluent or excipient. For example, the active compound is typically mixed with a carrier, or diluted by a carrier, or encapsulated in a carrier, which can be in the form of an ampoule, capsule, sachet, paper or other container. When the active compound is mixed with a carrier, or when the carrier acts as a diluent, it can be a solid, semisolid or liquid substance that acts as a vehicle, excipient or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example, contained in a pouch. Some examples of suitable carriers are water, saline solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talcum powder, gelatin, agar, pectin, gum arabic, stearic acid, or cellulose lower alkyl ethers, silicic acid, fatty acid, fatty acid amine, fatty acid monoglyceride and diglyceride, fatty acid pentaerythritol ester, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, carrier or diluent can include any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, used alone or in combination with wax.

[0693] As used herein, the term "pharmaceutical composition" refers to a composition containing a compound described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope compound or salt thereof, formulated with one or more pharmaceutically acceptable carriers (which may also include other additives), and manufactured or sold as part of a therapeutic regimen for treating a mammalian disease with the approval of a governmental regulatory agency. The pharmaceutical composition 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 a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); for administration to pediatric subjects (e.g., solutions, syrups, suspensions, elixirs, powders for reconstitution into 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 the form of any other formulation described herein. Conventional procedures and ingredients for selecting and preparing suitable formulations are described in, for example, Remington: The Science and Practice of Pharmacy, 21st edition, Gennaro, Ed., Lippencott Williams & Wilkins (2005) and The United States Pharmacopeia: The National Formulary (USP36NF31), published in 2013.

[0694] In some embodiments, the pharmaceutical composition comprises 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, and at least one pharmaceutically acceptable carrier, diluent or excipient, and the pharmaceutical composition further comprises a second therapeutically active agent.

[0695] As used herein, the term "pharmaceutically acceptable carrier" refers to any component other than the disclosed compound or its pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotopic compound or salt (e.g., a carrier capable of suspending or dissolving the active compound) and having the characteristics of being non-toxic and non-inflammatory to the patient. Excipients may include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending agents or dispersing agents, sweeteners or waters of hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, cross-linked povidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0696] The formulation may be mixed with auxiliary agents which do not adversely react with the active compound. These additives may include wetting agents, emulsifying agents and suspending agents, salts which influence the osmotic pressure, buffers and / or coloring substances, preservatives, sweeteners or flavoring agents. If necessary, the composition may also be sterilized.

[0697] In another embodiment, a method for preparing a composition of a compound described herein is provided, comprising formulating a compound of the present invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, a pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method may also include the step of formulating the composition into a tablet or capsule. In other embodiments, a pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method may also include the step of freeze-drying the composition to form a freeze-dried formulation. In some embodiments, the composition is formulated into a pediatric dosage form suitable for treating a child individual.

[0698] In certain embodiments, the present invention provides 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 pharmaceutically acceptable salts, isomers, hydrates, solvates, or isotopic compounds thereof. Such compounds can be synthesized using standard synthetic techniques known to those skilled in the art. For example, the synthetic methods listed in the following examples and reaction schemes can be used with appropriate modifications.

[0699] For this reason, the reactions, processes and synthetic methods described herein are not limited to the specific conditions described in the experimental section below, which are intended to provide guidance for appropriate technicians in the field. For example, the reaction can be carried out in any suitable solvent or other reagent to carry out the necessary conversion. In general, a suitable solvent is a protic solvent or an aprotic solvent, and the solvent does not react substantially with the reactant, intermediate or product at the temperature at which the reaction is carried out (i.e., the temperature range is from freezing point to boiling temperature). A given reaction can be carried out in a solvent or a mixture of multiple solvents. Depending on the specific reaction, a suitable solvent can be used for a specific post-treatment after the reaction. All reagents whose synthesis is not described in the experimental section are commercially available, or are known compounds, or can be formed by known compounds by known methods by those skilled in the art. The compounds and intermediates produced according to the method 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 multiple methods for purifying the same compound. In some cases, purification may not be required. In some cases, the compound can be purified by crystallization. In some cases, impurities can be stirred out using a suitable solvent. In some cases, the compounds can be purified by chromatography, particularly flash column chromatography, using specially made or pre-packed silica gel columns and eluents such as gradients of heptane, ether, ethyl acetate, acetonitrile, ethanol, etc. In some cases, the compounds can be purified by preparative HPLC using the methods described.

[0700] The purification methods described herein can provide the compounds of the invention with sufficiently basic or acidic functional groups in the form of salts, for example, trifluoroacetate or formate salts, where the compounds of the invention are sufficiently basic, or ammonium salts, where the compounds of the invention are sufficiently acidic. In subsequent bioassays, salts of this type can be converted to their free base or free acid forms, respectively, or used in the form of salts by various methods known to those skilled in the art. It should be understood that the particular form of the compounds of the invention isolated and described herein is not necessarily the only form in which the compounds can be applied to a bioassay to quantify a particular biological activity.

[0701] Chemical names were generated using ChemDraw nomenclature software (version 17.0.0.206) from PerkinElmer Informatics, Inc. In some cases, recognized names of commercially available reagents were used in place of names generated by the nomenclature software.

[0702] Treatment

[0703] In some embodiments, the present invention provides methods for treating NLRP3 inflammasome-dependent disorders, wherein "treatment" refers to intervention that improves the signs or symptoms of a disease or pathological condition. As used herein, the terms "treatment" and "treatment" in relation to a disease, pathological condition or symptom also refer to any observable beneficial effect of the treatment. The beneficial effect may be demonstrated by, for example, a delay in the onset of clinical symptoms of the disease in susceptible individuals, a reduction in the severity of some or all of the clinical symptoms of the disease, a slowing of disease progression, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the individual, or by other parameters specific to a particular disease as known in the art. Preventive treatment is a treatment administered to an individual who does not show signs of the disease or only shows early signs, with the goal of reducing the risk of developing a lesion. Therapeutic treatment is a treatment administered to an individual after the signs and symptoms of the disease appear.

[0704] In some embodiments, the present invention provides methods for treating NLRP3 inflammasome-dependent disorders in individuals, wherein "individual" refers to animals (e.g., mammals, such as humans). The individual to be treated according to the methods described herein can be an individual who has been diagnosed with an NLRP3 inflammasome-dependent disorder, such as inflammation, inflammatory disease, immune disease, cancer, infection, including viral infection; central nervous system disease, metabolic disease, cardiovascular disease, respiratory disease, liver disease, kidney disease, eye disease, skin disease, psychological disease or blood disease.

[0705] Diagnosis can be performed by any method or technique known in the art. It will be appreciated by those skilled in the art that individuals to be treated according to the present disclosure may have been subjected to standard testing, or may have been identified as being at risk due to the presence of one or more risk factors associated with a disease or condition without examination. The term "patient" may be used interchangeably with the term "individual". An individual may refer to an adult individual or a child individual.

[0706] The route of administration can be any route that effectively transports the active compound of the present invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, oral, subcutaneous, intradermal, transdermal, or parenteral, including intravenous, subcutaneous and / or intramuscular. In one embodiment, the route of administration is oral administration. In another embodiment, the route of administration is topical administration.

[0707] The dosage form can be administered once a day, or multiple times a day (e.g., twice or three times a day). Alternatively, if recommended by the prescribing physician or the prescribing information of the drug, the dosage form can be administered less frequently than once a day, such as once every other day or once a week. The dosage regimen includes, for example, titrating the dose to the extent required or useful for the indication to be treated, so that the patient's body adapts to the treatment, to minimize or avoid adverse side effects associated with the treatment, and / or to maximize the therapeutic effect of the compounds of the invention. Other dosage forms include delayed release or controlled release forms. Suitable dosage regimens and / or forms include, for example, those listed in the latest edition of the Physicians' Desk Reference, which is incorporated herein by reference.

[0708] In one embodiment, 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, and at least one pharmaceutically acceptable oral carrier, diluent or excipient. In another embodiment, 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, and at least one pharmaceutically acceptable topical carrier, diluent or excipient. In another embodiment, 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, and at least one pharmaceutically acceptable topical carrier, diluent or excipient.

[0709] In some embodiments, the present invention provides methods for treating a NLRP3 inflammasome-dependent disorder, wherein modulation of NLRP3 provides a medical benefit to the patient or individual.

[0710] In some embodiments, the NLRP3 inflammasome-dependent disorder is inflammation, an inflammatory disease, an immune disease, cancer, an infection, 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 psychological disease, or a blood disease.

[0711] In one embodiment, the NLRP3 inflammasome-dependent disorder is a neuroinflammation-related disorder or a neurodegenerative disease.

[0712] In one embodiment, the invention provides a method of inhibiting the NLRP3 inflammasome using an effective amount of a pharmaceutical composition described herein. In one embodiment, the pharmaceutical composition is selective for modulating NLRP3 inflammasome activity relative to hERG activity. In certain embodiments, the selectivity for NLRP3 inflammasome activity relative to hERG activity is greater than or equal to 1,000 times. In certain embodiments, the selectivity for NLRP3 inflammasome activity relative to hERG activity is greater than or equal to 10 times. In certain embodiments, the selectivity for NLRP3 inflammasome activity relative to hERG activity is greater than or equal to 100 times.

[0713] In another embodiment, the present invention provides a method of treating a NLRP3 inflammasome-dependent disorder by administering an effective amount of a pharmaceutical composition described herein to an individual in need thereof. In certain embodiments, the NLRP3 inflammasome-dependent disorder is a neuroinflammation-related disorder or a neurodegenerative disease.

[0714] In another embodiment, the invention provides methods for treating NLRP3 inflammasome-dependent disorders, including inflammation due to inflammatory disorders (e.g., autoinflammatory diseases), inflammation as a symptom of non-inflammatory disorders, inflammation due to infection, or inflammation secondary to trauma, injury, or autoimmunity. Examples of inflammation that can be treated or prevented include inflammatory responses associated with or caused by the following diseases:

[0715] (a) skin disorders, such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia;

[0716] (b) joint disorders, such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis crystal-induced arthritis (e.g., pseudogout, gout), or seronegative spondyloarthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, Reiter's disease);

[0717] (c) muscle disorders, such as polymyositis or myasthenia gravis;

[0718] (d) gastrointestinal disorders, such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that can remotely affect the intestine (e.g., migraine, rhinitis, or eczema);

[0719] (e) respiratory disorders, such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, in particular chronic or refractory asthma, such as late-stage 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;

[0720] (f) vascular disorders, such as atherosclerosis, Behcet's disease, vasculitis, or Wegener's granulomatosis;

[0721] (g) immune disorders, such as autoimmune disorders, such as systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease;

[0722] (h) ocular disorders such as uveitis, allergic conjunctivitis or vernal conjunctivitis;

[0723] (i) neurological disorders, such as multiple sclerosis or encephalomyelitis;

[0724] (j) infectious or infection-related conditions, such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Pneumocystis carinii pneumonia, orchitis / epididymitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease;

[0725] (k) renal disorders, such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia or nephritic syndrome;

[0726] (l) Lymphatic system disorders, such as Castleman's disease;

[0727] (m) immune system disorders or disorders involving the immune system, such as hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease;

[0728] (n) liver disorders, such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), or primary biliary cirrhosis;

[0729] (o) cancer, including those listed below;

[0730] (p) burns, wounds, trauma, hemorrhage or stroke;

[0731] (q) radiation exposure; and / or

[0732] (r) Obesity;

[0733] (s) pain, such as inflammatory hyperalgesia; and / or

[0734] (t) Neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

[0735] In another embodiment, the invention provides a method for treating a NLRP3 inflammasome-dependent disorder, such as an inflammatory disease. For example, inflammation due to an inflammatory disorder (e.g., an autoinflammatory disease), such as cold pyrin-associated periodic syndrome (CAPS), Mueller-Weiss syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal multisystem inflammatory disease (NOMID), Magid syndrome, suppurative arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), adult-onset Still's disease (AOSD), A20 haploinsufficiency (HA20), childhood granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammatory, antibody deficiency, and immune dysregulation (APLAID), or sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay (SIFD).

[0736] In another embodiment, the present invention provides a method for treating a NLRP3 inflammasome-dependent disorder, such as an immune disease. For example, autoimmune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), antisynthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, 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), multiple sclerosis (MS) (including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS)), myasthenia gravis, strabismus, 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 sclerosis, systemic connective tissue disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Beliefs disease, Chagas disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler's syndrome, macrophage activation syndrome, Blau's syndrome, giant cell arteritis, leukoplakia, or vulvodynia.

[0737] In another embodiment, the invention provides a method for treating a NLRP3 inflammasome-dependent disorder, such as cancer. For example, lung cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), Langerhans cell histiocytosis (LCH), myeloproliferative neoplasms (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndrome (MDS), leukemia (including acute lymphocytic leukemia (ALL) acute myeloid leukemia (AML), promyelocytic leukemia (APML, or APL)), adrenal cancer, anal cancer, basal cell skin cancer and squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors , gastrointestinal stromal tumor (GIST), gestational trophoblastic disease glioma, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumor, lymphoma (including cutaneous T-cell lymphoma), malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymic cancer, thyroid cancer (including anaplastic thyroid cancer), uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0738] In another embodiment, the invention provides methods for treating NLRP3 inflammasome-dependent disorders, such as infections, including viral infections. For example, viral infections (e.g., influenza virus, human immunodeficiency virus (HIV), alphaviruses (e.g., chikungunya alphavirus and Ross River virus), flaviviruses (e.g., dengue virus and Zika virus), herpesviruses (e.g., Epstein-Barr virus, cytomegalovirus, varicella zoster virus and KSHV), poxviruses (e.g., vaccinia virus (modified vaccinia virus Ankara) and myxoma virus), adenoviruses (e.g., adenovirus 5) or papillomavirus), bacterial infections (e.g., from Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordetella pertussis, Burkholderia pseudomallei, Corynebacterium diphtheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Lissinus monocytogenes In some embodiments, the present invention relates to infections caused by bacteria (e.g., bacteria from the genus Candida or Aspergillus), infections caused by protozoa (e.g., from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania, or Trypanosoma), infections caused by helminths (e.g., from Schistosoma, Ascaris, Tapeworms, or Treponema), and infections caused by prions.

[0739] In another embodiment, the invention provides a method for treating a NLRP3 inflammasome-dependent disorder, such as a central nervous system disease, for example, Parkinson's disease, Alzheimer's disease, frontotemporal dementia, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain damage caused by pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis.

[0740] In another embodiment, the invention provides a method for treating a NLRP3 inflammasome-dependent disorder, such as a neuroinflammation-related disease, such as multiple sclerosis, brain infection, acute injury, neurodegenerative disease, Parkinson's disease, or Alzheimer's disease.

[0741] In another embodiment, the invention provides methods of treating NLRP3 inflammasome-dependent disorders, such as neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

[0742] In one embodiment, the neurodegenerative disease is characterized by profound involvement of a cell-mediated neuroinflammatory process.

[0743] In another embodiment, the invention provides methods for treating NLRP3 inflammasome-dependent disorders, such as metabolic diseases, for example, type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout.

[0744] In another embodiment, the invention provides a method for treating NLRP3 inflammasome-dependent disorders, such as cardiovascular diseases. For example, hypertension, ischemia-reperfusion injury (including ischemic reperfusion injury after MI), stroke (including ischemic stroke), transient ischemic attack, myocardial infarction (including recurrent myocardial infarction), heart failure (including congestive heart failure and heart failure with preserved ejection fraction), embolism, aneurysm (including abdominal aortic aneurysm), cardiovascular risk reduction (CvRR) and pericarditis (including post-myocardial infarction syndrome).

[0745] In another embodiment, the invention provides methods for treating NLRP3 inflammasome-dependent disorders, such as respiratory diseases, for example, chronic obstructive pulmonary disease (COPD), asthma (e.g., allergic asthma and steroid-resistant asthma), asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis.

[0746] In another embodiment, the invention provides methods for treating NLRP3 inflammasome-dependent disorders, such as liver diseases, for example, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) (including advanced fibrosis stages F3 and F4), alcoholic fatty liver disease (AFLD) and alcoholic steatohepatitis (ASH).

[0747] In another embodiment, the invention provides a method for treating a NLRP3 inflammasome-dependent disorder, such as a kidney disease, for example, acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy;

[0748] In another embodiment, the invention provides methods of treating NLRP3 inflammasome-dependent disorders, such as ocular diseases, for example, ocular epithelial diseases, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma.

[0749] In another embodiment, the invention provides methods for treating NLRP3 inflammasome-dependent disorders, such as skin diseases, for example, dermatitis (e.g., contact dermatitis and atopic dermatitis), contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-causing skin diseases, and acne conglobata.

[0750] In another embodiment, the invention provides methods for treating NLRP3 inflammasome-dependent disorders, such as psychological disorders, for example, depression and psychological stress.

[0751] In another embodiment, the invention provides methods of treating NLRP3 inflammasome-dependent disorders, such as blood disorders, for example, sickle cell disease. Example

[0752] General Methods

[0753] Obtained in a solution of deuterated chloroform (CDCl3), deuterated methanol (CD3OD) or dimethyl sulfoxide – D6 (DMSO) 1 HNMR (400 MHz) spectrum. HPLC retention time, purity and mass spectrum (LCMS) were obtained using Shimadzu LCMS2010 (Shim-pack XR-ODS 3.0*30mm 2.2μm) in ES (+) ionization mode. Flow rate: 0.8 mL / min, acquisition time (Acquire Time): 3 min, wavelength: UV220, oven temperature: 50°C.

[0754] The following additional abbreviations are used: ethyl acetate (EtOAc), N,N-diisopropylethylamine (DIEA), water (H2O), hydrochloric acid (HCl), methanol (MeOH), dimethyl sulfoxide (DMSO), silica gel (SiO2), trifluoroacetic acid (TFA), 1-methyl-2-pyrrolidone (NMP), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) / palladium on carbon (Pd / C), 9-borabicyclo[3.3.1]nonane (9-BBN), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), sodium sulfate (Na2SO4), cesium carbonate (Cs2CO3), ammonia (NH3), tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile (MeCN or ACN), dichloroethane (DME), boron tribromide (BBr3), retention time (RT), molecular weight (MW), room temperature (rt), hours (h), volume / volume (v / v), proton nuclear magnetic resonance ( 1HNMR), sodium hydride (NaH), formic acid (HCHO), acetic acid (AcOH), methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)] palladium (II) (XPhosPdG3), degrees Celsius (℃), milligram (mg), gram (g), millimole (mmol), milliliter (mL), petroleum ether (PE), molar (M), sodium bicarbonate (NaHCO3), pH (pH), sodium cyanoborohydride (NaBH3CN), preparative high performance liquid chromatography (prep-HPLC), equivalent (N).

[0755] Example 1

[0756] General synthetic route A

[0757] General solution 1

[0758]

[0759] 2-[4-methyl-6-[[(3R)-1-methyl-3-piperidinyl]amino]pyridazin-3-yl]phenol (Compound No. 2) synthesis

[0760]

[0761] ( Synthesis of R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine

[0762]

[0763] To a solution of 3,6-dichloro-4-methyl-pyridazine (8.56 g, 52.5 mmol) in NMP (50 mL), (3R)-1-methylpiperidin-3-amine (5.0 g, 43.8 mmol) and DIEA (11 mL, 65.7 mmol) were added. Under a nitrogen atmosphere, the resulting mixture was stirred at 110 ° C for 14 h. Then, the mixture was poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure to give a crude residue. The residue was purified by silica gel column chromatography (4.6% MeOH in DCM) to obtain the desired product (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazine-3-amine (5.30 g), which was a yellow solid.

[0764] 2-[4-methyl-6-[[(3R)-1-methyl-3-piperidinyl]amino]pyridazin-3-yl]phenol (Compound No. 2) synthesis

[0765]

[0766] To 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) was added (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (100 mg, 0.415 mmol), Na2CO3 (110 mg, 1.04 mmol) and Pd(dppf)Cl2·DCM (17 mg, 0.021 mmol). The resulting mixture was stirred at 120°C for 4 h under nitrogen atmosphere. The mixture was then diluted with water (30 mL), acidified to pH 7-8 with 2N HCl aqueous solution, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (0.05% NH 3 .H 2 O as additive) to give the desired product, 2-[4-methyl-6-[[(3R)-1-methyl-3-piperidinyl]amino]pyridazin-3-yl]phenol (Compound No. 2, 43 mg, 33% yield) as a white solid.

[0767] Example 2

[0768] General synthetic route B

[0769] General solution 2

[0770]

[0771] (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol Synthesis of Compound No. 73)

[0772]

[0773] Synthesis of tert-butyl (R)-3-((6-chloro-5-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate

[0774]

[0775] To 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) in portions at 0 ° C. Under a nitrogen atmosphere, the mixture was stirred at 20 ° C for 2 h. Then, 3,6-dichloro-4-methylpyridazine (830 mg, 5.07 mmol) was added, and the resulting mixture was stirred at 20 ° C for another 14 h. The mixture was poured into water (30 mL) and extracted with EtOAc (3X 30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4 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, (R)-tert-butyl 3-((6-chloro-5-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate (1.27 g, 78% yield) as a yellow solid.

[0776] Synthesis of (R)-3-chloro-4-methyl-6-(piperidin-3-yloxy)pyridazine

[0777]

[0778] To a mixture of (R)-tert-butyl 3-((6-chloro-5-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate (11.6 g, 35.4 mmol) in DCM (110 mL) was added 4M HCl in dioxane (100 mL). The mixture was stirred at 20 °C for 2 h. Then, saturated aqueous NaHCO3 was added to adjust the pH to 8-9. The resulting mixture was extracted with EtOAc (3X 100 mL). The organic layers were combined, washed with brine (2X 100 mL), dried over anhydrous Na2SO4 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.

[0779] Synthesis of (R)-3-chloro-4-methyl-6-((1-methylpiperidin-3-yl)oxy)pyridazine

[0780]

[0781] 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) was added HCHO (2.48 g, 30.5 mmol) (37% in water), NaBH3CN (2.88 g, 45.8 mmol) and AcOH (1.83 g, 30.5 mmol). The mixture was stirred at 50 °C for 2 h under nitrogen atmosphere. Then, the mixture was poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous Na2SO4 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.

[0782] (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol Synthesis of Compound No. 73)

[0783]

[0784] To 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 [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (307 mg, 1.49 mmol), XPhosPdG3 (53 mg, 0.06 mmol) and Cs2CO3 (1.20 g, 3.72 mmol). The mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. Then, the mixture was poured into water (10 mL) and extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude residue. The crude residue was purified by preparative HPLC (0.05% NH3.H2O as 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.

[0785] Example 3

[0786] General synthetic route C

[0787] General solution 3

[0788]

[0789] (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

[0790]

[0791] Synthesis of 3-(2-(Benzyloxy)-4-fluorophenyl)-6-chloro-4-methylpyridazine

[0792]

[0793] To a solution of 6-chloro-4-methylpyridazine-3-yl trifluoromethanesulfonate (562 mg, 2.03 mmol) and (2-(benzyloxy)-4-fluorophenyl)boronic acid (500 mg, 2.03 mmol) in DME (7 mL) and H2O (1 mL) was added Pd(PPh3)4 (352 mg, 0.305 mmol) and Na2CO3 (843 mg, 6.10 mmol). Under a nitrogen atmosphere, the resulting mixture was stirred at 90 °C for 16 h. The mixture was then poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4 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.

[0794] tert-Butyl 3-((6-(2-(Benzyloxy)-4-fluorophenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate Synthesis

[0795]

[0796] To a solution of tert-butyl 3-methylidenepiperidin-1-carboxylate (300 mg, 1.52 mmol) in THF (10 mL) was added a solution of 1M 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, 3-(2-(benzyloxy)-4-fluorophenyl)-6-chloro-4-methylpyridazine (250 mg, 0.760 mmol), Pd(dppf)Cl2 (111 mg, 0.152 mmol), K2CO3 (315 mg, 2.28 mmol) and H2O (2 mL) were added to the mixture at room temperature. Under a nitrogen atmosphere, the resulting mixture was stirred at 65 ° C for 12 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (3x 30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4 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.

[0797] Synthesis of 3-(2-(Benzyloxy)-4-fluorophenyl)-4-methyl-6-(piperidin-3-ylmethyl)pyridazine

[0798]

[0799] To a solution of tert-butyl 3-((6-(2-(benzyloxy)-4-fluorophenyl)-5-methylpyridazine-3-yl)methyl)piperidine-1-carboxylate (90 mg, 0.18 mmol) in DCM (1 mL) was added a solution of 4M 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 a crude product of 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.

[0800] Synthesis of 3-(2-(Benzyloxy)-4-fluorophenyl)-4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazine

[0801]

[0802] To a solution of 3-(2-(benzyloxy)-4-fluorophenyl)-4-methyl-6-(piperidin-3-ylmethyl)pyridazine (90 mg) in THF (3 mL) and H2O (0.3 mL) was added 37% aqueous formaldehyde (20 mg, 0.25 mmol), NaBH3CN (20 mg, 0.32 mmol) and AcOH (13 mg, 0.21 mmol). The resulting mixture was stirred at 50 °C for 2 h. Then, a saturated aqueous solution of NaHCO3 was added to adjust the pH to ~7-8, and the mixture was extracted with EtOAc (3X 100 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4 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.

[0803] (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

[0804]

[0805] To a solution of 3-(2-(benzyloxy)-4-fluorophenyl)-4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazine (40 mg) in MeOH (1 mL) was added Pd / C (10 mg). The mixture was stirred at 30 °C for 14 h 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 purified by preparative supercritical fluid chromatography (preparative SFC) (DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​EtOH]; B%: 30%-30%, min) to obtain the expected products (R)-5-fluoro-2-(4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (compound No. 106, 5.6 mg, 43% yield) and (S)-5-fluoro-2-(4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (compound No. 36, 8.9 mg, 27% yield) as white solids.

[0806] Example 4

[0807] General synthetic route D

[0808] General solution 4

[0809]

[0810] (R)-3-methyl-2-(6-(methyl(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound No. 21) Synthesis

[0811]

[0812] (R Synthesis of tert-butyl 3-((6-chloropyridazin-3-yl)(methyl)amino)piperidine-1-carboxylate

[0813]

[0814] DIEA (2.6 g, 20 mmol) was added to a solution of 3,6-dichloropyridazine (1.00 g, 6.71 mmol) and (R)-3-(methylamino)piperidine-1-carboxylic acid tert-butyl ester (1.51 g, 7.05 mmol) in NMP (8 mL). Under a nitrogen atmosphere, the resulting mixture was stirred at 140 ° C for 16 h. Then, the mixture was poured into water (100 mL) and extracted with 6:1 DCM: MeOH (3X 80 mL). The organic layers were merged, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by silica gel column chromatography (30% EtOAc, in PE) to obtain the desired product (R)-3-((6-chloropyridazine-3-yl) (methyl) amino) piperidine-1-carboxylic acid tert-butyl ester (1.88 g, 70% yield), which was a yellow solid.

[0815] Synthesis of (R)-6-Chloro-N-methyl-N-(piperidin-3-yl)pyridazin-3-amine

[0816]

[0817] To a solution of (R)-tert-butyl 3-((6-chloropyridazin-3-yl)(methyl)amino)piperidine-1-carboxylate (1.83 g, 5.61 mmol) in DCM (2 mL) was added a solution of 4M HCl in 1,4-dioxane (15 mL). The resulting mixture was stirred at room temperature for 2 h. Then, a saturated aqueous solution of NaHCO3 was added to adjust the pH to ~7-8, and the mixture was extracted with 5:1 DCM:MeOH (3×50 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, 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.

[0818] Synthesis of (R)-6-Chloro-N-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine

[0819]

[0820] 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) was added 37% aqueous formaldehyde (0.60 g, 7.41 mmol), NaBH3CN (0.58 g, 9.26 mmol) and AcOH (0.37 g, 6.17 mmol). The resulting mixture was stirred at 50 °C for 2 h. Then, a saturated aqueous solution of NaHCO3 was added to adjust the pH to ~7-8, and the mixture was extracted with 5:1 DCM:MeOH (3X 30 mL). The organic layers were combined, dried over 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.

[0821] Synthesis of (R)-6-(2-methoxy-6-methylphenyl)-N-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine

[0822]

[0823] To a solution of (R)-6-chloro-N-methyl-N-(1-methylpiperidin-3-yl)pyridazine-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) was added Xphos-pd-G3 (53 mg, 0.062 mmol) and Cs2CO3 (406 mg, 1.25 mmol). Under a nitrogen atmosphere, the resulting mixture was stirred at 100 ° C for 16 h. Then, the mixture was poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4 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)pyridazin-3-amine (96 mg, 71% yield) as an off-white solid.

[0824] (R)-3-methyl-2-(6-(methyl(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound No. 21) Synthesis

[0825]

[0826] 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 slowly added BBr (0.25 mL, 2.6 mmol) 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 was added to adjust the pH to ~7-8, and the mixture was extracted with 5:1 DCM:MeOH (3X 50 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give a crude residue. The crude residue was purified by preparative HPLC (0.05% NH4HCO3 as 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.

[0827] Example 5

[0828] Synthesis of representative compounds

[0829] The compounds listed in Table 7 below were prepared by procedures analogous to those described in the representative schemes shown in the Examples, with appropriate changes in reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions. Characterization data for the compounds are also summarized in Table 7.

[0830] Table 7

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850] Example 6

[0851] NLRP3 inflammasome activation and cell viability assessment in THP1 macrophages

[0852] Human acute monocytic leukemia cells (ATCC, catalog number TIB-202) were cultured in Gibco RPMI-1640 medium (ThermoFisher cat#72400054) supplemented with 10% heat-inactivated FBS at a density between 3 and 8 x 10^5 viable cells / mL. When the cell concentration reached 8 x 10 5 Cells were subcultured at 1.5 cells / mL (every 2-3 days).

[0853] To determine the IC of a compound 50 , with 1.75x10 4 Cells / well were seeded in CELLSTAR 384-well plates (Greiner, Cat. No. 781091), 50ul per well, containing DMEM (ThermoFisher, Cat. No. 10393021), 10% FBS, 1x GlutaMax (ThermoFisher, Cat. No. 35050038) + 20nM PMA (Sigma, Cat. No. P1585), using only the inner 224 wells of the 384-well plate. The surrounding wells were filled with 50ul PBS and incubated at 37°C, 5% CO2 for 48 hours.

[0854] After incubation for 48 hours, the medium containing PMA was removed and replaced with 40 ul / well of fresh DMEM, 10% FBS, 1xGlutMax, and incubated at 37°C, 5% CO2 for 24 hours.

[0855] The next day, cells were primed with 20 ng / ml LPS (E. coli) (Sigma, Cat. No. L3129) in DMEM, 10% FBS, 1x GlutMax for 3 hours at 37°C, 5% CO2.

[0856] After the LPS initiation step, cells were treated with compounds at a maximum final concentration of 10 uM, diluted 8 times at 1:4: (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 MCC950 (InvivGen, catalog number inh-mcc) was used as a positive control, and incubated at 37°C, 5% CO2 for 1 hour.

[0857] After 1 hour of compound incubation, the NLRP3 inflammasome activation step was performed by treating the cells with nigericin (InvivoGen, Cat. No. tlrl-nig) at a final concentration of 6.7 uM for 3 hours at 37°C, 5% CO2.

[0858] Thereafter, 30ul cell supernatant samples were collected for cytokine analysis, which was performed on Hu IL-1βAlphaLISA (Perkin Elemer, Cat. No. AL220C) and Hu IL-6AlphaLISA (Perkin Elemer, Cat. No. AL220C). Cell viability was assessed by performing CellTiter-Glo luminescence assay (Promega, Cat. No. G7572) according to the manufacturer's protocol.

[0859] Tables 8 and 9 show the cell viability evaluation of selected NLRP3 inflammasome modulators.

[0860] For Table 8 - the activity ranges are as follows: “++++++” indicates IL-1β activity ≤1 nM; “+++++” indicates IL-1β activity >1 nM and ≤10 nM; “++++” indicates IL-1β activity >10 nM and ≤100 nM; “+++” indicates IL-1β activity >100 nM and ≤500 nM; “++” indicates IL-1β activity >500 nM and ≤1,000 nM; “+” indicates IL-1β activity >1,000 nM; and “*” indicates not tested.

[0861] For Table 4 - the activity ranges are as follows: "++++" indicates IL-6 activity ≤ 1 μM; "+++" indicates IL-6 activity > 1 μM and ≤ 5 μM; "++" indicates IL-6 activity > 5 μM and ≤ 10 μM; "+" indicates IL-6 activity > 10 μM; and "*" indicates not tested.

[0862] Table 8

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869] Table 9

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876] Example 7

[0877] hERG Assay Protocol in CHO-hERG Cells

[0878] CHO-hERG cells (Sophion Biosciences (Ballerup, Denmark), subcultured and frozen at WuXi AppTec (Suzhou) Co., Ltd.) were stored in liquid nitrogen and tested to be free of mycoplasma contamination. Cells were no longer used after 30 subcultures. CHO-hERG cells were cultured in a humidified incubator at 37°C (±2°C) in an air atmosphere containing 5% CO2 (4% to 8%). Cells were recovered with recovery medium (F12 medium supplemented with 10% fetal bovine serum, 1% The cells were subcultured in the presence of selective antibiotics (G418), 89 μg / mL hygromycin B (HB), and the medium was replaced with recovery medium at the last subculture before the patch clamp experiment.

[0879] To determine the IC of a compound 50 The selected compound ("test article") was dissolved in DMSO and then diluted with ECS to obtain a working solution. Five concentrations of 0.3, 1, 3, 10 and 30 μM were tested. Two cell replicates were tested for each concentration.

[0880] Exponentially growing CHO-hERG cells were collected and suspended in extracellular solution for use. The hERG current was recorded at physiological temperature (33.0°C to 37.0°C) using the whole-cell patch clamp technique. The output signal of the patch clamp amplifier was digitized and low-pass filtered at 2.9KHz. The recording was controlled by Patchmaster Pro software. The recording chamber containing the seeded cells was mounted on an inverted microscope stage. The cells in the recording chamber were randomly selected for testing. The cells were continuously perfused from the perfusion system. In manual patch clamp studies, micropipettes filled with ICS were used as recording electrodes. Micropipettes were prepared using glass capillaries (BF150-117-10, SUTTER INSTRUMENT USA) on the day of the patch clamp experiment. The resistance (Rp) of the pipette when ICS was full was in the range of 2 to 5MΩ. Starting from a holding potential of -80mV, the voltage was increased to +60mV and continued for 850ms to open the hERG channel. Thereafter, the voltage was reduced to -50 mV for 1275 milliseconds, inducing a "rebound" or tail current, and the peak tail current was measured and collected for data analysis. Finally, the voltage was reduced to the holding potential (-80 mV). This command voltage protocol was repeated continuously every 15 seconds during the application of the test article.

[0881] During the initial recording period using the vehicle control working solution, the peak tail current amplitude is monitored until it stabilizes and continues for at least 3 scans. The cells are then perfused with the test article / positive control working solution until the peak tail current amplitude reaches a steady state. When three consecutive super-imposable peak tail currents are collected, it is considered that a steady state is reached. At this point, the cells are perfused with the next concentration of the test article again. One or more test articles / positive controls or different concentrations of the same test article are tested on each cell, and the cells are washed with vehicle controls until the current amplitude recovers to at least 80% of the value measured before the application of the test article. 100nM cisapride is used as a positive control to evaluate the reliability of the test system. At least two cell replicates were tested for each concentration. According to scientific literature, 100nM cisapride inhibits more than 50% of the hERG current (Milnes, JT et al.).

[0882] Seal criteria: When acquiring the whole-cell configuration, a holding potential (e.g., -80 mV) is applied while collecting membrane parameters (Cm, Rm, and Rs). A "good" whole-cell recording is generally defined as: series resistance (Rs) less than 10 MΩ; membrane resistance (Rm) greater than 500 MΩ, and membrane capacitance (Cm) less than 100 pF. Current amplitude: Before applying the test article / positive control, the peak current amplitude must be between 400 pA and 5000 pA; otherwise the cell will be discarded. Leak criteria: At a holding potential of -80 mV, the absolute leak current value must be less than 200 pA. The current amplitude is adjusted based on the leak current at -80 mV. Scans with absolute leak current values ​​greater than 200 pA are not used for data analysis.

[0883] Table 10 shows the activity evaluation of selected compounds.

[0884] For Table 10 - the activity range is as follows: "++++++" indicates hERG activity ≤1 μM; "+++++" indicates hERG activity >1 μM and ≤3 μM; "++++" indicates hERG activity >3 μM and ≤10 μM; "+++" indicates hERG activity >10 μM and ≤20 μM; "++" indicates hERG activity >20 μM and ≤30 μM; "+" indicates hERG activity >30 μM; and "*" indicates not tested yet.

[0885] Table 10

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892] Example 8

[0893] Comparison of measurement data

[0894] hERG channel inhibition and associated QT interval prolongation in the electrocardiogram (ECG) associated with NLRP3 inflammasome modulators represent a recognized cardiovascular safety risk in humans (Hancox et al., Molecular Pharmacology 2008, 73: 1592-1595, incorporated herein by reference). QT interval prolongation can lead to torsades de pointes (TdP) arrhythmias and may develop into ventricular tachycardia and sudden death. Therefore, NLRP3 inflammasome modulators that overcome the liabilities of hERG safety are needed.

[0895] The NLRP3 modulators provided have surprising and unexpected technical advantages in terms of cardiac ion channel (e.g., hERG) activity. For example, compounds 2, 21, 22, and 51 (and their analogs) of the present invention exhibit potent IL-1 and IL-6 activity while having unexpectedly low hERG inhibition. In contrast, compounds A, B, C, D and compounds 3 and 15 shown in Table 6 below exhibit potent IL-1β activity while also having high hERG inhibition. These data suggest that the NLRP3 modulators attached to R 1 The chemical nature of the functional group at the position has a significant impact on whether the compound exhibits beneficial properties in the human body. Without being bound by theory, in R 1 Functional groups with small steric size and electron-withdrawing properties at the position resulted in potent IL-1β activity and low hERG inhibition. Thus, compounds 2, 21, 22 and 51 (and their analogs) showed surprisingly favorable data for human application.

[0896] Table 11 compares the IL-1β, IL-6 and hERG activity evaluations of selected compounds.

[0897] For Table 11 - the ranges of activity against IL-1 β, IL-6 and hERG are as described above (see Tables 3, 4 and 5, respectively).

[0898] Table 11

[0900]

[0901]

[0902] Characterization data for Compounds A, B, C and D are summarized in Table 12 below.

[0903] Table 12

[0904]

[0905]

[0906] The various embodiments described above can be combined to provide additional embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and / or listed in the application data sheet, including U.S. Provisional Application No. 63 / 341,975 filed on May 13, 2022, are incorporated herein by reference in their entirety. If necessary, various aspects of the embodiments can be modified to provide additional embodiments using the concepts of each patent, application, and publication.

[0907] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the appended claims, the terms used should not be interpreted as limiting the claims to the specific embodiments disclosed in the specification, and the claims should be interpreted to include all possible embodiments and the full range of equivalents of these claims. Therefore, the claims are not limited by the present disclosure.

Claims

1. A compound having structure (I''): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein: X is CR a R b NR a or O; R a and R b Each independently is H or C 1-6 alkyl; R 1 is H, F or CN; R 2 and R 5 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 8 is H or halogen; R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl; R 9’ is OH, halogen or C 3-5 Cycloalkyl; R 10 and R 13 are each independently H or halogen; R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl; R 16 is H or CO2H; and n is 0, 1 or 2.

2. The compound of claim 1 having structure (Ia''): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein: R a Is H or C 1-6 alkyl; R 1 is H, F or CN; R 2 and R 5 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 8 is H or halogen; R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl; R 9’ is OH, halogen or C 3-5 Cycloalkyl; R 10 and R 13 are each independently H or halogen; R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl; R 16 is H or CO2H; and n is 0, 1 or 2.

3. The compound of claim 1 or 2, having the structure (Ia-1''): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein: R a Is H or C 1-6 alkyl; R 1 is H, F or CN; R 2 and R 5 Each independently is 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 alkyl; R 11 and R 12 are independently H, F or C 1-6 Alkyl; and n is 0, 1 or 2.

4. The compound of claim 1 having the structure (Ib''): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein: R 1 is H, F or CN; R 2 and R 5 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 8 is H or halogen; R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl; R 9’ is OH, halogen or C 3-5 Cycloalkyl; R 10 and R 13 are each independently H or halogen; R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl; R 16 is H or CO2H; and n is 0, 1 or 2.

5. The compound of claim 1 or 4, having the structure (Ib-1''): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein: R 1 is H, F or CN; R 2 and R 5 Each independently is 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 alkyl; R 11 and R 12 Each independently is H or C 1-6 Alkyl; and n is 0, 1 or 2.

6. The compound of claim 1 having the structure (Ic''): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein: R a and R b Each independently is H or C 1-6 alkyl; R 1 is H, F or CN; R 2 and R 5 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 8 is H or halogen; R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl; R 9’ is OH, halogen or C 3-5 Cycloalkyl; R 10 and R 13 are each independently H or halogen; R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl; R 16 is H or CO2H; and n is 0, 1 or 2.

7. The compound of claim 1 or 6, having the structure (Ic-1″′): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein: R a and R b Each independently is H or C 1-6 alkyl; R 1 is H, F or CN; R 2 and R 5 Each independently is 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 alkyl; R 11 and R 12 Each independently is H or C 1-6 Alkyl; and n is 0, 1 or 2.

8. Compounds having structure (II): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein: R a Is H or C 1-6 alkyl; Each R 15 are independently halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl or C 3-5 Cycloalkyl; R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl; R 9’ is OH, halogen or C 3-5 Cycloalkyl; Each R 17 are independently halogen or CO2H; R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, or OC 1-6 Alkyl; and n is 0-2; m is 0-3; and p is 0-9.

9. Compounds having structure (III): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein: R 1 H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl or C 3-5 Cycloalkyl; R 2 and R 5 are independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl; R 18 Each is a halogen, CO2H, amine, C 3-5 Cycloalkyl, or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more R 9’ replace; R 9’ is OH, halogen or C 3-5 Cycloalkyl; n is 1 or 2; and p is 1-9.

10. Compounds having structure (IV): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein: Ring A is C 3-8 Cycloalkyl, or a saturated heterocyclic ring, wherein the heteroatom of the saturated heterocyclic ring consists of 1-2 oxygen atoms; Each R a and R b Each independently is H or C 1-6 alkyl; R 1 H, halogen, 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 independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 9 It is H, C 3-5 Cycloalkyl, or optionally substituted by one or more R 9’ Substituted C 1-6 alkyl; R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl; R 18 Each is a halogen, CO2H, amine, C 3-5 Cycloalkyl, or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more R 9’ replace; R 9’ is OH, halogen or C 3-5 Cycloalkyl; n is 0, 1, or 2; p is 0-9; and q is 1-3. The condition is that when R 1 is H and A is When R 9 Not an unsubstituted ethyl group.

11. Compounds having structure (V): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein: R a Is H or C 1-6 alkyl; Each R c and R d Each independently is H or C 1-6 Alkyl, or R c and R d Linked together to form oxo; R 1 H, halogen, 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 independently H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 3 or R 4 One of them is OH and the other is H, halogen, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl or OC 1-6 Haloalkyl; R 11 and R 12 are independently H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or OC 1-6 alkyl; R 19 It is C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more R 9’ replace; R 9’ is OH, halogen or C 3-5 cycloalkyl; and q is 1-3.

12. The compound of claim 1, wherein X is NR a .

13. The compound of claim 1 or 12, wherein X is O.

14. The compound of any one of claims 1, 12 or 13, wherein X is CR a R b .

15. The compound of any one of claims 1 to 14, wherein R 11 and R 12 One of them is H.

16. The compound of any one of claims 1 to 15, wherein R 11 It is C 1-6 Alkyl and R 12 It's H.

17. The compound of any one of claims 1 to 15, wherein R 11 is H and R 12 It is C 1-6 alkyl.

18. The compound of any one of claims 1 to 14, wherein R 11 and R 12 All are H.

19. The compound of any one of claims 1 to 14, wherein R 11 and R 12 None of them is H.

20. The compound of any one of claims 1-7 or 9-19, wherein R 1 It's H.

21. The compound of any one of claims 1-7 or 9-19, wherein R 1 It's F.

22. The compound of any one of claims 1-7 or 9-19, wherein R 1 It is CN.

23. The compound of any one of claims 1-2, 4, 6 or 9-22, wherein R 2 and R 5 Each independently is H, C 1-6 Alkyl, F, Cl, CF3, or CN.

24. The compound of any one of claims 1-2, 4, 6, or 9-22, wherein R 2 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 Alkyl, and R 5 It's H.

25. The compound of any one of claims 1-2, 4, 6, or 9-22, wherein R 2 is H, and R 5 It is OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl.

26. The compound of any one of claims 1-7 or 9-22, wherein R 2 It's H.

27. The compound of any one of claims 1-2, 4, 6, or 9-22, wherein R 2 It's OH.

28. The compound of any one of claims 1-2, 4, 6, or 9-22, wherein R 2 It's CF3.

29. The compound of any one of claims 1-7 or 9-22, wherein R 2 It is C 1-6 alkyl.

30. The compound of claim 29, wherein R 2 It's methyl.

31. The compound of claim 29, wherein R 2 It is ethyl.

32. The compound of claim 29, wherein R 2 It is isopropyl.

33. The compound of any one of claims 1-2, 4, 6, or 9-22, wherein R 2 It is CN.

34. The compound of any one of claims 1-2, 4, 6, or 9-22, wherein R 2 It's F.

35. The compound of any one of claims 1-2, 4, 6, or 9-22, wherein R 2 It is Cl.

36. The compound of any one of claims 1-2, 4, 6, or 9-22, wherein R 2 It's Br.

37. The compound of any one of claims 1-2, 4, 6, or 9-22, wherein R 2 It's OCF3.

38. The compound of any one of claims 1-2, 4, 6, or 9-22, wherein R 2 It's OC 1-6 alkyl.

39. The compound of claim 38, wherein R 2 It is OCH3.

40. The compound of any one of claims 1-7, 9-22 or 26-39, wherein R 5 It's H.

41. The compound of any one of claims 1-7, 9-22 or 26-39, wherein R 5 It's OH.

42. The compound of any one of claims 1-7, 9-22 or 26-39, wherein R 5 It's CF3.

43. The compound of any one of claims 1-7 or 9-22, wherein R 5 It is C 1-6 alkyl.

44. The compound of claim 43, wherein R 5 It's methyl.

45. The compound of claim 43, wherein R 5 It is ethyl.

46. ​​The compound of claim 43, wherein R 5 It is isopropyl.

47. The compound of any one of claims 1-7, 9-22 or 26-39, or 14-39, wherein R 5 It is CN.

48. The compound of any one of claims 1-7, 9-22 or 26-39, wherein R 5 It's F.

49. The compound of any one of claims 1-7, 9-22 or 26-39, wherein R 5 It is Cl.

50. The compound of any one of claims 1-7, 9-22 or 26-39, wherein R 5 It's Br.

51. The compound of any one of claims 1-7, 9-22 or 26-39, wherein R 5 It's OCF3.

52. The compound of any one of claims 1-7, 9-22 or 26-39, wherein R 5 It's OC 1-6 alkyl.

53. The compound of claim 52, wherein R 5 It is OCH3.

54. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 3 is OH, and R 4 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl.

55. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 4 is OH, and R 3 It is H, OH, CF3, C 1-6 Alkyl, CN, halogen, OCF3 or OC 1-6 alkyl.

56. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 3 is OH, and R 4 Is H or C 1-6 alkyl.

57. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 4 is OH, and R 3 Is H or C 1-6 alkyl.

58. The compound of any one of claims 1-7 or 9-53, wherein R 3 It's OH.

59. The compound of any one of claims 1-7 or 9-53, wherein R 3 It's H.

60. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 3 It's CF3.

61. The compound of any one of claims 1-7 or 9-53, wherein R 3 It is C 1-6 alkyl.

62. The compound of claim 61, wherein R 3 It's methyl.

63. The compound of claim 61, wherein R 3 It is ethyl.

64. The compound of claim 61, wherein R 3 It is isopropyl.

65. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 3 It is CN.

66. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 3 It's F.

67. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 3 It is Cl.

68. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 3 It's Br.

69. The compound of any one of claims 1-7 or 9-53, wherein R 3 It's OCF3.

70. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 3 It's OC 1-6 alkyl.

71. The compound of claim 70, wherein R 3 It is OCH3.

72. The compound of any one of claims 1-7, 9-53 or 59-71, wherein R 4 It's OH.

73. The compound of any one of claims 1-7 or 9-53, wherein R 4 It's H.

74. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 4 It's CF3.

75. The compound of any one of claims 1-7 or 9-53, wherein R 4 It is C 1-6 alkyl.

76. The compound of claim 75, wherein R 4 It's methyl.

77. The compound of claim 75, wherein R 4 It is ethyl.

78. The compound of claim 75, wherein R 4 It is isopropyl.

79. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 4 It is CN.

80. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 4 It's F.

81. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 4 It is Cl.

82. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 4 It's Br.

83. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 4 It's OCF3.

84. The compound of any one of claims 1, 2, 4, 6, or 9-53, wherein R 4 It's OC 1-6 alkyl.

85. The compound of claim 84, wherein R 4 It is OCH3.

86. The compound of any one of claims 1, 2, 4, 6, or 12-85, wherein R 8 It's H.

87. The compound of any one of claims 1, 2, 4, 6, or 12-85, wherein R 8 It's F.

88. The compound of any one of claims 1, 2, 4, 6, or 12-85, wherein R 8 It is Cl.

89. The compound of any one of claims 1, 2, 4, 6, or 12-85, wherein R 8 It's Br.

90. The compound of any one of claims 1, 2, 4, 6, 8, or 12-89, wherein R 9 It's H.

91. The compound of any one of claims 1, 2, 4, 6, 8, or 12-89, wherein R 9 Not H.

92. The compound of any one of claims 1, 2, 4, 6, 8, or 12-89, wherein R 9 It is C 1-6 alkyl.

93. The compound of claim 92, wherein R 9 It's methyl.

94. The compound of claim 92, wherein R 9 It is ethyl.

95. The compound of claim 92, wherein R 9 It is isopropyl.

96. The compound of any one of claims 1, 2, 4, 6, 8, or 12-89, wherein R 9 is C optionally substituted with one or more F 1-6 alkyl.

97. The compound of claim 96, wherein R 9 It is -CH2CH2F.

98. The compound of claim 96, wherein R 9 It is -CH2CHF2.

99. The compound of claim 96, wherein R 9 It is -CH2CF3.

100. The compound of any one of claims 1, 2, 4, 6, 8, or 12-89, wherein R 9 It is C 3-5 Cycloalkyl.

101. The compound of claim 100, wherein R 9 It is cyclopropyl.

102. The compound of any one of claims 1, 2, 4, 6, 8, or 12-89, wherein R 9 is optionally replaced by one or more C 3-5 Cycloalkyl substituted C 1-6 alkyl.

103. The compound of claim 102, wherein R 9 yes 104. The compound of any one of claims 1, 2, 4, 6, 8, or 12-89, wherein R 9 is C optionally substituted by one or more OH 1-6 alkyl.

105. The compound of claim 104, wherein R 9 yes 106. The compound of any one of claims 1, 2, 4, 6, or 12-105, wherein R 10 and R 13 All are H.

107. The compound of any one of claims 1, 2, 4, 6, or 12-105, wherein R 10 and R 13 All are halogens.

108. The compound of any one of claims 1, 2, 4, 6, or 12-105, wherein R 10 is H, and R 13 It's a halogen.

109. The compound of any one of claims 1, 2, 4, 6, or 12-105, wherein R 10 It's F.

110. The compound of any one of claims 1, 2, 4, 6, or 12-105, wherein R 10 It is Cl.

111. The compound of any one of claims 1, 2, 4, 6, or 12-105, wherein R 10 It's Br.

112. The compound of any one of claims 1, 2, 4, 6, 12-105 or 109-111, wherein R 13 It's F.

113. The compound of any one of claims 1, 2, 4, 6, 12-105 or 109-111, wherein R 13 It is Cl.

114. The compound of any one of claims 1, 2, 4, 6, 12-105 or 109-111, wherein R 13 It's Br.

115. The compound of any one of claims 8, 15-19, 90-105, wherein R 15 It's H.

116. The compound of any one of claims 8, 15-19 or 90-105, wherein R 15 It's a halogen.

117. The compound of claim 116, wherein R 15 It's F.

118. The compound of any one of claims 8, 15-19 or 90-105, wherein R 15 It is CN.

119. The compound of any one of claims 8, 15-19 or 90-105, wherein R 15 It is C 1-6 Halogenated alkyl.

120. The compound of claim 119, wherein R 15 It's CF3.

121. The compound of any one of claims 1, 2, 4, 6, or 12-114, wherein R 16 It's H.

122. The compound of any one of claims 1, 2, 4, 6, or 12-114, wherein R 16 It is CO2H.

123. The compound of any one of claims 8, 15-19, 90-105 or 115-120, wherein R 17 It's a halogen.

124. The compound of claim 123, wherein R 17 It's F.

125. The compound of any one of claims 8, 15-19, 90-105 or 115-120, wherein R 17 It is CO2H.

126. A compound according to any one of claims 9, 10 or 15-85, wherein R 18 It is an amine group.

127. The compound of claim 126, wherein R 18 It is NH(CH3)2.

128. A compound according to any one of claims 9, 10 or 15-85, wherein R 18 It's a halogen.

129. The compound of claim 128, wherein R 18 It's F.

130. The compound of any one of claims 11 or 15-85, wherein R 19 It's methyl.

131. The compound of any one of claims 1-8 or 10-130, wherein Ra is H.

132. The compound of any one of claims 1-8 or 10-130, wherein Ra is C 1-6 alkyl.

133. The compound of claim 132, wherein Ra is methyl.

134. The compound of any one of claims 1, 6, 7, 10, 14, 15-114, or 124-133, wherein Rb is H.

135. The compound of any one of claims 1, 6, 7, 10, 14, 15-114 or 124-133, wherein Rb is C 1-6 alkyl.

136. The compound of claim 135, wherein Rb is methyl.

137. The compound of any one of claims 11, 15-85, or 128-133, wherein Rc is H.

138. The compound of any one of claims 11, 15-85 or 128-133, wherein Rc is C 1-6 alkyl.

139. The compound of claim 138, wherein Rc is methyl.

140. The compound of any one of claims 11, 15-85, 130-133, or 137-139, wherein Rd is H.

141. The compound of any one of claims 11, 15-85, 130-133 or 137-139, wherein Rd is C 1-6 alkyl.

142. The compound of claim 141, wherein Rd is methyl.

143. The compound of any one of claims 11, 15-85, or 130-133, wherein Rc and Rd are linked together to form an oxo group.

144. The compound of any one of claims 1-8 or 10-143, wherein n is 0.

145. The compound of any one of claims 1-143, wherein n is 1.

146. The compound of any one of claims 1-143, wherein n is 2.

147. The compound of claim 8, wherein m is 1.

148. The compound of claim 8, wherein p is 0.

149. The compound of claim 9 or 10, wherein p is 1.

150. The compound of claim 10, wherein p is 2.

151. The compound of claim 10, wherein q is 1.

152. The compound of claim 11, wherein q is 2.

153. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein the compound has the following structure:

154. The compound of claim 153, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein the compound has the structure:

155. The compound of claim 153, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein the compound has the structure:

156. The compound of claim 153, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein the compound has the structure:

157. The compound of claim 153, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein the compound has the structure:

158. The compound of claim 8, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein the compound has the following structure:

159. The compound of claim 9, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein the compound has the following structure:

160. The compound of claim 10, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein the compound has the following structure:

161. The compound of claim 11, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein the compound has the following structure:

162. A pharmaceutical composition comprising a compound according to any one of claims 1-161 or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, and at least one pharmaceutically acceptable excipient.

163. A method of modulating NLRP3 inflammasome activity by contacting the NLRP3 inflammasome with an effective amount of the pharmaceutical composition of claim 162.

164. The method of claim 163, wherein the pharmaceutical composition is selective for modulating NLRP3 inflammasome activity relative to hERG activity.

165. The method of claim 164, wherein the selectivity for NLRP3 inflammasome activity relative to hERG activity is greater than or equal to 1,000-fold.

166. A method of treating a NLRP3 inflammasome-dependent disorder by administering an effective amount of the pharmaceutical composition of claim 162 to an individual in need thereof.

167. The method of claim 166, wherein the NLRP3 inflammasome-dependent disorder is a neuroinflammation-related disorder or a neurodegenerative disease.

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