N-oxide inhibitors of the NLRP3 inflammasome

Abstract

The present disclosure relates to compounds that act as NLRP3 inflammasome inhibitors, pharmaceutical compositions comprising the compounds, and methods of treating inflammation and inflammation-aging associated disorders, including hearing loss and other diseases associated with aging.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 304,164, filed January 28, 2022, U.S. Provisional Application No. 63 / 377,248, filed September 27, 2022, and U.S. Provisional Application No. 63 / 383,573, filed November 14, 2022, the contents of which are incorporated by reference in their entireties herein. [Background technology]

[0002] Age-related frailty causes extremely worrying problems regarding the overall health and well-being of individuals and has been characterized as a multisystem physiological dysregulation syndrome. Age-related frailty is a geriatric syndrome characterized by frailty, low physical activity, reduced exercise capacity, exhaustion, and unintentional weight loss (Yao, X. et al., Clinics in Geriatric Medicine 27(1):79-87(2011)). Furthermore, there are many studies showing a direct correlation between age-related frailty and inflammation (Hubbard, RE, et al., Biogerontology 11(5):635-641(2010)). Immunosenescence is characterized by a low-grade chronic systemic inflammatory state known as inflam-senescence (Franceshi, C. et al., Annals of the New York Academy of Sciences 908:244-254(2000)). This inflammatory state or heightened chronic inflammation seen in aging and age-related frailty leads to immune dysregulation and complex remodeling of both innate and adaptive immunity.

[0003] Inhibiting the NLRP3 inflammasome, an oligomeric protein complex that includes ASC and caspase-1, mediates inflammation in numerous preclinical models (Schwaid, AG, J. Med. Chem. 2021, 64(1), 101-122). At the same time, the NLRP3 inflammasome is part of a larger proinflammatory pathway, the regulation of which is also being investigated. NLRP3 is a well-studied inflammasome sensor protein in several disease contexts. Many different indications are associated with the NLRP3 inflammasome, including diseases of aging, cryopyrin-associated periodic syndromes (CAPS), nonalcoholic steatohepatitis (NASH), gout, coronary artery disease, Crohn's disease, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, Parkinson's disease, intestinal disorders, acute respiratory distress syndrome (ARDS), amyotrophic lateral sclerosis (ALS), cancer, and skin diseases.

[0004] It has also been shown that inflammation, as well as activation of the NLRP3 inflammasome, leads to hearing loss (Nakanishi, H., et al., Frontiers in Neurology, 2020, 11, 1-7; Nakanishi, H., et al., PNAS, 2017, E7766-E7775). Inflammation-associated hearing loss can be age-dependent (Fischer, N., et al., Gerontology, 2019, 1-7), noise-induced (Le Prell, CG, et al. Current Opinion in Physiology, 2020, 18, 32-36), and the result of viral infections such as Zika virus and coronavirus (Yee, KT, et al., Hearing Research, 2020, 395, 1-15).

[0005] The NLRP3 inflammasome is therefore a promising drug target, and the wide range of indications in which it is relevant highlights the need for therapeutic agents that target the NLRP3 inflammasome. Summary of the Invention

[0006] Provided herein are compounds that inhibit the NLRP3 inflammasome. These compounds are therefore useful for treating a variety of indications, including inflammation-aging and inflammation.

[0007] In one embodiment, the compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, provided herein, wherein Ring C is a pyridine N-oxide.

[0008] In yet another aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0009] In yet another aspect, provided herein is a method of inhibiting the NLRP3 inflammasome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Provided herein are compounds that inhibit NLRP3 inflammasome.Therefore, these compounds as well as pharmaceutical compositions that contain these compounds are useful for treating various indications, including inflammation aging, inflammation, and other age-related diseases.

[0011] definition Listed below are definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to those terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0012] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly used in the art.

[0013] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including" as well as other forms such as "include," "includes," and "included" are not limiting.

[0014] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent with the context in which it is used. As used herein, when referring to measurable values ​​such as amounts and temporal durations, the term "about" is intended to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1%, from the specified value, as such variations are appropriate for carrying out the disclosed methods.

[0015] As used herein, terms such as "administration" refer to providing a therapeutic agent to a subject. Multiple techniques of administering a therapeutic agent exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0016] The terms "treat," "treated," "treating," or "treatment" include the alleviation or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment includes alleviating symptoms of inflammation, aging, and age-related disorders.

[0017] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in an in vivo system. For example, "contacting" a cell with a compound includes administering a compound of the invention to an individual, subject, or patient, such as a human, and also includes introducing a compound into a sample, including, for example, a purified preparation, that contains the cell.

[0018] As used herein, the term "prevent" or "prevention" refers to the absence of onset of a disorder or disease if none has occurred, or the absence of further onset of a disorder or disease if onset of a disorder or disease is already present. Also contemplated is the ability to prevent some or all of the symptoms associated with a disorder or disease.

[0019] As used herein, the term "cell" is intended to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell that is living in an organism, such as a mammal.

[0020] As used herein, the terms "patient," "individual," or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, farm animals and pets, such as sheep, cows, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or individual is a human.

[0021] As used herein, the terms "effective amount," "pharmacologically effective amount," and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to provide a desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0022] As used herein, the term "pharmaceutical acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., that may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0023] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound has been modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two, with non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile being generally preferred. The phrase "pharmaceutically acceptable salts" is not limited to monosalts or 1:1 salts. For example, "pharmaceutically acceptable salts" also includes bis salts, such as bis hydrochlorides. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0024] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present disclosure and a pharma- ceutical acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering the compound exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0025] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound useful within the present disclosure to a patient and can thereby perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation containing the compound useful within the present disclosure and not harmful to the patient. Some examples of materials which may function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations.

[0026] As used herein, "pharmaceutically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the present disclosure and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. "Pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional components that may be included in pharmaceutical compositions are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0027] As used herein, "inflammagenesis" is defined as chronic sterile inflammation associated with many age-related diseases.

[0028] As used herein, "age-related disorder" refers to a disorder associated with the aging process. Alternatively, age-related disorder is a disease associated with elderly people. Non-limiting examples of age-related diseases include atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension, and Alzheimer's disease. The incidence of all these diseases increases exponentially with age.

[0029] As used herein, the term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C 1 -C 6 Alkyl means alkyl having 1 to 6 carbon atoms, including straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, neopentyl, and hexyl. 1 -C 6 Other examples of alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0030] The term "alkoxy", alone or in combination with other terms, refers to a radical of the formula -O-alkyl, where the alkyl group is as defined above. n-m The term "alkoxy" refers to an alkoxy group, whose alkyl group has n to m carbons. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0031] As used herein, the term "haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo substituents, where alkyl and halo are as defined herein. Haloalkyl includes, by way of example, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like.

[0032] As used herein, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0033] As used herein, the term "cycloalkyl" refers to a fully saturated non-aromatic carbocyclic ring system having one, two, or three rings, where such rings may be fused. The term "fused" means that a second ring is present (i.e., linked or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures, which may be bridged or spirocyclic in nature, with the individual rings in the bicycle each having 3-8 atoms. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl. In certain embodiments, "cycloalkyl" refers to any of the C 3-10 In another embodiment, "cycloalkyl" is C 3-6 It is cycloalkyl.

[0034] As used herein, the term "heterocyclyl" or "heterocycloalkyl" means a non-aromatic carbocyclic system having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and having 1, 2, or 3 rings, which may be fused (fused as defined above). Heterocyclyl also includes bicyclic structures, which may be bridged or spirocyclic in nature, where the individual rings in the bicycle each have from 3 to 8 atoms and have 0, 1, or 2 N, O, or S atoms. The term "heterocyclyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), including, specifically, epoxyzyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azicyclo[2.1.1]-hexanyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 4-azabicyclo[3.1.1]heptanyl, 5-azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3 ...4-azabicyclo[2.2.1]heptanyl, 5-azabicyclo[2.2.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 4-azabicyclo[2.2. cyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-5-azabicyclo[2.2.1 ]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]nonanyl, and 8-oxabicyclo[3.2.1]octanyl. In one embodiment, "heterocycloalkyl" refers to a 3- to 10-membered heterocycloalkyl. In another embodiment, "heterocycloalkyl" refers to a 4- to 10-membered heterocycloalkyl.In yet another embodiment, "heterocycloalkyl" refers to a 3-, 4-, 5-, or 6-membered heterocycloalkyl.

[0035] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0036] As used herein, the term "aryl" refers to an aromatic carbocyclic ring system having one, two, or three rings, which may be fused (fused as defined above). If the rings are fused, one of the rings must be fully unsaturated, and the fused ring(s) may be fully saturated, partially unsaturated, or fully unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. In some embodiments, an aryl group has 6 carbon atoms. In some embodiments, an aryl group has 6 to 10 carbon atoms. In some embodiments, an aryl group has 6 to 16 carbon atoms.

[0037] As used herein, the term "heteroaryl" refers to an aromatic carbocyclic ring system having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and having 1, 2, or 3 rings, which may be fused (fused as defined above). The term "heteroaryl" includes furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta-[c]pyridinyl, 1, These include, but are not limited to, 4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl, and 4,5,6,7-tetrahydro-2H-indazolyl.

[0038] Where an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be attached to the designated moiety through different ring atoms or may otherwise be attached (i.e., shown or described without indication of a specific point of attachment), it is understood that all possible points are intended, whether through a carbon atom or, for example, through a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3-, or 4-pyridinyl, the term "thienyl" means 2- or 3-thienyl, and so forth.

[0039] compound Provided herein are compounds that are NLRP3 inflammasome inhibitors and are therefore useful in the treatment of inflammatory disorders, including cancer and other proliferative diseases.

[0040] In one embodiment, the compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof is provided herein. (In the formula, [ka] is an optional double bond, X, Y, and Z each independently represent NH, NR 3 , N, CH, and CR 3 with the proviso that at least one of X, Y, or Z is CH or CR 3 Provided that, Ring A is C 6-10 Aryl, 5-6 membered heteroaryl, C 3-10 cycloalkyl, and 4- to 10-membered heterocycloalkyl; Ring B is phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; Ring C is a pyridine N-oxide; R 1 , H, C 3-6 Cycloalkyl and C 1-6 is selected from the group consisting of alkyl, R 2 and R 2a are each independently H, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; Each R 3 is independent, C 1-6 Alkyl and C 3-6 is cycloalkyl, Each R 4 is independent, C 1-6Alkyl, halo, OH, OR 6 , N.H. 2 , NH(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , N.H.C.O.R. 6 , C.N., C. 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, and COR 6 is selected from the group consisting of Each R 5 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, OH, OR 7 , N.H. 2 , NH(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , N.H.C.O.R. 7 , C.N., C. 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, COR 7 , and S.O. 2 R 7 is selected from the group consisting of Each R 6 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkyl-C 6-10 Aryl, C 0-6 Alkyl-5 to 10 membered heteroaryl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, halo, NH 2 , NH(C 1-6 alkyl), and N(C 1-6 Alkyl) 2 is selected from the group consisting of Each R 7 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkyl-C 6-10 Aryl, C 0-6 Alkyl-5 to 10 membered heteroaryl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halo, NH 2 , NH(C1-6 alkyl), and N(C 1-6 Alkyl) 2 is selected from the group consisting of Each R 9 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl-OH, C 3-6 Cycloalkyl, halo, CN, OH, NH 2 , NH(C 1-6 alkyl), and N(C 1-6 Alkyl) 2 is selected from the group consisting of m is 0, 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, 2, or 3).

[0041] In certain embodiments of formula I, [ka] is an optional double bond, X, Y, and Z each independently represent NH, NR 3 , N, CH, and CR 3 with the proviso that at least one of X, Y, or Z is CH or CR 3 Provided that, Ring A is C 6-10 Aryl, 5-6 membered heteroaryl, C 3-10 cycloalkyl, and 4- to 10-membered heterocycloalkyl; Ring B is phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; Alternatively, ring B is absent and m is 0; Ring C is a pyridine N-oxide; R 1 , H, C 3-6 Cycloalkyl and C 1-6 is selected from the group consisting of alkyl, R 2 and R 2a are each independently H, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; Alternatively, R 2 and R 2a C, along with the atoms to which they are attached. 3-6 forming a cycloalkyl or 3- to 6-membered heterocycloalkyl; Each R 3 is independent, C 1-6 Alkyl and C 3-6 is cycloalkyl, Each R 4 is independent, C 1-6 Alkyl, C 2-6 Alkynyl, halo, OH, OR 6 , N.H. 2 , NH(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , N.H.C.O.R. 6 , C.N., C. 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, and COR 6 is selected from the group consisting of Each R 5 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 2-6 Alkynyl, halo, OH, OR 7 , N.H. 2 , NH(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , N.H.C.O.R. 7 , C.N., C. 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, COR 7 , and S.O. 2 R 7 is selected from the group consisting of Each R 6 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6Alkyl-C 6-10 Aryl, C 0-6 Alkyl-5 to 10 membered heteroaryl, C 1-6 Alkoxy, C 0-6 Alkyl-C 3-6 Cycloalkyl, C 0-6 Alkyl-3 to 10 membered heterocycloalkyl, halo, NH 2 , NH(C 1-6 alkyl), and N(C 1-6 Alkyl) 2 is selected from the group consisting of Each R 7 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkyl-C 6-10 Aryl, C 0-6 Alkyl-5 to 10 membered heteroaryl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halo, NH 2 , NH(C 1-6 alkyl), and N(C 1-6 Alkyl) 2 is selected from the group consisting of Each R 9 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl-OH, C 3-6 Cycloalkyl, halo, CN, OH, NH 2 , NH(C 1-6 alkyl), and N(C 1-6 Alkyl) 2 is selected from the group consisting of m is 0, 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, 2, or 3.

[0042] In one embodiment, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt thereof.

[0043] In another embodiment, the compound of formula I is a compound of formula Ib: [ka] or a pharma- ceutically acceptable salt thereof.

[0044] In yet another embodiment, the compound of formula I is a compound of formula Ic: [ka] or a pharma- ceutically acceptable salt thereof.

[0045] In yet another embodiment, ring A is C 6-10 In yet another embodiment, ring A is phenyl.

[0046] In one embodiment, Ring B is phenyl or 5-6 membered heteroaryl. In another embodiment, Ring B is phenyl. In yet another embodiment, Ring B is thienyl.

[0047] In yet another embodiment, R 1 is C 1-6 is alkyl, R 2 , H, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; R 2a is H, Each R 4 is independent, C 1-6 Alkyl, Halo, and OR 6 is selected from the group consisting of Each R 5 is independent, C 1-6 Haloalkyl, Halo, CN, and COR 7 is selected from the group consisting of Each R 6 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; Each R 7 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, and NH(C 1-6 alkyl), Each R 9 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl-OH, C 3-6 is selected from the group consisting of cycloalkyl, cycloalkyl, and CN; m is 0, 1, or 2; n is 1 or 2.

[0048] In one embodiment, R 1 is C 1-3 It is an alkyl.

[0049] In another embodiment, R 2 is H. In another embodiment, R 2a is H.

[0050] In yet another embodiment, each R 4 is independent, C 1-6 Alkyl, Halo, and OR 6 In yet another embodiment, R 4 are independently O(ethyl), O(cyclopropyl), O(oxetanyl), and O(C 1-3 haloalkyl).

[0051] In one embodiment, each R 5 is independent, C 1-6 Haloalkyl, Halo, CN, and COR 7 In another embodiment, each R 5 is independent, C 1-6 Haloalkyl, halo, CN, and CONH(C 1-6alkyl).

[0052] In one embodiment, each R 6 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 It is selected from the group consisting of cycloalkyl, and 3- to 6-membered heterocycloalkyl.

[0053] In another embodiment, each R 7 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, and NH(C 1-6 alkyl).

[0054] In another embodiment, each R 9 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl-OH, C 3-6 In yet another embodiment, each R 9 is independent, C 1-6 It is an alkyl.

[0055] In yet another embodiment, m is 1 or 2. In some embodiments, m is 1. In another embodiment, m is 2. In yet another embodiment, m is 0.

[0056] In some embodiments, n is 1 or 2. In other embodiments, n is 1. In yet other embodiments, n is 2. In yet other embodiments, n is 0.

[0057] In another embodiment, p is 0 or 1. In yet another embodiment, p is 0. In yet another embodiment, p is 1. In some embodiments, p is 2.

[0058] In another embodiment, Ring A is phenyl; Ring B is phenyl or thienyl; R 1 is C 1-3 is alkyl, R 2 , H, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; Each R 4 is independent, C 1-6 Alkyl, Halo, and OR 6 is selected from the group consisting of Each R 5 is independent, C 1-6 Haloalkyl, Halo, CN, and COR 7 is selected from the group consisting of Each R 6 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; Each R 7 is independent, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, and NH(C 1-6 alkyl), Each R 9 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-6 Alkyl-OH, C 3-6 is selected from the group consisting of cycloalkyl, cycloalkyl, and CN; m is 1 or 2; n is 1 or 2; p is 0 or 1.

[0059] In yet another embodiment, X is N; Y and Z are each independently selected from the group consisting of NH and CH.

[0060] In yet another embodiment, the compound of formula I has the following core structure: [ka] has one of the following:

[0061] In certain embodiments, the compound of formula I has the following core structure: [ka] has.

[0062] In another embodiment, the compound of formula I is a compound of Table 1: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] or a pharma- ceutically acceptable salt thereof.

[0063] In yet another embodiment, the compound of formula I is a compound of Table 2: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] or a pharma- ceutically acceptable salt thereof.

[0064] In yet another embodiment, the compound of formula I is a compound of Table 3: [Table 3] or a pharma- ceutically acceptable salt thereof.

[0065] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0066] Compounds disclosed herein can exist as tautomers and optical isomers (eg, enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, etc.).

[0067] It is generally known in the art that any compound that is converted in vivo to provide a compound disclosed herein is a prodrug within the scope of the disclosure.

[0068] The compounds provided herein can also include all isotopes of atoms occurring in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present invention can be replaced or substituted with an isotope of the atom at natural or non-natural abundance. In some embodiments, the compounds include at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced or substituted with deuterium. In some embodiments, the compounds include two or more deuterium atoms. In some embodiments, the compounds include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0069] In embodiments, the compounds provided herein have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0070] Treatment method In certain aspects, provided herein is a method of inhibiting the NLRP3 inflammasome in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0071] In another aspect, provided herein is a method of treating inflammation in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0072] In another aspect, provided herein is a method of treating inflammaging in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0073] In another aspect, provided herein is a method of treating cryopyrin-associated periodic syndromes (CAPS) in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0074] In certain embodiments, the CAPS is selected from the group consisting of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease.

[0075] In another aspect, provided herein is a method of treating a dermatological disorder in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0076] In certain embodiments, the dermatological condition is selected from the group consisting of psoriasis, urticaria, skin photoaging, and eczema.

[0077] Also provided herein are methods of using the compounds provided herein for the therapeutic amelioration of aging or age-related conditions that adversely affect longevity or quality of life, comprising administering a compound provided herein to a subject in need thereof, the aging or age-related conditions that adversely affect longevity or quality of life including inflammation, anemia, hyperglycemia, dyslipidemia, hyperinsulinemia, insulin resistance, immunosuppression, liver disease, iron overload, hypertriglyceridemia, impaired skin integrity, wound healing, scarring, pain, allergies, sleep disorders and problems, gastrointestinal disorders and problems, Th Type 1 inflammation, Th2 inflammation, inflammatory diseases with T cell-dependent B cell proliferation, T cell-dependent B cell proliferation, allergy, asthma, atherosclerosis, autoimmunity, hypercholesterolemia, chronic inflammation, chronic obstructive pulmonary disease (COPD), Crohn's disease, skin response to tissue injury, fibrosis, hematological oncology, metabolic disease, cardiovascular disease, organ transplantation, psoriasis, liver fibrosis, dermatitis, pulmonary fibrosis, pulmonary response to respiratory infection, restenosis, rheumatoid arthritis, sarcoidosis, stromal biology in tumors, systemic lupus erythematosus (SLE), ulcerative colitis, vascular inflammation, and These include alpha smooth muscle actin (αSMA), CD40, CD69, collagen I, collagen III, decorin, e-selectin, eotaxin 3 (CCL26), fibroblast proliferation, human leukocyte antigen-DR isotype (HLA-DR), immunoglobulin G, interferon gamma-inducible protein 10 (IP-10 / CXCL10), interferon-inducible T cell alpha chemoattractant (I-TAC / CXCL11), interleukin (IL)-1, IL-1 alpha, IL-2, IL-6, IL-8 (CXCL8), IL-10, I L-17A, IL-17F, keratin 8 / 81, macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase (MMP)-1, MMP-9, monocyte chemoattractant protein 1 (MCP-1), gamma interferon-inducible monokine (MIG / CXCL9), plasminogen activator inhibitor 1 (PAI-1), prostaglandin E2 (PGE2), serum amyloid A, T-cell or B-cell proliferation, tissue plasminogen activator (tPA), tumor necrosis factor alpha (TNF alpha), vascular cell adhesion molecule (VCAM-1),and vascular endothelial growth factor 2 (VEGFR2).

[0078] In certain aspects, provided herein is a method of reversing the normal aging process in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharma- ceutically acceptable salt thereof.

[0079] In another aspect, provided herein is a method of reversing the normal aging process in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharma- ceutically acceptable salt thereof.

[0080] In yet another aspect, provided herein is a method of extending the lifespan of a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharma- ceutically acceptable salt thereof.

[0081] In yet another aspect, provided herein is a method of extending the lifespan of a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharma- ceutical acceptable salt thereof.

[0082] In another aspect, provided herein is a method of slowing and reversing the aging process in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharma- ceutically acceptable salt thereof.

[0083] In another aspect, provided herein is a method of inhibiting or modulating a proinflammatory pathway in a cell, comprising contacting the cell with a compound provided herein or a pharma- ceutically acceptable salt thereof. In yet another aspect, provided herein is a method of inhibiting or modulating NLRP3 in a cell, comprising contacting the cell with a compound provided herein or a pharma- ceutically acceptable salt thereof.

[0084] Treating cells (in vitro or in vivo) expressing the NLRP3 inflammasome with the compounds provided herein can inhibit the proinflammatory pathway and inhibit downstream events associated with the signaling pathway, such as inflammation or inflamed senescence.

[0085] In another aspect, provided herein is a method of treating a neurosensory disorder in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0086] In some embodiments, the neurosensory condition is selected from the group consisting of hearing loss, hearing damage, and eye disease, hi some embodiments, the eye disease is retinal damage and optic nerve damage.

[0087] In yet another aspect, provided herein is a method of treating an inflammatory disorder in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0088] In certain embodiments, the inflammatory disorder is selected from the group consisting of allergies, asthma, atopic dermatitis, atherosclerosis, autoimmune diseases, celiac disease, chronic inflammation, glomerulonephritis, hepatitis, inflammatory bowel disease, preperfusion injury, SARS-CoV-2 infection, transplant rejection, heart disease, diabetes, arthritis, Crohn's disease, ulcerative colitis, nonalcoholic steatohepatitis (NASH), gout, coronary artery disease, rheumatoid arthritis, intestinal disorders, and acute respiratory distress syndrome (ARDS).

[0089] In another embodiment, the inflammatory disorder is a neuroinflammatory disease, hi yet another embodiment, the inflammatory disorder is inner ear inflammation.

[0090] In some embodiments, chronic inflammation includes tissue inflammation. Tissue inflammation is chronic inflammation localized to a specific tissue or organ. In some embodiments, tissue inflammation includes, for example, skin inflammation, eye inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreatic inflammation, kidney inflammation, bladder inflammation, stomach inflammation, intestinal inflammation, neuroinflammation, and brain inflammation.

[0091] In another embodiment, chronic inflammation includes systemic inflammation. The process involved is the same as tissue inflammation, but systemic inflammation is not limited to a specific tissue, but actually overwhelms the body and involves endothelium and other organ systems. When it is caused by infection, the term "sepsis" is applied, the term bacteremia is applied specifically to bacterial sepsis, and the term viremia is applied specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infections that can lead to septic shock and death.

[0092] In yet another embodiment, the chronic inflammation comprises arthritis. Arthritis includes a group of conditions involving damage to the joints of the body due to synovial inflammation, including but not limited to osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthropathies such as ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, Whipple's disease and Behcet's disease, septic arthritis, gout (also known as gouty arthritis, crystalline synovitis, metabolic arthritis), pseudogout (calcium pyrophosphate deposition disease), and Still's disease. Arthritis may affect a single joint (monoarthritis), two to four joints (oligoarthritis), or five or more joints (polyarthritis), and may be either an autoimmune or non-autoimmune disease.

[0093] In yet another aspect, provided herein is a method of treating an age-related disorder in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0094] In certain embodiments, the age-related disorder is selected from the group consisting of neurodegeneration, cardiovascular disease, insulin resistance, diabetes, osteoporosis, osteoarthritis, cognitive decline, dementia, frailty, cataracts, arthritis, obesity, hypertension, angina, congestive heart failure, dyslipidemia, myocardial infarction, vascular disease, respiratory disease, renal disease, cerebrovascular disease, peripheral vascular disease, Alzheimer's disease, diastolic dysfunction, benign prostatic hyperplasia, aortic aneurysm, and emphysema.

[0095] In another aspect, provided herein is a method of treating a metabolic condition in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0096] In certain embodiments, the metabolic condition is selected from the group consisting of diabetes, obesity, cystic fibrosis, and hyperthyroidism.

[0097] In yet another aspect, provided herein is a method of treating a neurodegenerative disease in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0098] In certain embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Batten disease.

[0099] In certain aspects, provided herein are methods of treating a disease or disorder of the inner ear in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0100] In one embodiment, the disease or disorder of the inner ear is selected from the group consisting of hearing loss, hearing impairment, vertigo, Meniere's disease, and tinnitus. In another embodiment, the disease of the inner ear is hearing loss. In yet another embodiment, the disease of the inner ear is hearing impairment.

[0101] In another embodiment, the hearing loss is age-related, noise-induced, or the result of a viral infection, hi yet another embodiment, the viral infection is Zika virus or coronavirus.

[0102] The potency of the inhibitor is expressed as IC 50 A lower IC value determined under substantially similar conditions may also be used. 50 Compounds with higher IC 50 These compounds are more potent inhibitors compared to compounds having

[0103] In certain embodiments of the methods, the subject is a human.

[0104] In another aspect, the present disclosure provides a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for treating or preventing a disease involving the NLRP3 inflammasome.

[0105] In certain aspects, provided herein are methods of treating a condition selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and Alzheimer's disease, hi other embodiments, the condition is selected from proliferative disorders and neurodegenerative disorders.

[0106] One aspect of the present disclosure provides compounds useful for treating diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases, and neurodegenerative diseases. Examples of proliferative and hyperproliferative diseases include, but are not limited to, cancer.

[0107] Thus, in certain aspects, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0108] In certain embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, colorectal, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary pathway, kidney cancer, myeloid disorders, lymphoid disorders, Hodgkin's disease, hairy cell carcinoma, buccal and pharyngeal (oral) cancer, lip cancer, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colon cancer, rectal cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer, chronic myeloid leukemia (CML), and leukemia.

[0109] In another embodiment, the cancer is selected from the group consisting of myeloma, lymphoma, or a cancer selected from gastric cancer, renal cancer, head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, liver cancer, non-Hodgkin's lymphoma, and lung cancer.

[0110] In certain embodiments, the cancer is selected from the group consisting of prostate cancer, colon cancer, lung cancer, squamous cell carcinoma of the head and neck, esophageal cancer, hepatocellular carcinoma, melanoma, sarcoma, gastric cancer, pancreatic cancer, ovarian cancer, and breast cancer.

[0111] In certain embodiments, the cancer is selected from the group consisting of tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, the cancer includes, but is not limited to, mesothelioma, leukemia, and lymphomas, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphomas associated with human T-cell lymphotropic virus (HTLV), such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphoma, and multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas, solid tumors common in adults such as head and neck cancer (e.g., oral, laryngeal, nasopharyngeal, and esophageal cancer), genitourinary cancer (e.g., prostate, bladder, kidney, uterine, ovarian, testicular cancer), lung cancer (e.g., small cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin's syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Additional exemplary forms of cancer that may be treated by the subject compounds include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, small intestine cancer, rectum carcinoma, salivary gland cancer, endometrial cancer, adrenal gland cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0112] Additional cancers that the compounds described herein may be useful in treating are, for example, colon cancer, familial adenomatous polyposis cancer and hereditary nonpolyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain cancer such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor, gallbladder cancer, bronchial carcinoma, multiple myeloma, basaloma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0113] In another aspect, provided herein is the use of one or more compounds of the present disclosure in the manufacture of a medicament for treating cancer, including, but not limited to, the various types of cancer disclosed herein.

[0114] In some embodiments, the compounds of the present disclosure are useful for treating cancers such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer, as well as myeloproliferative disorders such as polycythemia vera, thrombocythemia, myelodysplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease. In some embodiments, the compounds of the present disclosure are useful for treating hematopoietic disorders, specifically acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute myeloid leukemia, and acute lymphoblastic leukemia (ALL).

[0115] Administration / Dosage / Formulation Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compounds, liquid dosage forms may contain, for example, inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, com oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavoring agents.

[0116] Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0117] In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material that is poorly soluble in water.The absorption rate of the drug in turn depends on its dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0118] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0119] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0120] The active compound can also be in microencapsulated form with one or more of the above-mentioned excipients. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms can also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is customary. In the case of capsules, tablets, and pills, the dosage forms can also contain buffering agents.

[0121] The dosage forms for topical or transdermal administration of the compounds of the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches.The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any necessary preservatives or buffers that may be required.Ophthalmic preparations, ear drops, eye ointments, powders, and solutions are also contemplated as being within the scope of the present disclosure.

[0122] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of the present disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0123] Powders and sprays can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[0124] Transdermal patches have the added advantage of providing controlled delivery of compounds to the body. Such dosage forms can be made by dissolving or dispensing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0125] The compounds of the present disclosure can be administered intratympanically, where a long thin burr needle is passed through the ear canal, through the tympanic membrane and into the middle ear cavity where it is absorbed into the inner ear.

[0126] According to the therapeutic method of the present disclosure, a disorder is treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the present disclosure in an amount and for a time period necessary to achieve a desired result. As used herein, the term "therapeutically effective amount" of a compound of the present disclosure refers to an amount of the compound sufficient to alleviate the symptoms of the disorder in a subject. As is well understood in the medical field, a therapeutically effective amount of a compound of the present disclosure is a reasonable benefit / risk ratio applicable to any medical treatment.

[0127] In general, the compounds of the present disclosure are administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, by any of the usual accepted modes known in the art. The therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. In general, satisfactory results are indicated to be obtained systemically at a daily dosage of about 0.03 to 2.5 mg / kg body weight. Indicated daily dosages in larger mammals, such as humans, are in the range of about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses or in delayed form up to four times a day. A suitable unit dosage form for oral administration contains about 1 to 50 mg of active ingredient.

[0128] In certain embodiments, the therapeutic amount or dose of the compounds of the present disclosure may range from about 0.1 mg / Kg to about 500 mg / Kg, or alternatively, from about 1 to about 50 mg / Kg. In general, a treatment regimen according to the present disclosure includes administering to a patient in need of such treatment, one or more times, from about 10 mg to about 1000 mg of the compound(s) of the present disclosure per day. The therapeutic amount or dose will vary depending on the route of administration as well as possible co-administration with other drugs.

[0129] When the condition of the subject is improved, a maintenance dose of the compound, composition or combination of the present disclosure can be administered as necessary.Then, the dosage or frequency of administration, or both, can be reduced as a function of symptoms to a level at which the improved condition is maintained, and treatment should be stopped when symptoms are alleviated to a desired level.However, the subject may require intermittent treatment over the long term upon recurrence of disease symptoms.

[0130] However, it will be understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment.The specific inhibitory dose for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the specific compound used, the specific composition used, the patient's age, weight, general health, sex, and diet, the administration time, route of administration, and excretion rate of the specific compound used, the duration of treatment, drugs used in combination or simultaneously with the specific compound used, and similar factors well known in the medical field.

[0131] The present disclosure also provides pharmaceutical combinations, e.g., kits, comprising a) a first agent that is a compound of the present disclosure disclosed herein in free form or in pharma- ceutically acceptable salt form, and b) at least one co-agent. The kit can include instructions for its administration.

[0132] Some examples of materials which can function as pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose, and sucrose, starches such as corn starch, and and potato starch, cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients, such as cocoa butter and suppository wax, oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, glycols, such as propylene glycol or polyethylene glycol, esters, such as ethyl oleate and ethyl laurate, agar, buffers, such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate buffer solution. In addition, non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents, and perfumes, preservatives, and antioxidants can also be present in the composition, according to the discretion of the formulator. The protein kinase inhibitors or pharmaceutical salts thereof can be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective for treating or preventing a protein kinase-mediated condition and a pharma- ceutical acceptable carrier, are other embodiments of the present disclosure.

[0133] kit In one aspect, provided herein is a kit comprising a compound capable of inhibiting NLRP3 inflammasome activity selected from one or more compounds disclosed herein, or a pharma- ceutically acceptable salt thereof, and instructions for use in treating an NLRP3 inflammasome-associated disorder.

[0134] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting NLRP3 inflammasome activity selected from the compounds disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0135] In yet another aspect, provided herein is a kit comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, for the treatment of any of the indications disclosed herein.

[0136] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and are encompassed by the claims appended hereto. For example, modifications of reaction conditions, including but not limited to reaction times, reaction sizes / volumes, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, such as nitrogen atmosphere, and reducing / oxidizing agents, using art-recognized alternatives and no more than routine experimentation, should be understood to be within the scope of this application.

[0137] When values ​​and ranges are provided herein, it is to be understood that all values ​​and ranges encompassed by those values ​​and ranges are intended to be encompassed within the scope of the disclosure. Moreover, all values ​​that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the application. The following examples further illustrate aspects of the present disclosure, however, they do not in any way limit the teachings of the disclosure described. EXAMPLES

[0138] The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, within the skill of the art. Abbreviation ACN Acetonitrile AcOH Acetic acid DCM Dichloromethane DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc Ethyl acetate EtOH Ethanol HPLC High Performance Liquid Chromatography LAH Lithium aluminum hydride LCMS Liquid Chromatography-Mass Spectrometry m-CPBA meta-chloroperoxybenzoic acid MeOH Methanol NMR nuclear magnetic resonance PE Petroleum Ether SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography

[0139] Example 1: Synthesis Procedure [ka] To a solution of compound 1 (20 mg, 49.45 umol, 1 equiv.) in DCM (1 mL) was added m-CPBA (10.04 mg, 49.45 umol, 85% purity, 1 equiv.) at 0° C., and the mixture was then stirred at 20° C. for 1 h. The reaction mixture was poured into water (1 mL), extracted with dichloromethane (3×2 mL), and the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 26%-56%, 9 min), and the purified solution was freeze-dried to give a white solid. The white solid was purified by preparative HPLC (column: Waters xbridge 150×25 mm 10 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 23%-53%, 8 min) and the purified solution was lyophilized to give a white solid. Compound 001 (16 mg, 36.08 umol, 72.95% yield, 94.8% purity) was obtained as a white solid. LCMS: Rt=0.527 min, m / z=421.2 (M+H) + 1H NMR (400 MHz, chloroform-d) δ=12.58-12.24(m,1H),8.77(d,J=1.3 Hz,1H),8.19-8.11(m,2H),7.37(td,J=3.0,7.8 Hz,2H),7.31(d,J=7.6 Hz,2H),7.12-7.01(m,3H),4.89(s,2H),4.08(q,J=7.0 Hz,2H),3.10(s,3H),1.38(t,J=6.9 Hz,3H).

[0140] Compound 003 was prepared in a similar manner to Scheme 1 and obtained as a brown solid (7.05 mg, 16.18 umol, 22.57% yield, and 99.72% purity). LCMS: Rt=0.482 min, m / z=435.3 (M+H + ). 1H NMR: (400 MHz, chloroform-d) δ = 12.53-12.36 (m, 1H), 8.80 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 7.38-7.35 (m, 1H), 7.34 (s, 1H), 7.15-7.07 (m, 3H), 6.52-6.42 (m, 1H), 4.21-4.03 (m, 2H), 2.91 (s, 3H), 1.87 (d, J = 7.1 Hz, 3H), 1.43 (t, J = 6.9 Hz, 3H).

[0141] [ka] To a solution of compound 1 (260 mg, 848.35 umol, 1.1 equiv.) and compound 2 (200.72 mg, 771.23 umol, 1 equiv.) in DCM (5 mL) was added EDCI (221.77 mg, 1.16 mmol, 1.5 equiv.) and DMAP (9.42 mg, 77.12 umol, 0.1 equiv.) and the mixture was stirred at 20° C. for 12 h. The solution was evaporated under reduced pressure using a rotary evaporator on a water bath. The residue was analyzed by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=0:1, Rf=0.4). Compound 3 (341 mg, 576.70 umol, 74.78% yield, 92.8% purity) was obtained as a white solid. LCMS: Rt=0.583 min, m / z=549.1 (M+H + )

[0142] To a solution of compound 3 (341 mg, 576.70 umol, 92.8% purity, 1 equiv.) in DCM (3 mL), TFA (4.29 g, 37.60 mmol, 2.78 mL, 65.20 equiv.) was added at 0° C., and the mixture was stirred at 20° C. for 1 h. The mixture was concentrated to give the crude product, which was dissolved in MeOH (10 mL) and 1 g of Na 2 CO 3 was added to the mixture, and the mixture was stirred at 20° C. for 0.5 h, after which the mixture was filtered and the filtrate was concentrated to give the crude product. The residue was analyzed by preparative TLC (SiO 2, dichloromethane:methanol=10:1, Rf=0.4). Compound 4 (146 mg, 348.90 umol, 60.50% yield, purity not applicable) was obtained as a colorless oil. LCMS: Rt=0.642 min, m / z=419.1 (M+H + )

[0143] To a solution of compound 4 (146 mg, 348.90 umol, 1 equiv.) in DCM (10 mL), m-CPBA (184.31 mg, 1.05 mmol, 98% purity, 3 equiv.) was added at 0° C., and the mixture was stirred at 30° C. for 12 h. After the reaction was complete, the mixture was filtered and the cake was washed with saturated Na 2 SO 3 The crude product was dissolved slowly in 1,000 ml of ethyl acetate (50 mL) and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (NH4.HO, column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (NH 3 H 2 The mixture was purified by HPLC using 100% ethyl acetate (100% ethyl acetate-ACN); B%: 25%-55%, 8 min) and the purified solution was lyophilized to give a white solid. Compound 002 (46.91 mg, 104.79 umol, 30.03% yield, 97.05% purity) was obtained as a white solid. LCMS: Rt=0.665 min, m / z=453.3 (M+Na + ). 1 H NMR(400 MHz, chloroform-d)δ=12.54-12.22(m,1H),8.45-8.27(m,1H),8.19(s,1H),7.41-7.34(m,2H),7.33-7.28(m,2 H),7.11-7.02(m,3H),4.98-4.80(m,2H),4.18-3.93(m,2H),3.09(s,3H),2.95-2.78(m,3H),1.38(t,J=6.9 Hz,3H).

[0144] Compound 005 was prepared in a similar manner to Scheme 2 (11.9 mg, 26.55 umol, 47.62% yield, 99.6% purity) as a white solid. LCMS: Rt=0.384 min, m / z=447.3 (M+H). +1H NMR(400 MHz, chloroform-d)δ=8.35-8.28(m,1H),8.20-8.13(m,1H),7.47-7.40(m,1H),7.38-7.29(m,2H),7.24-7.20(m,1H),7.20-7.15(m,1H), 7.13-7.08(m,1H),7.06-6.99(m,1H),4.93-4.84(m,2H),3.81-3.71(m,1H),3.14-3.05(m,3H),2.89-2.81(m,3H),0.84-0.72(m,4H).

[0145] Compound 008 was prepared in a similar manner to Scheme 2 (5.7 mg, 12.67 umol, 54.69% yield, 99.5% purity) as a white solid. LCMS: Rt=0.401 min, m / z =448.2(M+H)+ 1H NMR(400 MHz,chloroform-d)δ ppm 12.35-12.60(m,1 H)8.39-8.42(m,1 H)8.24-8.26(m,1 H)7.94-7.96(m,1 H)7.71(d,J=1.25 Hz,1 H)7.67-7.70(m,1 H)7.08-7.11(m,2 H)4.88-4.92(m,2 H)4.19-4.26(m,2 H)3.08-3.11(m,3 H)2.92(s,3 H)1.54-1.59(m,3 H).

[0146] Compound 013 was prepared in a similar manner to Scheme 2 (11.81 mg, 27.18 umol, 22.75% yield, 100% purity) and obtained as a white solid. LCMS: Rt=0.529 min, m / z=435.2(M+H+).1H NMR:(400 MHz,chloroform-d)δ=13.39-13.05(m,1H),9.52(d,J=1.8 Hz,1H),8.51(s,1H),7.39(br dd,J=2.9,5.5 Hz,2H),7.34-7.30(m,3H),7.11-7.05(m,2H),5.19(br s,2H),4.12-4.04(m,2H),3.14(s,3H),3.06(d,J=2.1 Hz,3H),1.39(br s,3H).

[0147] Compound 018 was prepared in a similar manner to Scheme 2 (14.1 mg, 28.69 umol, 38.97% yield) and obtained as a white solid. LCMS: Rt=0.545 min, m / z=492.3 [M+H + ] 1H NMR (400 MHz, chloroform-d) δ=12.59-12.43(m,1H),8.38(s,1H),8.28(dd,J=2.4,7.7 Hz,1H),8.24(s,1H),7.71-7.65(m,1H),7.38(d,J=7.8 Hz,1H),7.16(dd,J=8.6,11.7 Hz,1H),7.09(dd,J=1.4,7.8 Hz,1H),7.06(s,1H),6.83-6.71(m,1H),4.89(s,2H),4.12-4.02(m,2H),3.10(s,3H),3.06(d,J=4.1 Hz,3H),2.92(s,3H),1.37(t,J=6.9 Hz,3H).

[0148] Compound 034 was prepared in a similar manner as in Scheme 2. Compound 034 (9.8 mg, 20.90 umol, 31.55% yield, 100% purity) was isolated as a white solid. LCMS: Rt=0.407 min, m / z=469.2(M+H)+ 1H NMR(400 MHz, chloroform-d)δ=12.26-12.12(m,1H),8.23(s,1H),8.15(s,1H),7.43-7.36(m,1H),7.15(s,1H),7. 12-7.07(m,1H),7.07-7.02(m,1H),7.01-6.97(m,1H),6.95-6.91(m,1H),4.85(s,2H),3.99(q,J=6.9 Hz,2H),3.12-3.06(m,3H),2.84(s,3H),1.28-1.22(m,3H).

[0149] Compound 037 was prepared in a similar manner to Scheme 2 and was obtained as a white solid. LCMS: Rt=0.431 min, m / z=485.4 (M+H). +1H NMR (400 MHz, chloroform-d) δ = 12.35 (s, 1H), 8.28 (s, 1H), 8.19-8.16 (m, 1H), 7.38-7.37 (m, 1H), 7.36 (s, 1H), 7.28-7.27 (m, 1H), 7.18-7.16 (m, 1H), 7.16-7.14 (m, 1H), 6.94-6.92 (m, 1H), 4.85 (s, 2H), 4.03-3.96 (m, 2H), 3.10 (s, 3H), 2.86 (s, 3H), 1.26 (t, J = 6.9 Hz, 3H). [ka]

[0150] To a solution of compound 1 (400 mg, 1.48 mmol, 1 equiv.) in dioxane (4 mL), compound 2 (412.88 mg, 2.95 mmol, 2 equiv.), Pd(dppf)Cl 2 ·CH 2 Cl 2 (120.49 mg, 147.54 umol, 0.1 equivalents), and Cs 2 CO 3 (961.45 mg, 2.95 mmol, 2 equiv.) was added and the reaction mixture was treated with N 2 The mixture was stirred at 100° C. for 12 h under reduced pressure. The reaction mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography on silica gel eluting with petroleum ether:ethyl acetate=1:0-20 / 1 (desired compound Rf=0.5). Compound 3 (375 mg, 1.21 mmol, 81.67% yield, 92% purity) was obtained as a brown oil. LCMS: Rt=0.642 min, m / z=287.0 (M+H+).

[0151] H in compound 3 2 In a solution of 2 mL of HO and 6 mL of MeOH, LiOH.H 20 (153.90 mg, 3.67 mmol, 3 equiv) was added and the reaction mixture was stirred at 20° C. for 12 h. 1 mol / L HCl was added to acidify the reaction mixture to pH=5. The reaction mixture was then concentrated to give the crude product, which was used in the next step without further purification. Compound 4 (319 mg, 1.04 mmol, 84.99% yield, 88.68% purity) was obtained as a white solid. LCMS: Rt=0.571 min, m / z=273.0 (M+H+).

[0152] To a solution of compound 4 (90 mg, 290.89 umol, 88% purity, 1 eq.) in DCM (2 mL), compound 5 (102.08 mg, 349.06 umol, 1.2 eq.), EDCI (83.65 mg, 436.33 umol, 1.5 eq.), and DMAP (3.55 mg, 29.09 umol, 0.1 eq.) were added and the reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate=0:1, desired compound Rf=0.5). Compound 6 ((117 mg, 188.33 umol, 64.74% yield, 88% purity) was obtained as a colorless oil. LCMS: Rt=0.610 min, m / z=547.1 (M-H+)

[0153] To a solution of compound 6 (117 mg, 188.33 umol, 88% purity, 1 equiv.) in DCM (2 mL), TFA (3.08 g, 27.01 mmol, 2 mL, 143.43 equiv.) was added and the reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by preparative TLC (dichloromethane:methanol=10:1, desired compound Rf=0.5). Compound 7 (98 mg, crude) was obtained as a colorless oil. LCMS: Rt=0.491 min, m / z=417.0 (M-H+)

[0154] To a solution of compound 7 (98 mg, 235.32 umol, 1 equiv.) in DCM (2 mL) was added m-CPBA (143.33 mg, 705.97 umol, 85% purity, 3 equiv.) at 0° C., and the reaction mixture was stirred at 20° C. for 2 h. After the reaction was complete, the mixture was diluted with saturated Na2 SO 3 The solution was poured into 100 mL of water and extracted with EtOAc (25 mL×3). The combined organic phase was washed with brine (50 mL) and anhydrous Na 2 SO 4 The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10um; mobile phase: [water (FA)-ACN]; B%: 38%-68%, 9min). After purification by preparative HPLC, the eluent was concentrated to remove the organic solvent. The residual aqueous solution was lyophilized to obtain a white solid. 004 (21.68mg, 49.13umol, 20.88% yield, 98% purity) was obtained as a white solid. LCMS: Rt=0.503min, m / z =433.0(M+H+). 1 H NMR(400 MHz, chloroform-d)δ=9.09-8.98(m,1H),8.51-8.42(m,1H),8.38-8.30(m,1H) ,7.49-7.44(m,1H),7.40-7.34(m,2H),7.27-7.25(m,1H),7.25-7.22(m,1H ),7.24-7.18(m,2H),7.17-7.11(m,1H),7.09-7.03(m,1H),5.00(s,2H),3 .83-3.76(m,1H),3.21-3.15(m,3H),0.86-0.82(m,2H),0.81-0.76(m,2H).

[0155] Compound 010 was prepared in a similar manner to Scheme 3 (8.2 mg, 17.84 umol, 38.94% yield, 98.462% purity) and obtained as a white solid. LCMS: Rt=0.637 min, m / z=453.2 (M+H + ). 1H NMR(400 MHz,chloroform-d)δ=12.46-12.16(m,1H),8.35(s,1H),8.21(s,1H),7.43-7.36(m,1H),7.19(d,J=7.6 Hz,1H),7.14(br d,J=9.6 Hz,1H),7.11-7.05(m,1H),6.89-6.84(m,2H),4.99-4.77(m,2H),4.11-3.97(m,2H),3.11(s,3H),2.93-2.78(m,3H),1.32(t,J=6.9 Hz,3H).

[0156] Compound 011 was prepared in a similar manner to Scheme 3 (5.23 mg, 11.38 umol, 16.28% yield, 100% purity) and obtained as a pale yellow solid. LCMS: Rt=0.407 min, m / z=460.2 (M+H + ) 1 H NMR:(400 MHz,chloroform-d)δ=13.17-12.48(m,1H),8.69-8.59(m,1H),8.52-8.39(m,1H),7.78-7.72(m,1H),7.67(br t,J=6.5 Hz,2H),7.58-7.51(m,1H),6.95-6.81(m,2H),4.95(s,2H),4.06(q,J=7.2 Hz,2H),3.17(s,3H),3.09(s,3H),1.33(t,J=7.0 Hz,3H).

[0157] Compound 014 was prepared in a similar manner as Scheme 3 (14 mg, 29.80 umol, 33.35% yield, 96.312% purity) and obtained as a white solid. LCMS: Rt=0.539 min, m / z=453.1 (M+H + ). 1 H NMR: (400 MHz, chloroform-d) δ = 12.83-12.02 (m, 1H), 8.35 (s, 1H), 8.23 ​​(s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.13-6.99 (m, 4H), 6.81 (tt, J = 2.3, 8.9 Hz, 1H), 4.89 (s, 2H), 4.09 (q, J = 7.0 Hz, 2H), 3.09 (s, 3H), 2.91 (s, 3H), 1.40 (t, J = 6.9 Hz, 3H).

[0158] Compound 017 was prepared in a similar manner to Scheme 3 (7.7 mg, 16.58 umol, 12.39% yield, 100% purity) and obtained as a white solid. LCMS: Rt=0.440 min, m / z=465.2 (M+H). + 1H NMR(400 MHz,chloroform-d)δ ppm 8.34-8.44(m,1 H)8.23(s,1 H)7.44(d,J=1.38 Hz,1 H)7.32(br d,J=1.63 Hz,1 H)7.28-7.31(m,1 H)7.18-7.21(m,1 H)7.16-7.18(m,1 H)7.11(dd,J=7.75,1.50 Hz,1 H)4.89-4.93(m,2 H)3.75-3.80(m,1 H)3.08-3.14(m,3 H)2.90(s,3 H)0.80-0.86(m,2 H)0.73-0.79(m,2 H).

[0159] Compound 019 was prepared in a similar manner to Scheme 3 (6.9 mg, 14.24 umol, 16.68% yield, 100% purity) and obtained as a white solid. LCMS: Rt=0.567 min, m / z=485.2 (M+H+). 1 H NMR: (400 MHz, chloroform-d) δ = 8.76-8.37 (m, 1H), 7.87 (s, 1H), 7.72-7.72 (m, 1H), 7.77-7.71 (m, 1H), 7.66-7.61 (m, 1H), 7.59-7.52 (m, 1H), 7.45-7.39 (m, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.10-7.00 (m, 1H), 5.02-4.91 (m, 2H), 4.15-4.05 (m, 2H), 3.23-2.99 (m, 6H), 1.42-1.36 (m, 3H).

[0160] Compound 046 was prepared in a similar manner to Scheme 3 and obtained as a white solid (13.1 mg, 27.13 umol, 63.07% yield, 99.6% purity). LCMS: Rt=0.429 min, m / z=481.3 (M+H). +1H NMR (400 MHz, chloroform-d) δ = 8.29 (s, 1H), 8.17 (s, 1H), 7.37-7.31 (m, 3H), 7.25-7.19 (m, 2H), 6.93-6.86 (m, 1H), 4.87 (s, 2H), 3.77-3.73 (m, 1H), 3.11 (s, 3H), 2.85 (s, 3H), 0.83-0.76 (m, 2H), 0.75-0.69 (m, 2H). [ka]

[0161] To a solution of 1 (2.2 g, 10.38 mmol, 1 equiv) in 2-MeTHF (30 mL) was added NaH (622.45 mg, 15.56 mmol, 60% purity, 1.5 equiv) at 0 °C and the mixture was stirred at 0 °C for 1 h. Then, SEM-Cl (2.08 g, 12.45 mmol, 2.20 mL, 1.2 equiv) was added dropwise and the mixture was stirred at 20 °C for 12 h. The mixture was diluted with saturated NH 4 Cl (200 mL), extracted with EtOAc (200 mL x 3), and the combined organic phase was washed with brine (200 mL) and anhydrous Na 2 SO 4 The crude product was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:1). 2 (1.55 g, 4.52 mmol, 43.57% yield) was obtained as a brown oil. LCMS: Rt = 0.533 min, m / z = 343.9 (M+H + )

[0162] A solution of 2 (1.55 g, 4.53 mmol, 1 equiv.) in MeOH (20 mL) was added to Pd(OAc) 2 (203.32 mg, 905.62 umol, 0.2 equiv), DPPF (502.06 mg, 905.62 umol, 0.2 equiv), and TEA (2.29 g, 22.64 mmol, 3.15 mL, 5 equiv) were added and the mixture was stirred under CO (50 psi) at 80° C. for 12 h. After the reaction was complete, the mixture was purged with N 2The crude product was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 40 / 1-60 / 1). 3 (1.42 g, 4.41 mmol, 97.35% yield) was obtained as a brown oil. LCMS: Rt = 0.367 min, m / z = 322.2 (M+H + )

[0163] To a solution of 3 (1.42 g, 4.42 mmol, 1 equiv.) in 2-MeTHF (15 mL) was added LAH (251.47 mg, 6.63 mmol, 1.5 equiv.) at 0° C., and the mixture was stirred at 0° C. for 1 h. After the reaction was completed, the resulting mixture was treated with Na 2 SO 4 .10H 2 0 (2 g) was added. Then the mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was used in the next step without further purification. 4 (1.1 g, crude) was obtained as a yellow oil. LCMS: Rt=0.709 min, m / z=409.0 (M+Na + )

[0164] A solution of 4 (1.1 g, 3.75 mmol, 1 equiv.) in DCM (15 mL) was added to MnO 2 (6.52 g, 74.97 mmol, 20 equiv.) was added and the mixture was stirred at 30° C. for 12 h. After the reaction was complete, the mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 40 / 1-60 / 1). 5 (821 mg, 2.82 mmol, 75.23% yield) was obtained as a yellow oil. 4 (373 mg, 1.27 mmol, 33.91% yield) was obtained as a yellow oil. LCMS: Rt = 0.507 min, m / z = 292.1 (M+H + ). 1 H NMR: (400 MHz, chloroform-d) δ = 10.20 (s, 1H), 8.79 (s, 1H), 8.27 (s, 1H), 6.23 (s, 2H), 3.52 (dd, J = 7.8, 8.8 Hz, 2H), 2.92 (s, 3H), 0.87-0.82 (m, 2H), -0.09 (s, 9H)

[0165] To a solution of 5 (821 mg, 2.82 mmol, 1 equiv) in MeOH (10 mL), 2 A 2M / THF solution (7.04 mL, 5 eq.) and AcOH (16.92 mg, 281.72 umol, 16.11 uL, 0.1 eq.) were added and the mixture was stirred at 20° C. for 1 h. NaBH 4 (319.75 mg, 8.45 mmol, 3 equiv.) was added to the solution and the mixture was stirred at 20° C. for 1 h. The reaction mixture was diluted with saturated NH 4 It was quenched with aqueous Cl (10 mL) and the resulting mixture was concentrated in vacuo to give a residue. The crude product was used in the next step without further purification. 6 (900 mg, crude) was obtained as a yellow oil. LCMS: Rt=0.302 min, m / z=307.1 (M+H + )

[0166] To a solution of compound 7 (80 mg, 286.44 umol, 1 equiv.) and 6 (131.68 mg, 429.66 umol, 1.5 equiv.) in DCM (2 mL) was added EDCI (82.37 mg, 429.66 umol, 1.5 equiv.) and DMAP (3.50 mg, 28.64 umol, 0.1 equiv.). The mixture was stirred at 20° C. for 12 h. The solution was evaporated under reduced pressure on a water bath using a rotary evaporator. The residue was analyzed by preparative TLC (SiO 2 , EtOAc=1). Compound 8 (78 mg, 128.23 umol, 44.77% yield, 93.337% purity) was obtained as a colorless oil. LCMS: Rt=0.528 min, m / z=568.4 (M+H + )

[0167] To a solution of compound 8 in DCM (1 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 49.15 equiv). The mixture was stirred at 20° C. for 12 h. The solution was evaporated under reduced pressure using a rotary evaporator on a water bath. The residue was analyzed by preparative TLC (SiO 2, DCM:MeOH=10:1). Compound 9 (57 mg, 109.44 umol, 79.66% yield, 84% purity) was obtained as a colorless oil. LCMS: Rt=0.543 min, m / z=438.2 (M+H + )

[0168] To a solution of 4-(3-cyanophenyl)-3-(cyclopropyl)-N-methyl-N-[(4-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl)methyl]benzamide (57 mg, 130.29 umol, 1 equiv.) in DCM (2 mL) was added m-CPBA (79.35 mg, 390.86 umol, 85% purity, 3 equiv.) at 0° C. The mixture was stirred at 37° C. for 2 h. 2 The mixture was stirred at 30° C. for 12 hours under reduced pressure. After the reaction was completed, the mixture was filtered and the cake was washed with saturated Na 2 SO 3 The crude product was purified by preparative HPLC. Column: Welch Xtimate C18 150×25mm×5um; Mobile phase: [Water (NH 3 H 2 O)-ACN]; B%: 15%-45%, 8 min. Lyophilized. Compound 006 (10.88 mg, 23.99 umol, 18.41% yield, 100% purity) was obtained as a white solid. LCMS: Rt=0.461 min, m / z=454.2 (M+H + ). 1 H NMR:(400 MHz,chloroform-d)δ=12.88-12.63(m,1H),8.61-8.52(m,1H),8.36(br s,1H),7.78(s,1H),7.69(s,1H),7.63(s,1H),7.52(s,1H),7.45(s,1H),7.34(d,J=7.8 Hz,1H),7.14(dd,J=1.4,7.8 Hz,1H),4.96(br s,2H),3.82-3.74(m,1H),3.16(s,3H),3.02(br s,3H),0.85(br d,J=6.3 Hz,2H),0.75(br d,J=2.0 Hz,2H).

[0169] Compound 007 was prepared in a similar manner to Scheme 4 (10.88 mg, 23.99 umol, 18.41% yield, 100% purity) and obtained as a white solid. LCMS: Rt=0.461 min, m / z=454.2 (M+H + ). 1 H NMR:(400 MHz,chloroform-d)δ=12.88-12.63(m,1H),8.61-8.52(m,1H),8.36(br s,1H),7.78(s,1H),7.69(s,1H),7.63(s,1H),7.52(s,1H),7.45(s,1H),7.34(d,J=7.8 Hz,1H),7.14(dd,J=1.4,7.8 Hz,1H),4.96(br s,2H),3.82-3.74(m,1H),3.16(s,3H),3.02(br s,3H),0.85(br d,J=6.3 Hz,2H),0.75(br d,J=2.0 Hz,2H). [ka]

[0170] To a solution of compound 1 (300 mg, 1.22 mmol, 1 equiv.) and iodoethane (954.62 mg, 6.12 mmol, 489.55 uL, 5 equiv.) in DMF (10 mL), Cs 2 CO 3 (797.70 mg, 2.45 mmol, 2 equiv.) was added. The mixture was stirred at 80° C. for 12 h. The reaction was clean by TLC. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL×3), and the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1), and the purified solution was concentrated under vacuum to give compound 2 (330 mg, 1.21 mmol, 98.70% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ = 7.52-7.48 (m, 1H), 7.46-7.42 (m, 1H), 3.95 (q, J = 7.0 Hz, 2H), 3.90-3.88 (m, 3H), 2.55 (s, 3H), 1.51-1.45 (m, 3H).

[0171] To a solution of compound 2 (330 mg, 1.21 mmol, 1 equiv.) in dioxane (5 mL), compound 3 (507.17 mg, 3.62 mmol, 3 equiv.), K 2 CO 3 (333.97 mg, 2.42 mmol, 2 equiv.), and Pd(dppf)Cl 2 ·CH 2 Cl 2 (98.67 mg, 120.82 umol, 0.1 equiv.) was added and the reaction mixture was treated with N 2 The mixture was stirred at 100° C. for 12 hours under reduced pressure. The reaction mixture was filtered and the filtrate was concentrated to give the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=20 / 1-10 / 1) and the purified solution was concentrated under vacuum to give compound 4 (270 mg, 936.48 umol, 77.51% yield) as a colorless oil. LCMS: Rt=0.549 min, m / z=289.0 (M+H) + 1H NMR (400 MHz, chloroform-d) δ = 7.71-7.66 (m, 1H), 7.43-7.32 (m, 3H), 7.22 (d, J = 8.0 Hz, 1H), 7.10-7.04 (m, 1H), 3.94-3.89 (m, 3H), 3.50 (q, J = 7.0 Hz, 2H), 2.59-2.55 (m, 3H), 1.13 (t, J = 7.1 Hz, 3H)

[0172] Compound 4 (270 mg, 936.48 umol, 1 equiv.) in MeOH (3 mL) and H 2 In a solution of LiOH H 2HO (117.89 mg, 2.81 mmol, 3 equiv) was added and the mixture was stirred at 20° C. for 1 h. NaOH (112.37 mg, 2.81 mmol, 3 equiv) was added to the reaction and the reaction was then stirred at 20° C. for 1 h. The organic solvent was evaporated under vacuum and the resulting mixture was acidified to pH 4 with 1N HCl, then the mixture was filtered, washed with water (10 mL) and the filter cake was dried under vacuum to give compound 5 (200 mg, 729.17 umol, 77.86% yield) as a white solid which was used directly in the next step. LCMS: Rt=0.338 min, m / z=273.1 (MH). + 1H NMR (400 MHz, chloroform-d) δ = 7.79-7.71 (m, 1H), 7.41-7.28 (m, 3H), 7.22-7.15 (m, 1H), 7.09-7.02 (m, 1H), 3.49-3.43 (m, 2H), 2.57 (s, 3H), 1.10 (t, J = 7.0 Hz, 3H)

[0173] To a solution of compound 5 (140 mg, 510.42 umol, 1 equiv.) in DCM (1 mL), compound 6 (156.43 mg, 510.42 umol, 1 equiv.), EDCI (146.77 mg, 765.62 umol, 1.5 equiv.), and DMAP (6.24 mg, 51.04 umol, 0.1 equiv.) were added, and the reaction mixture was then stirred at 20° C. for 1 h. The reaction mixture was concentrated under vacuum to give a residue. The residue was analyzed by preparative TLC (SiO 2 , petroleum ether / ethyl acetate=0 / 1) and the purified solution was concentrated under vacuum to give compound 7 (120 mg, 213.24 umol, 41.78% yield) as a colorless oil. LCMS: Rt=0.484 min, m / z=563.3 (M+H) + A solution of compound 7 (140 mg, 248.78 umol, 1 equiv.) in TFA (1 mL) was stirred at 20° C. for 1 h. The reaction mixture was diluted with saturated NaHCO 3 The reaction mixture was then basified with aqueous solution (10 mL) of H 2 The mixture was diluted with 200 mL of EA (10 mL × 3) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine and 2 SO 4Drying at 40° C., filtration and concentration under reduced pressure gave compound 8 (100 mg, 231.22 umol, 92.94% yield) as a yellow oil which was used directly in the next step. LCMS: Rt=0.448 min, m / z=433.3 (M+H). +

[0174] To a solution of compound 8 (90 mg, 208.10 umol, 1 equiv.) in DCM (1 mL), m-CPBA (42.25 mg, 208.10 umol, 85% purity, 1 equiv.) was added and the mixture was stirred at 20° C. for 1 h. The reaction mixture was diluted with NaHCO 3 (50mg), the reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150x25mmx10um; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 9min), and the purified solution was lyophilized to give 009 (16.4mg, 35.03umol, 16.83% yield, 95.8% purity) as a white solid. LCMS: Rt=0.391min, m / z=449.3(M+H) + 1H NMR(400 MHz, chloroform-d)δ=8.40(s,1H),8.22-8.20(m,1H),7.42-7.35(m,1H),7.34-7.28(m,2H),7 .24-7.19(m,1H),7.09-7.02(m,1H),6.98-6.94(m,1H),5.11-4.73(m,2H),3.48(q,J=6.8 Hz,2H),2.93(s,3H),2.91-2.88(m,3H),2.11-2.06(m,3H),1.10(t,J=7.0 Hz,3H). [ka]

[0175] To a solution of compound 1 (6.8 g, 28.57 mmol, 1 equiv.) and compound 2 (1.66 g, 28.57 mmol, 1 equiv.) in DMF (120 mL) was added Cs 2 CO 3(18.62 g, 57.15 mmol, 2 equiv.) was added and stirred at 25° C. for 12 h. TLC (PE:EtOAC=10:1) showed that 20% of compound 1 remained, and one major new spot with higher polarity was detected. The reaction mixture was diluted with H 2 The combined organics were washed with aqueous NaCl (500 mL×3) and extracted with EtOAc (300 mL×3). 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0-10 / 1) to give the product. Compound 3 (5.42 g, 19.63 mmol, 68.70% yield) was obtained as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ = 7.36-7.33 (m, 1H), 7.06-7.02 (m, 1H), 3.90-3.84 (m, 1H), 0.89-0.86 (m, 4H).

[0176] To a solution of compound 3 (5.4 g, 19.56 mmol, 1 equiv.) in MeOH (60 mL), Pd(OAc) 2 (439.16 mg, 1.96 mmol, 0.1 equiv), DPPF (2.17 g, 3.91 mmol, 0.2 equiv), and TEA (9.90 g, 97.81 mmol, 13.61 mL, 5 equiv) were added and stirred at 80 °C under CO (50 psi) for 16 h. The reaction mixture was diluted with 100 mL of H 2 Dilute with 202.2 O and extract with 150 mL of EtOAc (5 mL x 3). Combine the organic layers and pour into Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0-10 / 1) to give the product. Compound 4 (3.43 g, 15.23 mmol, 77.86% yield) was obtained as a light yellow solid. LCMS: Rt = 0.457 min, m / z = 226.2 (M+H). +1H NMR(400 MHz,DMSO-d6)δ=7.54-7.46(m,1H),7.32-7.24(m,1H),5.59-5.47(m,2H),3.98-3.91(m,1H),3.81-3.73(m,3H),0.81-0.69(m,4H)

[0177] To a solution of compound 4 (3.3 g, 14.65 mmol, 1 equiv.) in ACN (70 mL), CuBr (4.20 g, 29.31 mmol, 892.53 uL, 2 equiv.) and isoamyl nitrite (3.43 g, 29.31 mmol, 3.95 mL, 2 equiv.) were added at 0° C., and the mixture was stirred at 20° C. for 1 h. TLC (PE:EtOAc=10:1) showed that compound 4 was completely consumed and a new spot appeared. The reaction mixture was diluted with H 2 O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organics were washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0-10 / 1) to give the product. Compound 5 (2.72 g, 9.41 mmol, 64.21% yield) was obtained as a white solid. Compound 5 (2.72 g, 9.41 mmol, 1 equiv.) in THF (30 mL) and H 2 In a solution of LiOH H 2 0 (1.18 g, 28.23 mmol, 3 equiv.) was added and stirred at 20° C. for 1 h. The organic solvent was evaporated under vacuum and the resulting mixture was acidified to pH 4 with 1N HCl, then the mixture was filtered, washed with water (10 mL) and the filter cake was dried under vacuum to give the product. Compound 6 (2.5 g, 9.09 mmol, 96.60% yield) was obtained as a light yellow solid. LCMS: Rt=0.569 min, m / z=272.9 (MH). +

[0178] Compound 6 (1 g, 3.64 mmol, 1 equiv.) and compound 7 (801.28 mg, 5.45 mmol, 1.5 equiv.) in dioxane (10 mL) and H 2In a solution of Pd(dppf)Cl in 2 mL of HO (2 mL), 2 ·CH 2 Cl 2 (148.44 mg, 181.77 umol, 0.05 equivalents) and K 2 CO 3 (753.66 mg, 5.45 mmol, 1.5 equiv.) was added and the mixture was treated with N 2 The reaction mixture was stirred at 100° C. for 12 h under reduced pressure. The reaction mixture was diluted with EtOAc (50 mL×3) and H 2 The organic phase was separated and diluted with Na 2 SO 4 The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50 mm×15 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 17%-47%, 8 min), filtered and concentrated under reduced pressure to give the product. Compound 8 (700 mg, 2.35 mmol, 64.77% yield) was obtained as a yellow oil. LCMS: Rt=0.623 min, m / z=296.0 (MH). +

[0179] To a solution of compound 8 (80 mg, 269.11 umol, 1 equiv.), compound 9 (82.48 mg, 269.11 umol, 1 equiv.) in DCM (4 mL) was added EDCI (77.38 mg, 403.66 umol, 1.5 equiv.) and DMAP (16.44 mg, 134.55 umol, 0.5 equiv.). The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under vacuum to give a residue. The residue was analyzed by preparative TLC (SiO 2 , DCM:MeOH=10:1) to give the product. Compound 10 (68 mg, 116.09 umol, 43.14% yield) was obtained as a pale yellow oil. LCMS: Rt=0.544 min, m / z=586.5 (M+H) +

[0180] To a solution of compound 10 (68 mg, 116.09 umol, 1 equiv) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 116.34 equiv) and the mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was analyzed by preparative TLC (SiO 2 , DCM:MeOH=10:1) to give the product. Compound 11 (29 mg, 63.67 umol, 54.84% yield) was obtained as a colorless oil. LCMS: Rt=0.386 min, m / z=443.2 (M+H) +

[0181] To a solution of compound 11 (29 mg, 63.67 umol, 1 equiv.) in DCM (1 mL) was added m-CPBA (11.21 mg, 63.67 umol, 98% purity, 1 equiv.) and the mixture was stirred at 20° C. for 1 h. The reaction mixture was diluted with Na 2 SO 3 (10 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; B%: 26%-56%, 9 min), and the purified solution was lyophilized to give the product. 012 (7.3 mg, 15.48 umol, 24.32% yield, 100% purity) was obtained as a white solid. LCMS: Rt=0.484 min, m / z=472.3 (M+H) + 1H NMR(400 MHz, chloroform-d)δ=12.44-12.07(m,1H),8.37-8.28(m,1H),8.21-8.13(m,1H),7.68-7.62(m,2H),7.61-7.57(m,1H),7.56-7.50(m,1H),7.26- 7.23(m,1H),6.94-6.89(m,1H),4.92-4.86(m,2H),3.79-3.73(m,1H), 3.14-3.10(m,3H),2.87(s,3H),0.86-0.78(m,2H),0.74-0.67(m,2H).

[0182] Compound 038 was prepared in a similar manner to Scheme 6 and obtained as a white solid (18.2 mg, 39.52 umol, 16.42% yield, 100% purity). LCMS: Rt=0.549 min, m / z=461.0 (M+H + ). 1 H NMR:(400 MHz,chloroform-d)δ=12.30(br s,1H),8.22(br s,1H),8.15(s,1H),7.45-7.27(m,4H),7.16-6.98(m,2H),6.90(s,1H),4.85(br s,2H),4.68(br t,J=6.9 Hz,1H),3.07(s,3H),2.84(br s,3H),2.43(br d,J=5.5 Hz,2H),2.23-2.04(m,2H),1.75(br s,2H). [ka]

[0183] Compound 1 was dissolved in EtOH (6 mL), THF (2 mL), and H 2 In a solution of LiOH H2O (2 mL), 2 0 (460.93 mg, 10.98 mmol, 3 equiv.) was added. The mixture was stirred at 20° C. for 1 h. The reaction mixture was acidified to pH 4 with 1N HCl, extracted with EtOAc (15 mL×3), filtered, and then concentrated in vacuo to give compound 2 (490 mg, 2.00 mmol, 54.61% yield) as a white solid, which was used in the next step. LCMS: Rt=0.278 min, m / z=245.0 (MH). +

[0184] Compound 2 (240 mg, 979.31 umol, 1 eq.), Compound 3 (323.04 mg, 1.96 mmol, 2 eq.), K 2 CO 3 (270.69mg, 1.96mmol, 2eq), Pd(dppf)Cl 2 ·CH 2 Cl 2 (39.99 mg, 48.97 umol, 0.05 equiv.) in dioxane (5 mL) and H 2 O (0.5 mL), then the mixture was rinsed with N2 The mixture was stirred at 100° C. for 12 hours under atmospheric pressure. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with Na 2 SO 4 The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [water (NH 3 H 2 The mixture was purified by HPLC using 100% C-ACN; B%: 8%-38%, 8 min) and the purified solution was lyophilized to give compound 4 (90 mg, 309.18 umol, 31.57% yield, 98% purity) as a white solid. LCMS: Rt=0.343 min, m / z=284.1 (MH). +

[0185] To a solution of compound 4 (60 mg, 210.33 umol, 1 eq.) and compound 5 (96.69 mg, 315.49 umol, 1.5 eq.) in DCM (1 mL) was added EDCI (60.48 mg, 315.49 umol, 1.5 eq.) and DMAP (2.57 mg, 21.03 umol, 0.1 eq.). The mixture was stirred at 20° C. for 12 h. The reaction mixture was poured into water (5 mL) and extracted with DCM (5 mL×3), the organic phase was dried and concentrated under vacuum to give a residue. The residue was analyzed by preparative TLC (SiO 2 , petroleum ether / ethyl acetate=0:1) and the purified solution was concentrated in vacuo to give compound 6 (20 mg, 34.86 umol, 16.57% yield) as a colorless oil. LCMS: Rt=0.517 min, m / z=574.3 (M+H). +

[0186] To a solution of compound 6 (20 mg, 34.86 umol, 1 eq) in DCM (1 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 774.88 eq). The mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure at 20° C. to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 17%-47%, 9 min), and the purified solution was lyophilized to give compound 7 (10 mg, 22.55 umol, 64.69% yield) as a white solid. LCMS: Rt=0.440 min, m / z=444.2 (M+H) +

[0187] To a solution of compound 7 (10 mg, 22.55 umol, 1 equiv.) in DCM (2 mL) was slowly added m-CPBA (11.91 mg, 67.65 umol, 98% purity, 3 equiv.) at 0° C. The mixture was stirred at 20° C. for 1 h. The reaction mixture was filtered and the cake was washed with saturated Na 2 SO 3 Slowly dissolved in 0.1% hexanediaminetetraacetate (5 mL) and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 27%-57%, 9 min), and the purified solution was lyophilized to give 015 (2.3 mg, 5.01 umol, 22.20% yield, 100% purity) as a white solid. LCMS: Rt=0.373 min, m / z=460.2 (M+H). + 1H NMR (400 MHz, chloroform-d) δ=12.49-12.32(m,1H),8.41-8.34(m,1H),8.24-8.19(m,1H),7.67-7.63(m,1H),7.54(dd,J=1.6,9.6 Hz,1H),7.38-7.32(m,2H),7.14-7.06(m,2H),4.95-4.85(m,2H),4.10(q,J=6.9 Hz,2H),3.14-3.06(m,3H),2.94-2.86(m,3H),1.39(t,J=6.9 Hz,3H).

[0188] Compound 016 was prepared in a similar manner to Scheme 7 (11.8 mg, 25.41 umol, 16.28% yield, 100% purity) and obtained as a white solid. LCMS: Rt=0.438 min, m / z=465.2 (M+H). + 1H NMR(400 MHz,chloroform-d)δ ppm 8.39-8.44(m,1 H)8.23(s,1 H)7.45(d,J=1.38 Hz,1 H)7.33(d,J=7.75 Hz,1 H)7.11(dd,J=7.88,1.50 Hz,1 H)6.97-7.04(m,2 H)6.75-6.84(m,1 H)4.91(s,2 H)3.75-3.81(m,1 H)3.12(s,3 H)2.90(s,3 H)0.81-0.87(m,2 H)0.74-0.80(m,2 H).

[0189] Compound 045 was prepared in a similar manner to Scheme 7, using HCl / dioxane instead of TFA / DCM. Compound 045 was isolated as a white solid (3 mg, 6.30 umol, 18.93% yield, 98.029% purity). LCMS: Rt=0.449 min, m / z=467.2 (M+H). + 1H NMR:(400 MHz,chloroform-d)δ=12.69-12.54(m,1H),9.85-9.68(m,1H),8.15-8.11(m,2H),7.88(s,1H),7.61(br d,J=8.6 Hz,1H),7.36-7.32(m,3H),7.23(br s,1H),4.82(br d,J=6.1 Hz,2H),3.88(dt,J=2.8,6.0 Hz,1H),2.78(s,3H),0.87-0.81(m,2H),0.74-0.69(m,2H). [ka]

[0190] To a solution of compound 1 (10 g, 45.46 mmol, 1 equiv.) in THF (100 mL) in a 250 mL three-necked round-bottom flask, EtOH (4.19 g, 90.91 mmol, 2 equiv.) and KOH (7.65 g, 136.37 mmol, 3 equiv.) were added. The reaction mixture was stirred at 30° C. for 12 h. TLC (petroleum ether:ethyl acetate=10 / 1) showed that compound 1 was completely consumed and one new spot appeared. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (200 mL×3), and the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=10 / 1) and the purified solution was concentrated under vacuum to give compound 2 (9 g, 36.58 mmol, 80.47% yield) as an orange oil.

[0191] To a solution of compound 2 (9 g, 36.58 mmol, 1 equiv.) in MeOH (100 mL) in a glass bottle (1 L), Pd(OAc) 2 (821.18 mg, 3.66 mmol, 0.1 equiv), DPPF (4.06 g, 7.32 mmol, 0.2 equiv), and TEA (11.10 g, 109.73 mmol, 15.27 mL, 3 equiv) were added and stirred at 80° C. for 12 h under CO (50 psi). The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1-5 / 1) and the purified solution was concentrated under vacuum to give compound 3 (3.1 g, 15.88 mmol, 43.42% yield) as an orange oil. LCMS: Rt = 0.366 min, m / z = 196.2 (M+H). + 1H NMR(400 MHz,DMSO-d6)δ=7.37(dd,J=1.7,8.2 Hz,1H),7.29-7.25(m,1H),6.64(d,J=8.3 Hz,1H),5.58(s,2H),4.06-4.02(m,2H),3.76-3.71(m,3H),1.35(t,J=6.9 Hz,3H)

[0192] To a solution of compound 3 (500 mg, 2.56 mmol, 1 equiv.) in MeCN (5 mL) in a 100 mL round-bottom flask, NCS (342.02 mg, 2.56 mmol, 1 equiv.) was added and the mixture was stirred at 20° C. for 12 h. The mixture was stirred at 50° C. for 1 h. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phase was dried and concentrated under vacuum to give the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=5 / 1) and the purified solution was concentrated under vacuum to give compound 4 (540 mg, 2.35 mmol, 91.80% yield) as a dark brown oil. LCMS: Rt=0.396 min, m / z=230.1 (M+H). + 1H NMR (400 MHz, chloroform-d) δ=7.65(d,J=1.3 Hz,1H),7.35(d,J=1.3 Hz,1H),4.61(br s,2H),4.14(q,J=7.0 Hz,2H),3.87(s,3H),1.46(t,J=7.0 Hz,3H)

[0193] To a solution of compound 4 (710 mg, 3.09 mmol, 1 equiv) and CuBr (886.96 mg, 6.18 mmol, 188.31 uL, 2 equiv) in ACN (8 mL) in a 50 mL round bottom flask, isoamyl nitrite (724.32 mg, 6.18 mmol, 832.55 uL, 2 equiv) was added and the mixture was stirred at 50° C. for 1 h. TLC (petroleum ether:ethyl acetate=5:1) showed that many new spots had formed. The reaction was messy by TLC (petroleum ether:ethyl acetate=5:1). The reaction mixture was washed with 20 mL of H 2 The mixture was diluted with 20 mL of EtOAc and extracted with 60 mL of EtOAc (20 mL x 3). The combined organic layers were washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 5 / 1) and the purified solution was concentrated under vacuum to give compound 5 (540 mg, 1.84 mmol, 59.50% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.69-7.64 (m, 1H), 7.47-7.43 (m, 1H), 4.22 (q, J = 6.9 Hz, 2H), 3.87 (s, 3H), 1.41-1.36 (m, 3H).

[0194] To a solution of compound 5 (360 mg, 1.23 mmol, 1 equiv.) in dioxane (4 mL) in a glass vial (40 mL), compound 6 (257.40 mg, 1.84 mmol, 1.5 equiv.), K 2 CO 3 (338.99 mg, 2.45 mmol, 2 equiv.), and Pd(dppf)Cl 2 ·CH 2 Cl 2 (50.08 mg, 61.32 umol, 0.05 equiv.) was added and the mixture was then rinsed with N 2 The mixture was stirred at 100° C. for 12 h under reduced pressure. The reaction mixture was filtered, poured into water (20 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phases were dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1) and the purified solution was concentrated under vacuum to give compound 7 (300 mg, 971.72 umol, 79.23% yield) as an off-white oil. 1H NMR (400 MHz, chloroform-d) δ = 7.77 (d, J = 1.5 Hz, 1H), 7.52 (d, J = 1.5 Hz, 1H), 7.43-7.37 (m, 1H), 7.09-7.07 (m, 1H), 7.07-7.05 (m, 1H), 7.04-6.99 (m, 1H), 4.06 (q, J = 6.9 Hz, 2H), 3.96 (s, 3H), 1.27-1.24 (m, 3H).

[0195] To a mixture of compound 7 (300 mg, 971.72 umol, 1 equiv.) in MeOH (4 mL) in a 100 mL round bottom flask was added LiOH H 2 O (122.33 mg, 2.92 mmol, 3 equiv.) and H2 HO (1 mL) was added and the mixture solution was then stirred at 20° C. for 1 h. The organic solvent was evaporated under vacuum and the resulting mixture was acidified to pH 4 with 1N HCl, then the mixture was filtered, washed with water (10 mL) and the filter cake was dried under vacuum to give compound 8 (280 mg, 950.10 umol, 97.78% yield) as a light yellow solid, which was used directly in the next step. LCMS: Rt=0.441 min, m / z=293.0 (M+H). +

[0196] To a solution of compound 8 (280 mg, 950.10 umol, 1 equiv) in DCM (3 mL) in a 100 mL round bottom flask, EDCI (273.20 mg, 1.43 mmol, 1.5 equiv), DMAP (11.61 mg, 95.01 umol, 0.1 equiv), and compound 9 (333.00 mg, 950.10 umol, 1 equiv) were added. The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=0 / 1) and the purified solution was concentrated under vacuum to give compound 10 (380 mg, 605.89 umol, 63.77% yield) as a yellow oil. LCMS: Rt=0.612 min, m / z=627.5 (M+H) +

[0197] To a solution of compound 10 (380 mg, 605.89 umol, 1 equiv.) in MeOH (5 mL) in a 100 mL round bottom flask was added LiBH 4 (65.99 mg, 3.03 mmol, 5 equiv.) was added slowly at 0° C. The mixture was stirred at 20° C. for 1 h. The reaction mixture was diluted with saturated NH 4 Poured into aqueous Cl (20 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phases were dried and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate=0 / 1 and dichloromethane:methanol=10 / 1) and the purified solution was concentrated under vacuum to give compound 11 (260 mg, 433.94 umol, 71.62% yield) as a yellow oil. LCMS: Rt=0.463 min, m / z=599.6 (M+H). +

[0198] To a solution of compound 11 (260 mg, 433.94 umol, 1 equiv) in DCM (10 mL) in a 100 mL round bottom flask, add BAST (192.01 mg, 867.87 umol, 190.11 uL, 2 equiv) in N 2 The mixture was then heated under 0° C. for 2 hours at room temperature and cooled to room temperature. 2 The reaction mixture was stirred at 0° C. for 30 min under reduced pressure. 3 Poured into aqueous solution (20 mL), extracted with DCM (20 mL x 3), the combined organic phase was dried and concentrated in vacuo to give a residue. The residue was analyzed by preparative TLC (SiO 2 , petroleum ether / ethyl acetate=0 / 1) and the purified solution was concentrated under vacuum to give compound 12 (75 mg, 124.76 umol, 28.75% yield) as a yellow oil. LCMS: Rt=0.554 min, m / z=601.5 (M+H) +

[0199] To a solution of compound 12 (75 mg, 124.76 umol, 1 equiv) in a round-bottom flask (100 mL) was added TFA (1.23 g, 10.80 mmol, 0.8 mL, 86.61 equiv) and DCM (0.4 mL), and the mixture was then stirred at 20° C. for 1 h. The reaction mixture was diluted with saturated NaHCO 3 The reaction mixture was then basified with aqueous solution (10 mL) of H 2 The mixture was diluted with 200 mL of 2H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine and 2 SO 4The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 43%-73%, 9 min), and the purified solution was lyophilized to give compound 13 (15 mg, 31.85 umol, 25.53% yield) as a yellow solid. LCMS: Rt=0.412 min, m / z=471.3 (M+H). +

[0200] To a solution of compound 13 (15 mg, 31.85 umol, 1 equiv.) in DCM (1 mL) in a round-bottom flask (100 mL), m-CPBA (19.40 mg, 95.56 umol, 85% purity, 3 equiv.) was added and the mixture was stirred at 20° C. for 1 h. After the reaction was complete, the mixture was filtered and the cake was washed with saturated Na 2 SO 3 The residue was slowly dissolved in 10 mL of ethyl acetate and the filtrate was concentrated to give the crude product. The residue was purified by preparative HPLC (column: Waters xbridge 150×25 mm 10 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 30%-60%, 8 min) and the purified solution was lyophilized to give compound 034 (10.4 mg, 21.25 umol, 66.72% yield, 99.5% purity) as a white solid. LCMS: Rt=0.435 min, m / z=487.3 (M+H). + 1H NMR (400 MHz, chloroform-d) δ=12.41-12.24(m,1H),8.39(d,J=3.5 Hz,1H),8.14(s,1H),7.44-7.35(m,1H),7.16(s,1H),7.12-7.08(m,1H),7.05(br d,J=7.9 Hz,1H),6.99(br d,J=9.6 Hz,1H),6.95-6.92(m,1H),6.12-5.95(m,2H),4.93-4.84(m,2H),4.00(q,J=6.9 Hz,2H),3.10(s,3H),1.25(t,J=6.9 Hz,3H).

[0201] Compound 036 was prepared in a similar manner to Scheme 8 and isolated as a white solid (7 mg, 13.40 umol, 12.98% yield, 95.8% purity). LCMS: Rt=0.517 min, m / z=501.2 (M+H + ) 1 H NMR:(400 MHz,chloroform-d)δ=8.40(d,J=3.6 Hz,1H),8.17-8.14(m,1H),7.21-7.13(m,2H),7.06-6.99(m,2H),6.89-6.80(m,1 H),6.10(s,1H),6.00-5.96(m,1H),4.92(s,2H),3.96-3.90(m,1H),3.03(d,J=1.5 Hz,3H),0.60-0.54(m,2H),0.50-0.43(m,2H).

[0202] Compound 047 was prepared in a similar manner to Scheme 8 and obtained as a brown solid (9.3 mg, 19.04 umol, 59.97% yield, 100% purity). LCMS: Rt=0.450 min, m / z=489.2 (M+H)+ 1 H NMR(400 MHz,chloroform-d)δ=11.94-12.47(m,1 H)8.38(br s,1 H)8.15(br s,1 H)7.13-7.22(m,2 H)7.08(br d,J=7.13 Hz,2 H)6.85(br t,J=8.76 Hz,1 H)5.92-6.14(m,2 H)4.92(br s,2 H)3.87-3.97(m,2 H)3.01(s,3 H)1.20(br t,J=6.94 Hz,3 H).

[0203] Compound 048 was prepared in a similar manner as in Scheme 8 using DAST and was obtained as a yellow solid (5.6 mg, 11.44 umol, 29.66% yield, 98.6% purity). LCMS: Rt=0.541 min, m / z=483.2 (M+H + ) 1H NMR(400 MHz,chloroform-d)δ=12.68-12.07(m,1H),8.39(d,J=3.6 Hz,1H),8.14(s,1H),7.45(d,J=1.4 Hz,1H),7.34(d,J=7.8 Hz,1H),7.12(dd,J=1.4,7.8 Hz,1H),7.03-6.97(m,2H),6.80(tt,J=2.3,8.9 Hz,1H),6.12-5.95(m,2H),4.90(s,2H),3.82-3.75(m,1H),3.10(s,3H),0.87-0.82(m,2H),0.80-0.74(m,2H).

[0204] Compound 049 was prepared in a similar manner to Scheme 8 and obtained as a white solid (3 mg, 6.69 umol, 19.26% yield, 99.342% purity). LCMS: Rt=0.447 min, m / z=446.3 (M+H)+ 1 H NMR (400 MHz, chloroform-d) δ = 8.23 ​​(s, 1H), 8.18 (s, 1H), 7.40-7.37 (m, 2H), 7.33-7.29 (m, 2H), 7.11-7.05 (m, 3H), 4.90 (s, 2H), 4.08 (q, J = 7.0 Hz, 2H), 3.12 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H).

[0205] Compound 050 was prepared in a similar manner to Scheme 8 and obtained as a white solid (3.0 mg, 6.09 umol, 10.53% yield, 98% purity). LCMS: Rt=0.529 min, m / z=483.1 (M+H + ).1H NMR(400 MHz,chloroform-d)δ=12.24-12.50(1H,m),8.50(1H,d,J=3.3 Hz),8.32(1H,s),7.40(1H,dt,J=6.1 and 7.9 Hz),7.07-7.25(5H,m),6.03-6.19(2H,m),4.96(2H,s),3.89(1H,dt,J=2.9 and 6.0 Hz),3.06(3H,d,J=1.0 Hz),0.51-0.57(2H,m),0.39-0.46(2H,m).

[0206] Compound 052 was prepared in a similar manner as in Scheme 8 using DAST and obtained as a white solid (5.25 mg, 10.57 umol, 20.80% yield, 98.3% purity). LCMS: Rt=0.506 min, m / z=489.3 (M+Na + ) 1 H NMR (400 MHz, chloroform-d) δ = 12.39-12.20 (m, 1H), 8.42-8.38 (m, 1H), 8.15-8.12 (m, 1H), 6.99-6.92 (m, 2H), 6.89-6.81 (m, 3H), 6.09 (s, 1H), 5.98 (s, 1H), 4.88 (s, 2H), 4.11-4.01 (m, 2H), 3.08 (s, 3H), 1.34 (t, J = 6.9 Hz, 3H).

[0207] Compound 053 was prepared in a similar manner to Scheme 8 and obtained as a white solid (15 mg, 31.88 umol, 48.30% yield, 100% purity). LCMS: Rt=0.447 min, m / z=446.3 (M+H). + 1H NMR: (400 MHz, chloroform-d)δ=12.49-12.10(m,1H),8.41(d,J=3.6 Hz,1H),8.22(s,1H),7.44-7.37(m,1H),7.33-7.27(m,2H),7.23-7.18(m,1 H),7.16-7.05(m,2H),6.11(s,1H),5.99(s,1H),4.94(s,2H),3.88(q,J=7.0 Hz,2H),3.03(d,J=1.4 Hz,3H),1.18(t,J=7.1 Hz,3H). [ka]

[0208] To a solution of compound 1 (100 mg, 412.76 umol, 1 equiv.) in DCM (2 mL) in an 8 mL bottle, EDCI (118.69 mg, 619.15 umol, 1.5 equiv.), DMAP (5.04 mg, 41.28 umol, 0.1 equiv.), and compound 2 (72.74 mg, 412.76 umol, 1 equiv.) were added, and the reaction mixture was stirred at 20° C. for 1.5 h using a magnetic stirring apparatus. After the reaction was completed, the mixture was concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 19%-49%, 10 min). After purification by preparative HPLC, the eluent was concentrated to remove the organic solvent. The aqueous solution of the residue was lyophilized to give a white solid. Compound 3 (85 mg, 212.25 umol, 42.85% yield) was obtained as a white solid. LCMS: Rt=0.360 min, m / z=401.8 (M+H + ).

[0209] To a solution of compound 3 (85 mg, 212.25 umol, 1 equiv.) in DCM (2 mL) in a 100 mL single-neck round-bottom flask, m-CPBA (129.27 mg, 636.75 umol, 85% purity, 3 equiv.) was slowly added at 0° C., and the mixture was stirred at 20° C. for 1 h using a magnetic stir bar. After the reaction was complete, the reaction mixture was washed with Na 2 SO 3 (10 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The crude product was purified by preparative HPLC (column: Phenomenex C18 150 x 25 mm x 10 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 22%-52%, 8 min). After purification by preparative HPLC, the eluent was concentrated to remove the organic solvent. The aqueous solution of the residue was lyophilized to give a brown solid. The aqueous solution of the residue was lyophilized to give a white solid. Compound 4 (55 mg, 130.74 umol, 61.60% yield, 99% purity) was obtained as a brown solid. LCMS: Rt=0.465 min, m / z=417.3 (M+H + )

[0210] Compound 4 (55 mg, 132.06 umol, 1 equiv.) was purified by SFC to give 039 (23.1 mg, 54.91 umol, 41.58% yield, 99% purity) and 040 (24.9 mg, 59.19 umol, 44.82% yield, 99% purity). The products were purified by SFC (column: DAICEL CHIRALCEL OD (250 mm × 50 mm, 10 um); mobile phase: [0.1% NH 3 H 2 O MEOH]; B%: 40%-40%, A6.2; 30 min). After purification by SFC, the eluent was concentrated to remove the organic solvent. The residual aqueous solution was lyophilized to give a brown solid. 039 (23.1 mg, 54.91 umol, 41.58% yield, 99% purity) was obtained as a brown solid. 040 (24.9 mg, 59.19 umol, 44.82% yield, 99% purity) was obtained as a brown solid. LCMS of 039: Rt=0.483 min, m / z=417.3 (M+H + ).039 1 H NMR:(400 MHz,chloroform-d)δ=12.48-12.26(m,1H),8.75(d,J=1.1 Hz,1H),8.23(s,1H),8.16(s,1H),7.59-7.52(m,2H),7.44(s,2H),7.40-7.34(m,2H),7.12-7.07(m,2H),6.44(br d,J=7.0 Hz,1H),4.14-4.02(m,2H),2.89(s,3H),1.83(d,J=7.1 Hz,3H),1.38(t,J=6.9 Hz,3H).LCMS of 040:Rt=0.484 min,m / z=417.3(M+H + ).040 1H NMR:(400 MHz,chloroform-d)δ=12.53-12.29(m,1H),8.78(s,1H),8.32-8.12(m,2H),7.56(d,J=7.3 Hz,2H),7.46-7.35(m,4H),7.13-7.07(m,2H),6.51-6.40(m,1H),4.08(br dd,J=7.1,14.9 Hz,2H),2.89(s,3H),1.84(d,J=7.1 Hz,3H),1.38(t,J=6.9 Hz,3H).

[0211] Compound 041 and compound 042 were prepared in a similar manner to the compounds in Scheme 9. Compound 041 was isolated as a brown solid (34.1 mg, 74.61 umol, 42.20% yield, 99% purity). LCMS: Rt=0.512 min, m / z=453.2 (M+H + ). 1 H NMR: (400 MHz, chloroform-d) δ = 12.33-12.21 (m, 1H), 8.74-8.61 (m, 1H), 8.20-8.04 (m, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.06-6.94 (m, 4H), 6.78-6.68 (m, 1H), 6.34 (br d, J = 7.0 Hz, 1H), 4.09-3.93 (m, 2H), 2.78 (s, 3H), 1.74 (d, J = 7.3 Hz, 3H), 1.32 (t, J = 6.9 Hz, 3H). Compound 042 was isolated as a brown solid (35.7 mg, 78.11 umol, 44.18% yield, 99% purity). LCMS: Rt=0.507 min, m / z=453.2(M+H + ). 1 H NMR:(400 MHz,chloroform-d)δ=12.40-12.20(m,1H),8.69(br s,1H),8.22-8.05(m,2H),7.27(d,J=7.6 Hz,1H),7.05-6.95(m,4H),6.79-6.67(m,1H),6.34(br d,J=6.9 Hz,1H),4.10-3.92(m,2H),2.78(s,3H),1.75(d,J=7.1 Hz,4H),1.32(t,J=6.9 Hz,4H).

[0212] Compound 043 and compound 044 were prepared in a similar manner to the compounds in Scheme 9. Compound 043 was isolated as a white solid (6.4 mg, 14.05 umol, 25.34% yield, 99% purity). LCMS: Rt=0.524 min, m / z=451.4 (M+H+).1H NMR (chloroform-d): δ 8.74 (1H,s), 8.11-8.25 (2H,m), 7.54 (1H,s), 7.40-7.44 (1H,m), 7.32-7.37 (3H,m), 7.04-7.10 (2H,m), 6.36-6.47 (1H,m), 4.00-4.16 (2H,m), 2.86 (3H,s), 1.82 (3H,d,J=7.1 Hz), 1.38 (3H,t,J=6.9 Hz). Compound 044 was isolated as a white solid (5.2 mg, 11.07 umol, 19.97% yield, 96% purity). LCMS: Rt=0.522 min, m / z=451.2(M+H+).1H NMR(chloroform-d): δ 12.35(1H,br s),8.74(1H,d,J=1.1 Hz),8.12-8.26(2H,m),7.54(1H,s),7.40-7.44(1H,m),7.32-7.38(3H,m),7.04-7.11(2H,m),6.42(1H,q,J=7.0 Hz),3.97-4.16(2H,m),2.86(3H,s),1.82(3H,d,J=7.1 Hz),1.38(3H,t,J=6.9 Hz m),6.39-6.62(1H,m),3.78(1H,br d,J=3.0 Hz),2.84(3H,s),1.90(3H,br d,J=7.1 Hz),0.80-0.88(4H,m). [ka]

[0213] To a solution of compound 1 (400 mg, 1.26 mmol, 1 equiv.) and compound 2 (343.06 mg, 1.26 mmol, 1 equiv.) in DCM (10 mL) in a glass bottle (40 mL), EDCI (362.32 mg, 1.89 mmol, 1.5 equiv.) and DMAP (15.39 mg, 126.00 umol, 0.1 equiv.) were added. The mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated in vacuum to give a residue. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 67%-97%, 10 min), and the purified solution was concentrated under vacuum to give compound 3 (100 mg, 174.91 umol, 13.88% yield) as a white solid. LCMS: Rt=0.589 min, m / z=572.3(M+H) +

[0214] To a solution of compound 3 (60 mg, 104.95 umol, 1 equiv.) in AcOH (1 mL) in a glass bottle (8 mL), 2 O 2 (23.80 mg, 209.89 umol, 20.17 uL, 30% purity, 2 eq.) was added. The mixture was stirred at 100° C. for 12 hours. The reaction mixture was diluted with saturated Na 2 SO 3 Poured into aqueous solution (2 mL), extracted with dichloromethane (2 mL x 3), combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:2), and the purified solution was concentrated under vacuum to give compound 4 (45 mg, 76.57 umol, 72.96% yield) as a yellow oil. LCMS: Rt = 0.555 min, m / z = 588.3 (M + H). +

[0215] A solution of compound 4 (50 mg, 85.08 umol, 1 equiv), TFA (1 mL), and DCM (1 mL) in a round bottom flask (100 mL) was stirred at 20° C. for 2 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 39%-69%, 9 min), and the purified solution was lyophilized to give 051 (1 mg, 2.19 umol, 2.57% yield, 100% purity) as a white solid. LCMS: Rt=0.457 min, m / z=458.2 (M+H) + 1H NMR:(400 MHz, chloroform-d)δ=8.23(s,1H),8.19(s,1H),7.45(s,1H),7.39-7.34(m,2H),7.24-7.18(m,2H ),7.14-7.10(m,1H),7.08-7.02(m,1H),4.92(s,2H),3.82-3.75(m,1H),3.14(s,3H),0.83(br t,J=5.5 Hz,2H),0.80-0.75(m,2H). [ka]

[0216] To a solution of compound 1 (300 mg, 716.91 umol) in THF (5 mL) in a 10 mL glass bottle, SEM-Cl (143.43 mg, 860.29 umol, 152.26 uL) was added at 0° C. and the mixture was stirred at 0° C. for 1 h. Then, NaH (43.01 mg, 1.08 mmol, 60% purity) was added dropwise and the mixture was stirred at 20° C. for 1 h. The mixture was diluted with saturated NH 4 Cl (50 mL), extracted with EtOAc (50 mL x 3), and the combined organic phase was washed with brine (50 mL) and anhydrous Na 2 SO 4The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=0 / 1-1 / 1). Compound 2 (45 mg, 82.01 umol, 11.44% yield) was obtained as a colorless oil. LCMS: Rt=0.451 min, m / z=549.2 (M+H + )

[0217] Dissolve compound 2 (45 mg, 82.01 umol) in MeOH (1 mL) and H in an 8 mL vial. 2 To the 20O (0.1 mL) solution was added ammonia; sulfooxy hydrogen sulfate (61.76 mg, 270.63 umol, 58.82 uL) and the mixture was stirred at 60° C. for 1.5 h. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH=10:1). Compound 3 (18 mg, 31.10 umol, 37.92% yield) was obtained as a colorless oil. LCMS: Rt=0.445 min, m / z=579.2 (M+H + )

[0218] To a solution of compound 3 (18.00 mg, 31.10 umol) in DCM (1 mL) was added m-CPBA (12.63 mg, 62.20 umol, 85% purity) at 25° C., and the mixture was stirred at 25° C. for 2 h. The mixture was diluted with saturated Na 2 SO 3 The mixture was poured into aqueous solution (20 mL) and stirred for 0.25 h. It was then extracted with EtOAc (20 mL×3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH=10:1). Compound 4 (8 mg, 12.91 umol, 41.52% yield, 96% purity) was obtained as a white oil. LCMS: Rt=0.601 min, m / z=595.4 (M+H + )

[0219] To a solution of compound 4 (8 mg, 13.45 umol) in DCM (5 mL), TFA (749.27 mg, 6.57 mmol, 486.54 uL) was added and the mixture was stirred at 25° C. for 1 h. The mixture was concentrated to give the crude product. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 32%-62%, 9 min) and lyophilized. Compound 077 (0.99 mg, 1.94 umol, 14.39% yield, 90.8% purity) was obtained as a white solid. LCMS: Rt=0.489 min, m / z=465.4 (M+H + ). 1 H NMR(400 MHz,chloroform-d)δ=12.69-12.13(m,1H),8.26(s,1H),8.20(s,1H),7.35(d,J= 7.6 Hz,2H),7.32-7.27(m,2H),7.04(s,3H),6.41(br d,J= 6.7 Hz,1H),5.16(s,2H),4.12-4.02(m,2H),3.72(d,J= 7.1 Hz,1H),2.85(s,3H),1.82(d,J= 7.1 Hz,3H),1.27-1.23(m,3H). [ka]

[0220] To a solution of compound 1 (80 mg, 141.66 umol, 1 equiv.) in DCM (3 mL) was added m-CPBA (57.52 mg, 283.33 umol, 85% purity, 2 equiv.) at 0° C. The reaction mixture was stirred at 25° C. for 2 h. The mixture was diluted with saturated Na 2 SO 3 The mixture was poured into aqueous solution (20 mL) and stirred for 0.25 h. It was then extracted with EtOAc (20 mL×3). The combined organic layers were washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA=0:1) to give the product (Rf=0.05). Compound 2 (50 mg, 78.01 umol, 55.06% yield, 90.6% purity) was obtained as a light brown oil. LCMS: Rt=0.588 min, m / z=581.3 (M+H). + .

[0221] To a solution of compound 2 (40 mg, 68.88 umol, 1 equiv) in DCM (2 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 392.17 equiv). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was directly concentrated to give the crude product. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 150×30 mm×7 um; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 10 min). 078 (17.2 mg, 37.34 umol, 54.21% yield, 97.8% purity) was obtained as a light yellow solid. LCMS: Rt=0.484 min, m / z=451.1 (M+H) + .1H NMR(400 MHz,DMSO-d6)δ ppm 1.22-1.32(m,3 H)3.07(s,3 H)3.32(br s,2 H)4.09-4.17(m,1 H)4.91(br s,1 H)4.95(br d,J=5.38 Hz,2 H)5.93(t,J=5.50 Hz,1 H)7.12-7.27(m,3 H)7.31-7.50(m,4 H)8.02(br d,J=3.18 Hz,1 H)8.51(br s,1 H).

[0222] Example 2: THP-1 cell-based NLRP3 activation assay THP-1 cells are cultured in complete medium (CM) until they reach logarithmic growth and achieve >90% viability. CM consists of RPMI-1640 (+Glutamax) / 10% fetal bovine serum / 55 μM β-mercaptoethanol / pen / strep. Cells are spun down and resuspended to 1,000,000 cells / mL in CM containing either 20 nM or 500 nM PMA. 150,000 cells (150 μL) are then added to each well of a 96-well TC plate and incubated in a standard cell culture incubator (37° C., 5% CO). 2 ) for either 24 or 3 hours, respectively. After this incubation, the plate is tilted and the medium is carefully removed. Then, 200 μL of CM containing 100 ng / mL LPS is added to the wells and the cells are incubated for an additional 3 hours. The medium is again removed and replaced with Opti-Mem medium containing a given dilution of the test compound in duplicate wells. After a 30 minute incubation, 10 μM nigericin (final concentration) in Opti-Mem medium with the corresponding concentration of compound is added to the wells for an additional 1 hour. Positive control wells contain 10 μM nigericin in Opti-Mem in the absence of test compound, while negative control wells contain only Opti-Mem. The supernatants are then transferred to fresh 96-well plates for storage and assayed for IL-1β (human; DuoSet; R&D) and TNFα (human; DuoSet; R&D) levels and relative pyroptosis using a CytoTox 96 kit (not frozen prior to testing; Promega). After removing the supernatants, the relative viability of adherent cells in the 96-well TC plates is determined using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega).

[0223] Table 4 below shows the IC of the compounds disclosed herein. 50 Provide data where "+" is an IC less than 50uM 50 Values ​​are indicated, and "++" indicates IC less than 10uM 50 "+++" indicates IC value less than 1uM 50 Indicates the value. [Table 4]

[0224] Example 3: Metabolic stability of N-oxides The stability of the N-oxide compounds provided herein was studied in comparison with analogs without N-oxide. These data show that the metabolic stability of the compounds provided herein is unexpectedly and dramatically improved in human liver microsome stability assay (HLM) compared with the comparative compounds shown in the table below. This enhanced metabolic stability corresponds to an increased half-life and duration of action when administered in vivo. These results are shown in Table 5 below. [Table 5-1] [Table 5-2]

[0225] The scope of the disclosed subject matter is not limited by the specific embodiments and examples described herein. Indeed, various modifications of the present disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0226] All references (e.g., publications or patents or patent applications) cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula, 【Chemistry 2】 is an optional double bond, X, Y, and Z are each independently NH, NR ３ , N, C.H., and C.R. ３ with the proviso that at least one of X, Y, or Z is CH or CR ３ Provided that, Ring A is C ６－１０ Aryl, 5-6 membered heteroaryl, C ３－１０ cycloalkyl, and 4- to 10-membered heterocycloalkyl; Ring B is phenyl, 5- to 6-membered heteroaryl, C ３－６ cycloalkyl, and 3- to 6-membered heterocycloalkyl; Alternatively, ring B is absent and m is 0; Ring C is a pyridine N-oxide; R １ is H, C ３－６ Cycloalkyl, and C １－６ is selected from the group consisting of alkyl, R ２ and R ２ａ are each independently H, C １－６ Alkyl, C １－６ Alkoxy, and C ３－６ cycloalkyl; Alternatively, R ２ and R ２ａ together with the atoms to which they are attached, C ３－６ forming a cycloalkyl or 3- to 6-membered heterocycloalkyl; Each R ３ is independent, C １－６ Alkyl and C ３－６ is cycloalkyl, Each R ４ is independent, C １－６ Alkyl, C ２－６ Alkynyl, halo, OH, OR ６ , N.H. ２ , NH(C １－６ Alkyl), N(C １－６ Alkyl) ２ , NHCOR ６ , C.N., C. １－６ Haloalkyl, C ３－７ Cycloalkyl, 3- to 7-membered heterocycloalkyl, and COR ６ is selected from the group consisting of Each R ５ is independent, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkyl-OH, C ２－６ Alkynyl, halo, OH, OR ７ , N.H. ２ , NH(C １－６ Alkyl), N(C １－６ Alkyl) ２ , NHCOR ７ , C.N., C. ３－７ Cycloalkyl, 3- to 7-membered heterocycloalkyl, COR ７ , and S.O. ２ R ７ is selected from the group consisting of Each R ６ is independent, C １－６ Alkyl, C １－６ Haloalkyl, C ０－６ Alkyl-C ６－１０ Aryl, C ０－６ alkyl-5 to 10 membered heteroaryl, C １－６ Alkoxy, C ０－６ Alkyl-C ３－６ Cycloalkyl, C ０－６ Alkyl-3 to 10 membered heterocycloalkyl, halo, NH ２ , NH(C １－６ alkyl), and N(C １－６ Alkyl) ２ is selected from the group consisting of Each R ７ is independent, C １－６ Alkyl, C １－６ Haloalkyl, C ０－６ Alkyl-C ６－１０ Aryl, C ０－６ alkyl-5 to 10 membered heteroaryl, C １－６ Alkoxy, C ３－６ Cycloalkyl, halo, NH ２ , NH(C １－６ alkyl), and N(C １－６ Alkyl) ２ is selected from the group consisting of Each R ９ is independent, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Alkyl-OH, C ３－６ Cycloalkyl, halo, CN, OH, NH ２ , NH(C １－６ alkyl), and N(C １－６ Alkyl) ２ is selected from the group consisting of m is 0, 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, 2, or 3).

2. The compound of formula I is a compound of formula Ia: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

3. The compound of formula I may be a compound of formula Ib: 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

4. The compound of formula I may be a compound of formula Ic: 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

5. Ring A is C ６－１０ The compound according to any one of claims 1 to 4, which is aryl.

6. The compound according to any one of claims 1 to 5, wherein Ring A is phenyl.

7. The compound according to any one of claims 1 to 6, wherein Ring B is phenyl or 5- to 6-membered heteroaryl.

8. The compound according to any one of claims 1 to 7, wherein Ring B is phenyl.

9. R １ is C １－６ is alkyl, R ２ is H, C １－６ Alkyl, C １－６ Alkoxy, and C ３－６ cycloalkyl; R ２ａ is H, Each R ４ is independent, C １－６ Alkyl, halo, and OR ６ is selected from the group consisting of Each R ５ is independent, C １－６ Haloalkyl, halo, CN, and COR ７ is selected from the group consisting of Each R ６ is independent, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, and 3- to 6-membered heterocycloalkyl; Each R ７ is independent, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, and NH(C １－６ alkyl), Each R ９ is independent, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Alkyl-OH, C ３－６ cycloalkyl, and CN; m is 0, 1, or 2; The compound according to any one of claims 1 and 5 to 8, wherein n is 1 or 2.

10. R １ is C １－６ is alkyl, R ２ is H, C １－６ Alkyl, C １－６ Alkoxy, and C ３－６ cycloalkyl; Each R ４ is independent, C １－６ Alkyl, halo, and OR ６ is selected from the group consisting of Each R ５ is independent, C １－６ Haloalkyl, halo, CN, and COR ７ is selected from the group consisting of Each R ６ is independent, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, and 3- to 6-membered heterocycloalkyl; Each R ７ is independent, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, and NH(C １－６ alkyl), Each R ９ is independent, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Alkyl-OH, C ３－６ cycloalkyl, and CN; m is 0, 1, or 2; The compound according to any one of claims 1 to 8, wherein n is 1 or 2.

11. R １ is C １－３ The compound according to any one of claims 1 to 10, which is alkyl.

12. R ２ The compound according to any one of claims 1 to 11, wherein is H.

13. Each R ４ is independent, C １－６ Alkyl, halo, and OR ６ The compound according to any one of claims 1 to 12, selected from the group consisting of:

14. Each R ４ are independently O(ethyl), O(cyclopropyl), O(oxetanyl), and O(C １－３ The compound according to any one of claims 1 to 13, selected from the group consisting of: haloalkyl.

15. Each R ５ is independent, C １－６ Haloalkyl, halo, CN, and COR ７ The compound according to any one of claims 1 to 14, selected from the group consisting of:

16. Each R ５ is independent, C １－６ Haloalkyl, halo, CN, and CONH(C １－６ 16. The compound according to any one of claims 1 to 15, wherein the compound is selected from the group consisting of:

17. Each R ９ is independent, C １－６ The compound according to any one of claims 1 to 16, which is alkyl.

18. The compound according to any one of claims 1 to 17, wherein m is 1 or 2.

19. The compound according to any one of claims 1 to 18, wherein n is 1 or 2.

20. The compound according to any one of claims 1 to 8 and 11 to 19, wherein p is 0 or 1.

21. Ring A is phenyl; Ring B is phenyl or thienyl; R １ is C １－３ is alkyl, R ２ is H, C １－６ Alkyl, C １－６ Alkoxy, and C ３－６ cycloalkyl; Each R ４ is independent, C １－６ Alkyl, halo, and OR ６ is selected from the group consisting of Each R ５ is independent, C １－６ Haloalkyl, halo, CN, and COR ７ is selected from the group consisting of Each R ６ is independent, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, and 3- to 6-membered heterocycloalkyl; Each R ７ is independent, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, and NH(C １－６ alkyl), Each R ９ is independent, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－６ Alkyl-OH, C ３－６ cycloalkyl, and CN; m is 1 or 2; n is 1 or 2; The compound of claim 2 , wherein p is 0 or 1.

22. X is N; 2. The compound of claim 1, wherein Y and Z are each independently selected from the group consisting of NH and CH.

23. The compounds of formula I have the following core structure: 【Chemistry 6】 The compound of claim 1 having one of the following:

24. The compounds of formula I have the following core structure: 【Chemistry 7】 2. The compound of claim 1 having the formula:

25. The compound of any one of claims 1 to 22, wherein the compound of formula I is selected from the group consisting of the compounds of Table 1, or a pharma- ceutically acceptable salt thereof.

26. The compound of any one of claims 1 to 22, wherein the compound of formula I is selected from the group consisting of the compounds of Table 2, or a pharma- ceutically acceptable salt thereof.

27. The compound of any one of claims 1 to 24, wherein the compound of formula I is selected from the group consisting of the compounds of Table 3, or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

29. A method for inhibiting the NLRP3 inflammasome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of claims 1 to 27, or a pharmaceutical composition described in claim 28.

30. A method of treating inflammation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutical composition according to claim 28.

31. A method for treating inflammation-aging in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutical composition according to claim 28.

32. A method of treating cryopyrin-associated periodic syndromes (CAPS) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutical composition according to claim 28.

33. 29. A method of treating a disease or disorder of the inner ear in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutical composition according to claim 28.

34. 34. The method of claim 33, wherein the disease or disorder of the inner ear is selected from the group consisting of hearing loss, hearing impairment, vertigo, Meniere's disease, and tinnitus.

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