Benzimidazole derivatives for treatment and / or prevention of diseases and disorders mediated by NLRP3

Abstract

To provide benzimidazole derivatives for treatment and / or prevention of diseases and disorders mediated by NLRP3.SOLUTION: The disclosure relates to a method for preventing and / or treating a disease or disorder mediated by NLRP3 in a subject comprising administering an effective amount of a compound of formula (I) or pharmaceutically acceptable salt, solvate or prodrug thereof as disclosed herein.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to methods for treating and / or preventing diseases and disorders mediated by NOD-like receptor protein 3 (NLRP3). In particular, the methods use benzimidazole derivatives for treating and / or preventing diseases and disorders mediated by NLRP3. [Background technology]

[0002] NOD-like receptor protein 3 (NLRP3) is a protein-coding gene. The protein belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as "pyrin domain-containing protein 3". The gene encodes a protein that contains a pyrin domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif. In response to sterile inflammatory danger signals, NLRP3 interacts with adaptor proteins, apoptosis-associated speck-like protein (ASC), and procaspase-1 to form the NLRP3 inflammasome. NLRP3 inflammasome activation then leads to the release of the proinflammatory cytokines IL-1β and IL-18.

[0003] Dysregulation of inflammasome activation often contributes to human diseases such as inflammatory bowel disease, gout, type II diabetes, cardiovascular disease, Alzheimer's disease and sepsis, a common fatal response to systemic infections, and rare genetic disorders caused by mutations in NLRP3 and the pyrin inflammasome. Gain-of-function mutations in the NLRP3 gene result in cryopyrin-associated periodic syndromes such as familial cold urticaria syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous and articular syndrome, also known as neonatal-onset multisystem inflammatory disease. Summary of the Invention [Problem to be solved by the invention]

[0004] Therefore, there is a need to develop candidates with NLRP3 inflammasome inhibitory effects to provide new and / or alternative treatments for NLRP3-mediated diseases / disorders. [Means for solving the problem]

[0005] The present disclosure provides a method for preventing and / or treating a disease or disorder mediated by NLRP3 in a subject, comprising administering to the subject an effective amount of a benzimidazole derivative represented by formula (I) as described herein or a pharma- ceutically acceptable salt, solvate or prodrug thereof as an active ingredient.

[0006] In some embodiments, the disease or disorder is a neurological disorder, an inflammasome-associated disease or disorder, an immune disease, an inflammatory disease, an autoimmune or autoinflammatory disease, a liver-related disease or disorder, an inflammatory arthritis-related disorder, a kidney-related disease, a neuroinflammatory-related disease, a cardiovascular or metabolic disease or disorder, an inflammatory skin disease, wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration, or a cancer-related disease or disorder. Examples of diseases or disorders include, but are not limited to, autoinflammatory fever syndromes, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, alcoholic liver disease, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-associated inflammation, multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's Disease (AD), cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure, sweat gland abscess, acne, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), bone marrow fibrosis, multiple system atrophy (MSA), or dementia with Lewy bodies, schizophrenia and schizoaffective disorder symptom areas (including negative, cognitive, depressive, positive, and general psychopathology symptom areas), depression, Tourette's syndrome, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), analgesia, memory and / or cognitive loss associated with a neurodegenerative disease or loss of neurological function characteristic of a neurodegenerative disease, mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, schizophrenia, pain, ataxia, seizures, anxiety, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), fragile X syndrome (FXS), autism, or attention deficit hyperactivity disorder (ADHD).

[0007] Examples of benzimidazole derivatives represented by formula (I) include, but are not limited to, those described in the present disclosure below. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 shows the results of Western blot in human THP-1 cells. [Diagram 2] Figure 2A shows the ELISA results in LPS-treated cells and ATP-treated cells, and Figure 2B shows the ELISA results in LPS-treated cells and MSU-treated cells. [Diagram 3] FIG. 1 shows the therapeutic effect of RS-D7 on neuronal alpha-synucleinopathy-associated locomotor activity defects in the TgM83 mouse model of neurodegenerative disease. [Figure 4] FIG. 1 shows the therapeutic effect of RS-D7 on neuronal alpha-synucleinopathy-associated motor coordination deficits in the TgM83 mouse model of neurodegenerative disease. [Diagram 5] Fig. 5A is a diagram showing the therapeutic effect of RS-D7 on the inflammatory cytokine IL-1β in the cerebellum of a TgM83 mouse model of neurodegenerative disease. Fig. 5B is a diagram showing the therapeutic effect of RS-D7 on the inflammatory cytokine IL-6 in the cerebellum of a TgM83 mouse model of neurodegenerative disease. Fig. 5C is a diagram showing the therapeutic effect of RS-D7 on the inflammatory cytokine TNF-α in the cerebellum of a TgM83 mouse model of neurodegenerative disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] As used herein and in the appended claims, the singular articles "a," "and," and "the" refer to both the singular and the plural unless otherwise indicated. When ranges are used for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of the ranges, as well as all specific embodiments, are intended to be included. The term "or" means "and / or," unless otherwise specified to refer to alternatives only, or to exclude alternatives from one another. The term "about," when used in reference to a number or range of values, is used to express approximation of the number or range of values ​​within experimental variability (or within statistical experimental error). The term "comprising" (and related terms such as "having") is not intended to exclude that an embodiment of any component of, for example, the subject matter, composition, method, or process described herein "consists of" or "consists essentially of" the recited features in other specific embodiments.

[0010] definition "Alkyl" means an alkyl group containing no unsaturation and having 1 to 15 carbon atoms (e.g., C 1 -C 15 Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms having 1 to 13 carbon atoms (e.g., C 1 -C 10 In certain embodiments, alkyl includes 1 to 8 carbon atoms (e.g., C 1 -C 8 In other embodiments, alkyl includes 1 to 5 carbon atoms (e.g., C 1 -C 6 In other embodiments, alkyl includes 1 to 4 carbon atoms (e.g., C 1 -C 4 In other embodiments, alkyl includes 1 to 3 carbon atoms (e.g., C 1 -C 3 In other embodiments, alkyl includes 1 to 2 carbon atoms (e.g., C 1 -C2 In other embodiments, an alkyl group contains one carbon atom (e.g., C 1 In other embodiments, alkyl includes 5 to 15 carbon atoms (e.g., C 5 -C 15 In other embodiments, alkyl includes 5 to 8 carbon atoms (e.g., C 5 -C 8 In other embodiments, alkyl includes 2 to 5 carbon atoms (e.g., C 2 -C 5 In other embodiments, alkyl includes 3 to 5 carbon atoms (e.g., C 3 -C 5 In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted with one or more substituents.

[0011] "Alkoxy" is a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0012] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond. Examples include ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise in the specification, alkenyl groups are optionally substituted with one or more substituents.

[0013] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond and having from 2 to 12 carbon atoms. In certain embodiments, an alkynyl contains from 2 to 8 carbon atoms. In other embodiments, an alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond. For example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, alkynyl groups are optionally substituted with one or more substituents.

[0014] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from 5 to 18 carbon atoms, and at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic, delocalized (4n+2) π-electron system according to the Hückel theory. Ring systems from which aryl groups can be derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specifically stated herein, the term “aryl” or the prefix “ar-” (e.g., ar in “aralkyl”) is meant to include aryl radicals optionally substituted with one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b --OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2, -R b --N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -ORC(O)N(R a ) 2 , -R b --N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b --S(O).sub t R a (t is 1 or 2), and -R b -S(O) t N(R a ) 2 (t is 1 or 2), wherein R a are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R b (R.sup.b) each independently represents a direct bond or a straight or branched alkylene or alkenylene chain. Yes, R c (R.sup.c) is a straight or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise specified.

[0015] "Heteroaryl" refers to a radical derived from a 3-18 membered aromatic ring radical containing 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, where at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic, delocalized (4n+2) π-electron system according to the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryl is attached to the remainder of the molecule through any atom of the ring(s). Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]iphenyl, and the like. midazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2- Oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2 ... Rimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H- Includes cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise in this specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above optionally substituted by one or more substituents selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R,b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b --N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O) N(R a ) 2 , -R b -ORC(O)N(R a ) 2 , -R b --N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b --S(O).sub t R a (t is 1 or 2), and -R b -S(O) t N(R a ) 2 (t is 1 or 2), wherein R a are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R b (R.sup.b) are each independently a direct bond or a straight or branched alkylene or alkenylene chain; R c(R.sup.c) is a straight or branched alkylene or alkenylene chain and each of the above substituents is unsubstituted unless otherwise specified.

[0016] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds within the scope of the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present disclosure, and are generally prepared by reacting the free base with a suitable organic or inorganic acid.Representative salts of the basic compounds of the present disclosure include, but are not limited to, acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentanepropionate, diethylacetate, digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formic, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2-hydrogen Salts include: oxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic acid salt, isothioate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, paclitaxel, phenylalanine ... These include: molate (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate / diphosphate, pimelic, phenylpropionic, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate, valerate, and the like.Additionally, when the compounds of the present disclosure contain an acidic moiety, suitable pharma- ceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc. Also included are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharma- ceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexylamine, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Additionally, included basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides, for example, methyl, ethyl, propyl, and butyl chloride, bromide, and iodide; dialkyl and diamyl sulfates, for example, dimethyl, diethyl, dibutyl, and the like; longer chain halides, for example, decyl, lauryl, myristyl, and stearyl chloride, bromide, and iodide; and aralkyl halides, for example, benzyl and phenethyl bromide.

[0017] The term "pharmaceutical composition" refers to a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, together with at least one pharma- ceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0018] The term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, which may be known to those of skill in the art.

[0019] The term "subject" includes living organisms such as humans, monkeys, cows, sheep, horses, pigs, cattle, goats, dogs, cats, mice, rats, cultured cells, and transgenic species thereof. In a preferred embodiment, the subject is a human.

[0020] As used herein, the terms "administer", "administering" or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling or taking a compound of the present invention, or a pharmaceutical composition thereof, into or into a subject. The terms "co-administration" and "in combination with" include simultaneous, concurrent, separate or sequential administration of two or more therapeutic agents without specific time limitations, unless otherwise indicated. In one embodiment, the therapeutic agents are in the same composition or in the same unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or separate unit dosage forms.

[0021] As used herein, the terms "condition," "disease," and "disorder" are used interchangeably.

[0022] The term "treat" or "treatment" refers to a method of reducing the effects of a disease or condition. Treatment can refer to a method of reducing not only the symptoms, but also the underlying cause of the disease or condition itself. Treatment can result in some reduction from the original level, and can include, but is not limited to, complete elimination of the disease, condition, or symptoms of the disease or condition.

[0023] As used herein, the terms "prevent", "preventing" and "prevention" refer to the prevention of the onset, recurrence or spread of a disease or disorder or one or more symptoms thereof. In certain embodiments, the terms refer to treatment with or administration of a compound or antibody or dosage form provided herein, with or without one or more other additional active agents, prior to the onset of symptoms, particularly to patients at risk of a disease or disorder as indicated herein. The terms encompass the inhibition or alleviation of a particular disease symptom. In this regard, the term "prevention" can be used interchangeably with the term "prophylactic treatment".

[0024] The term "therapeutically effective amount" of a compound as used in the present disclosure refers to an amount of a compound that elicits a biological or medical response in a subject, such as reducing or inhibiting an enzyme or protein activity, or improves symptoms, alleviates symptoms, slows or delays the progression of a disease, or prevents a disease, etc. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound as used in the present disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, and / or ameliorate (i) a condition or disorder or disease mediated by NLRP3, or (ii) a condition or disorder or disease associated with NLRP3 activity, or (iii) a condition or disorder or disease characterized by the activity (normal or abnormal) of NLRP3; or (2) reduce or inhibit the activity of NLRP3; or (3) reduce or inhibit the expression of NLRP3. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound used in the present disclosure that, when administered to a cell, or tissue, or non-cellular biological material, or medium, is effective to at least partially reduce or inhibit the activity of NLRP3; or to at least partially reduce or inhibit the expression of NLRP3.

[0025] The terms "inhibit", "inhibition", or "inhibiting" refer to the alleviation or suppression of a given symptom, sign, or disorder, or disease, or a significant decrease in the basal activity of a biological activity or biological process. In particular, inhibiting NLRP3 or inhibiting the NLRP3 inflammasome pathway includes reducing the function of NLRP3 or the NLRP3 inflammasome pathway to induce the production of IL-1b and / or IL-18. This can be achieved by mechanisms including, but not limited to, inactivating, disrupting, and / or altering the distribution of NLRP3.

[0026] The term "NLRP3" includes, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, variants, and active fragments thereof.

[0027] The term "neurological disorder" refers to any undesirable condition of the central or peripheral nervous system of a mammal. The term "neurological disorder" includes neurodegenerative and neuropsychiatric disorders. Exemplary neurological disorders include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, schizophrenia, and anxiety, e.g., generalized anxiety disorder, MLS (cerebellar ataxia), Huntington's disease, Down's syndrome, multi-infarct dementia, status epilepticus, contusion injury (e.g., spinal cord injury and head injury), neurodegeneration due to viral infection (e.g., AIDS, encephalopathy), epilepsy, benign amnesia, closed head injury, sleep disorder, depression (e.g., bipolar disorder), dementia, movement disorder, psychosis, alcoholism, post-traumatic stress disorder, and the like. "Neurological disorder" also includes any undesirable condition associated with the disorder. For example, methods of treating a neurodegenerative disorder include methods of treating memory loss and / or cognitive loss associated with a neurodegenerative disorder. Such methods would also include treating or preventing the loss of neuronal function that is characteristic of neurodegenerative disorders.

[0028] Diseases or disorders mediated by NLRP3 Diseases or disorders mediated by NLRP3 are well known in the art. For example, WO2020021447(A1) discloses diseases or disorders mediated by NLRP3 in detail. The NLRP3 inflammasome complex has been associated with neurodegenerative and neurological diseases, including its activation and subsequent inflammatory cytokine release and downstream signaling events. Therefore, inhibition or regulation of the NLRP3 inflammasome-associated complex, cytokine, or signaling activity is a promising target for the treatment of neurodegenerative or neurological diseases. As disclosed in references, NLRP3 mutations have been found to be a factor in a series of rare autoinflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS), which are genetic disorders characterized by recurrent fever and inflammation and are composed of three autoinflammatory disorders that form a clinical continuum. These diseases, Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and Chronic Infantile Neurological, Cutaneous, and Articular Syndrome (CINCA; also called Neonatal-onset Multisystem Inflammatory Disease, NOMID), were all shown to be caused by gain-of-function mutations in the NLRP3 gene that lead to increased secretion of IL-1β. NLRP3 has also been implicated in many autoinflammatory diseases, such as septic arthritis, pyoderma gangrenosum, and acne (PAPA), Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris.

[0029] Many autoimmune diseases, particularly multiple sclerosis, type I diabetes, psoriasis, rheumatoid arthritis (RA), Behcet's disease, Schnitzler syndrome, macrophage activation syndrome, systemic lupus erythematosus and its complications, such as lupus nephritis, and systemic sclerosis, have been shown to require NLRP3. NLRP3 has also been shown to play a role in many lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis. NLRP3 has also been suggested to be involved in many central nervous system conditions, such as multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, intracranial aneurysms, and traumatic brain injury. NRLP3 activity has also been implicated in various metabolic diseases, such as type 2 diabetes and its organ-specific complications, atherosclerosis, obesity, gout, pseudogout, metabolic syndrome, and nonalcoholic steatohepatitis. A role for NLRP3 through IL-1β has also been suggested in atherosclerosis, myocardial infarction, aortic aneurysm, and aortic dissection, as well as other cardiovascular events.

[0030] Accumulation of misfolded aggregated forms of α-synuclein plays an important role in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies. Evidence of accumulation showed that α-synuclein activated the NLRP3 inflammasome, especially in microglia. Moreover, recent studies have also shown that the NLRP3 inflammasome was significantly upregulated and associated with the neurodegenerative processes of AD, PD, MSA, and amyotrophic lateral sclerosis (ALS).

[0031] In addition, inflammasome regulators demonstrated effects on α-synuclein pathology. Transgenic mice expressing human α-synuclein in CNS neurons, A53T and M83, exhibited behavioral defects and aggregated α-synuclein inclusions in the cerebellum. TgM83 mice expressing mutant α-synuclein, with age-dependent effects, develop severe and complex motor, emotional, and cognitive decline leading to paralysis and death. Aged TgM83 mice also showed α-synuclein accumulation in the striatum and nigrostriatal neuronal loss. Studies involving TgM83 mice suggested therapeutic interventions for synucleinopathies involving the NLRP3 inflammasome in diseases such as MSA, anxiety, and PD.

[0032] Other diseases in which NLRP3 has been shown to be required include eye diseases, such as both wet and dry age-related macular degeneration, diabetic retinopathy, non-infectious uveitis, and optic nerve damage; liver diseases such as non-alcoholic steatohepatitis (NASH) and acute alcoholic hepatitis; inflammatory responses in the lungs and skin, such as contact hypersensitivity (e.g., bullous pemphigoid), atopic dermatitis, hidradenitis suppurativa, and sarcoidosis; inflammatory responses in the joints; amyotrophic lateral sclerosis; cystic fibrosis; stroke; chronic kidney disease; and inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. The NLRP3 inflammasome has been found to be activated in response to oxidative stress. NLRP3 has also been shown to be involved in inflammatory hyperalgesia.

[0033] Activation of the NLRP3 inflammasome has been shown to enhance some pathogenic infections, such as influenza and leishmaniasis.

[0034] NLRP3 has also been implicated in the development of many cancers. For example, several previous studies have suggested a role for IL-1β in cancer invasiveness, growth, and metastasis, and inhibition of IL-1β with canakinumab was shown to reduce lung cancer incidence and total cancer mortality in a randomized, double-blind, placebo-controlled trial. Inhibition of the NLRP3 inflammasome or IL-1β was also shown to inhibit lung cancer cell growth and metastasis in vitro. A role for the NLRP3 inflammasome has also been suggested in the carcinogenesis of various other cancers, including myelodysplastic syndromes, myelofibrosis, and other myeloproliferative neoplasms, and acute myeloid leukemia (AML), as well as gliomas, inflammation-driven tumors, multiple myeloma, and squamous cell carcinoma of the head and neck. Activation of the NLRP3 inflammasome has been shown to mediate drug resistance of tumor cells to 5-fluorouracil, and activation of the NLRP3 inflammasome in peripheral nerves contributes to chemotherapy-induced neuropathic pain. NLRP3 has also been shown to be required for effective control of viruses, bacteria, and fungi.

[0035] Activation of NLRP3 leads to cell pyroptosis, a property that plays an important role in clinical disease manifestations. Therefore, inhibitors of NLRP3 are predicted to block pyroptosis and the release of proinflammatory cytokines (e.g., IL-1β) from cells.

[0036] Benzimidazole Derivatives for Treating and / or Preventing Diseases or Disorders Mediated by NLRP3 - Patent application In the present disclosure, the method comprises the step of:

[0037] [ka] (In the formula, n is 0 or 1, X is -S-, -S(=O)-, or -NR n - and R n H or

[0038] [ka] and A is -CH, -CR c , or N, R a is -C(=O)OR a1 , -OR a2 , -OC(=O)R a3 , or -OC(=O)-T-OR a4 and R a1 is H or straight or branched chain C 1-15 is alkyl, R a2 is H, straight or branched chain C 1-15 an alkyl, phosphonate, or diaryl phosphonate; R a3 and R a4 are independently linear or branched C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, -TC 3-10 Cycloalkyl, -T-NHR a3p , -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 Heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl, or -C 1-3 Alkylene-C 6-10 Aryl (where alkylene is -T-NHR a3p substituted with R a3p is H, fluorenylmethoxycarbonyl (Fmoc) or tert-butoxycarbonyl (Boc), R b is H, straight or branched chain C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10Cycloalkenyl, -T'-C 6-10 Aryl, or -T'-C 5-10 is heteroaryl, R c each independently represents a halogen, a straight-chain or branched-chain C 1-15 Alkyl, straight or branched chain C 1-15 Alkoxyl, hydroxyl, or -C 1-10 Alkylene-YC 6-10 Heteroaryl (wherein -Y- is -CH 2 -, -NH, -O-, or -S-; The symbol * represents the bond position; m is an integer from 0 to 4; -T- is absent or C 1-3 Alkylene or C 2-3 alkenylene, -T'- is C 1-3 Alkylene or C 2-3 alkenylene, and Heteroaryl contains at least one heteroatom, each heteroatom being independently S, N, or O; alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene, and alkenylene are each independently unsubstituted or substituted with at least one substituent; The substituents are each independently halogen, amino, nitro, nitroso, straight or branched chain C 1-15 Alkyl, or straight or branched chain C 1-15 Alkoxy or C 3-10 is cycloalkyl, and R b is H, tautomers are included) or a pharma- ceutically acceptable salt thereof.

[0039] In one embodiment, the compound of formula (I) is a compound of formula (Ia):

[0040] [ka] (In the formula, n is 0 or 1, X is -S-, -S(=O)-, or -NR n - and R n H or

[0041] [ka] and A is -CH, -CR c , or N, R a is -C(=O)OR a1 , -OR a2 , -OC(=O)R a3 , or -OC(=O)-T-OR a4 and R a1 is H or straight or branched chain C 1-15 is alkyl, R a2 is H, straight or branched chain C 1-15 an alkyl or diaryl phosphonate, R a3 and R a4 are independently linear or branched C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, -TC 3-10 Cycloalkyl, -T-NHR a3p , -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 Heteroaryl, -T-NH-C(=O)-OC 1-10 alkyl, or -T-adamantyl; R a3p is H, Fmoc, or Boc; R b is H, straight or branched chain C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C3-10 Cycloalkenyl, -T'-C 6-10 Aryl, or -T'-C 5-10 is heteroaryl, R c each independently represents a halogen, a straight-chain or branched-chain C 1-15 Alkyl, straight or branched chain C 1-15 Alkoxyl, hydroxyl, or -C 1-10 Alkylene-YC 6-10 Heteroaryl (wherein -Y- is -CH 2 -, -NH, -O-, or -S-; The symbol * represents the bond position; m is an integer from 0 to 4; -T- is absent or C 1-3 Alkylene or C 2-3 alkenylene, -T'- is C 1-3 Alkylene or C 2-3 alkenylene, and Heteroaryl contains at least one heteroatom, each heteroatom being independently S, N, or O; alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene, and alkenylene are each independently unsubstituted or substituted with at least one substituent; The substituents are each independently halogen, amino, nitro, nitroso, straight or branched chain C 1-15 Alkyl, straight or branched chain C 1-15 Alkoxy or C 3-10 is cycloalkyl, R b is H, tautomers are included) or a pharma- ceutically acceptable salt thereof.

[0042] In one embodiment, the compound of formula (I) is a compound of formula (Ib)

[0043] [ka] (In the formula, n is 0 or 1, X is -S-, -S(=O)-, or -NR n - and Rn is H or

[0044] [ka] and A is -CH, -CR c , or N, R a is -C(=O)OR a1 , -OR a2 , or -OC(=O)R a3 and R a1 is H or straight or branched chain C 1-15 is alkyl, R a2 is H, straight or branched chain C 1-15 an alkyl, phosphonate, or diaryl phosphonate; R a3 -T-NHR a3p , -T-NH-C(=O)-OC 1-10 Alkyl or -C 1-3 Alkylene-C 6-10 Aryl (where alkylene is -T-NHR a3p substituted with R a3p is H, Fmoc, or Boc; R b is H, straight or branched chain C 1-15 Alkyl, C 1-3 Alkoxy-C 1-10 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl, or -T'-C 5-10 is heteroaryl, R c each independently represents a halogen, a straight-chain or branched-chain C 1-15 Alkyl, straight or branched chain C 1-15Alkoxyl, hydroxyl, or -C 1-10 Alkylene-YC 6-10 Heteroaryl (wherein -Y- is -CH 2 -, -NH, -O-, or -S-; The symbol * represents the bond position; m is an integer from 0 to 4; -T- is absent or C 1-3 Alkylene or C 2-3 alkenylene, -T'- is C 1-3 is alkylene, and Heteroaryl contains at least one heteroatom, each heteroatom being independently S, N, or O; alkyl, alkenyl, alkoxy, cycloalkyl, aryl, and heteroaryl are each independently unsubstituted or substituted with at least one substituent; The substituents are each independently halogen, amino, nitro, nitroso, straight or branched chain C 1-15 Alkyl, straight or branched chain C 1-15 Alkoxy or C 3-10 is cycloalkyl, and R b is H, tautomers are included) or a pharma- ceutically acceptable salt thereof.

[0045] In one embodiment, the compound is a compound of formula (I) (In the formula, n is 0 or 1, X is -S-, -S(=O)-, or -NR n - and R n H or

[0046] [ka] and A is -CH, -CR c , or N, R a -ORa2 , -OC(=O)R a3 , or -OC(=O)-T-OR a4 and R a2 is H, straight or branched chain C 1-15 an alkyl, phosphonate, or diaryl phosphonate; R a3 and R a4 are independently linear or branched C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, -TC 3-10 Cycloalkyl, -T-NHR a3p , -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 Heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl, or -C 1-3 Alkylene-C 6-10 Aryl (where alkylene is -T-NHR a3p substituted with R a3p is H, Fmoc, or Boc; R b is H, straight or branched chain C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl, or -T'-C 5-10 is heteroaryl, R c each independently represents a halogen, a straight-chain or branched-chain C 1-15 Alkyl, straight or branched chain C 1-15 Alkoxyl, hydroxyl, or -C 1-10 Alkylene-YC 6-10 Heteroaryl (wherein -Y- is -CH 2 -, -NH, -O-, or -S-; The symbol * represents the bond position; m is an integer from 0 to 4; -T- is absent or C 1-3 Alkylene or C 2-3 alkenylene, -T'- is C 1-3 Alkylene or C 2-3 alkenylene, and Heteroaryl contains at least one heteroatom, each heteroatom being independently S, N, or O; alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene, and alkenylene are each independently unsubstituted or substituted with at least one substituent; The substituents are each independently halogen, amino, nitro, nitroso, straight or branched chain C 1-15 Alkyl, or straight or branched chain C 1-15 Alkoxy or C 3-10 is cycloalkyl, and R b When is H, tautomers are included. or a pharma- ceutically acceptable salt thereof.

[0047] In a further embodiment, the compound is a compound of formula (I), n is 0, X is -S(=O)-, A is N, R a -OR a2 , -OC(=O)R a3 , or -OC(=O)-T-OR a4 and R a2 is H, straight or branched chain C 1-15 an alkyl, phosphonate, or diaryl phosphonate; R a3 and R a4 are independently linear or branched C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, -TC 3-10Cycloalkyl, -T-NHR a3p , -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 Heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl, or -C 1-3 Alkylene-C 6-10 Aryl (where alkylene is -T-NHR a3p substituted with R a3p is H, Fmoc, or Boc; R b is H, m is 3, and R c are each independently a straight or branched chain C 1-15 Alkyl, straight or branched chain C 1-15 (alkoxyl) or a pharma- ceutically acceptable salt thereof.

[0048] In one embodiment, the compound is of formula (I) wherein n is 0.

[0049] In one embodiment, the compound is of formula (I), wherein m is an integer from 0 to 3.

[0050] In one embodiment, the compound is a compound of formula (I), n is 0, X is -S(=O), A is N, R a is -OC(=O)R a3 Or -OC(=O)-T-OR a4 and R a3 is a straight or branched chain C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, -TC 3-10 Cycloalkyl, -T-NHR a3p , -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC5-10 Heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl, or -C 1-3 Alkylene-C 6-10 Aryl (where alkylene is -T-NHR a3p substituted with R a4 is a straight or branched chain C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, -TC 3-10 Cycloalkyl, -T-NHR a3p , -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 Heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl, or -C 1-3 Alkylene-C 6-10 Aryl (where alkylene is -T-NHR a3p substituted with R a3p is H or an N-protecting group selected from Fmoc or Boc. or a pharma- ceutically acceptable salt thereof.

[0051] In one embodiment, the compound is a compound of formula (I), A is N, R b is H, m is 3, and R c are each independently a straight or branched chain C 1-15 Alkyl, linear or branched C 1-15 (alkoxyl) Or a pharma- ceutically acceptable salt thereof.

[0052] In some embodiments, the compound is a compound of formula (I), a is -OC(=O)R a3 (In the formula, R a3 adamantyl; straight or branched chain unsubstituted or substituted with halogen1-10 Alkyl;C 1-4 Alkoxy; unsubstituted or C 1-10 Alkyl, Nitro, C 1-15 Alkoxy or halogen substituted -C 6-10 Aryl;C 3-10 Cycloalkyl;-C 3-10 Cycloalkenyl; straight or branched chain C 2-10 Alkenyl;-C 5-10 Heteroaryl;-C 1-3 Alkylene-C 3-10 Cycloalkyl;C 2-3 Alkenylene-C 6-10 Aryl (where C 6-10 Aryl is unsubstituted or substituted with halogen);-OC(=O)-OC 1-10 (alkyl).

[0053] In some embodiments, the compound is a compound of formula (I), a is -OC(=O)R a3 (In the formula, R a3 adamantyl; straight or branched chain unsubstituted or substituted with halogen 1-8 Alkyl;C 1-4 Alkoxy; unsubstituted or C 1-6 Alkyl, Nitro, C 1-4 Phenyl substituted with alkoxy or halogen; C 3-6 Cycloalkyl;-C 3-6 Cycloalkenyl; straight or branched chain C 2-6 Alkenyl;-C 5-6 Heteroaryl;-C 1-3 Alkylene-C 3-6 Cycloalkyl;C 2-3 alkenylene-phenyl (wherein phenyl is unsubstituted or substituted with halogen); -OC(=O)-OC 1-4 (alkyl).

[0054] In some embodiments, the compound is a compound of formula (I), a is -OC(=O)-C1-6 Alkyl, -OC(=O)-C 1-3 Alkylene-NHFmoc, -OC(=O)-C 1-3 Alkylene-NHBoc or -OC(=O)-NH-C(=O)-OC 1-10 (alkyl).

[0055] In some embodiments, the compound is a compound of formula (I), c each independently represents a halogen, a straight-chain or branched-chain C 1-6 Alkyl, straight or branched chain C 1-6 Alkoxyl or -C 1-10 Alkenylene-YC 6-10 Heteroaryl (wherein Y is S and C 6-10 Heteroaryl is unsubstituted or C 1-15 Alkyl, C 1-15 Alkoxy, -OH, -NH 2 , -NO 2 , or substituted with halogen).

[0056] In some embodiments, the compound is a compound of formula (I), X is -S-, A is N, R a -C(=O)OR a1 (In the formula, R a1 is H or straight or branched chain C 1-15 is alkyl or a pharma- ceutically acceptable salt thereof.

[0057] In some embodiments, the compound is a compound of formula (I), a is -C(=O)OH or -C(=O)OC 1-4 (alkyl).

[0058] In some embodiments, the compound is a compound of formula (I), c each independently represents a halogen, a straight-chain or branched-chain C 1-6 Alkyl, straight or branched chain C1-6 Alkoxyl or -C 1-10 Alkenylene-YC 6-10 Heteroaryl (wherein Y is S and C 6-10 Heteroaryl is unsubstituted or C 1-15 Alkyl, C 2-15 Alkenyl, C 1-15 Alkoxy, -OH, -NH 2 , -NO 2 , or substituted with halogen).

[0059] In some embodiments, the compound is a compound of formula (I), a -C(=O)OH, -C(=O)OC 1-4 Alkyl, H, -OR a2 (In the formula, R a2 is H, linear or branched C 1-10 alkyl);-OC(=O)R a3 (In the formula, R a3 are independently tert-butyl; straight or branched C which is unsubstituted or substituted with halogen, tert-butyl, or amino; 1-10 Alkyl; straight or branched chain C 2-10 Alkenyl; C 1-4 Alkoxy;C 3-10 Cycloalkyl;-C 1-3 Alkylene-C 3-10 Cycloalkyl;-C 3-10 Cycloalkenyl; unsubstituted or 1-10 Alkyl, Nitro, C 1-15 Alkoxy or halogen substituted -C 6-10 Aryl; unsubstituted or C 1-10 Alkoxy-substituted -C 5-10 Heteroaryl;C 2-3 Alkenylene-C 6-10 Aryl (where C 6-10 Aryl is unsubstituted or substituted with halogen);-C 1-3 Alkylene-NH--C(=O)-OC 1-10 alkyl; or adamantyl; or -OC(=O)-OC1-10 (alkyl).

[0060] In some embodiments, the compound is a compound of formula (I), a -OC 1-10 Alkyl or -OC(=O)R a3 (In the formula, R a3 is tert-butyl; adamantyl; straight or branched C unsubstituted or substituted with halogen or tert-butyl; 1-10 Alkyl;C 1-4 Alkoxy; unsubstituted or C 1-10 Alkyl, Nitro, C 1-15 Alkoxy or halogen substituted -C 6-10 Aryl;C 3-10 Cycloalkyl;-C 3-10 Cycloalkenyl; straight or branched chain C 2-10 Alkenyl;-C 5-10 Heteroaryl;-C 1-3 Alkylene-C 3-10 Cycloalkyl;C 2-3 Alkenylene-C 6-10 Aryl (where C 6-10 Aryl is unsubstituted or substituted with halogen);-OC(=O)-OC 1-10 In some embodiments, R a -OC 1-4 Alkyl, -O-tert-butyloxycarbonyl, or -OC(=O)R a3 (In the formula, R a3 is tert-butyl; adamantyl; straight or branched C unsubstituted or substituted with halogen or tert-butyl; 1-8 Alkyl;C 1-4 Alkoxy; unsubstituted or C 1-6 Alkyl, Nitro, C 1-4 Phenyl substituted with alkoxy or halogen; C 3-6 Cycloalkyl;-C 3-6 Cycloalkenyl; straight or branched chain C 2-6 Alkenyl;-C 5-6 Heteroaryl;-C1-3 Alkylene-C 3-6 Cycloalkyl;C 2-3 alkenylene-phenyl (wherein phenyl is unsubstituted or substituted with halogen); -OC(=O)-OC 1-4 In some further embodiments, C 3-6 Cycloalkyl is cyclopropyl or cyclohexyl. In some further embodiments, -C 3-10 Cycloalkenyl is cyclohexenyl.

[0061] In some further embodiments, heteroaryl is pyrrolidinyl, pyrrolinyl, pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, furanyl, dioxolanyl, tetrahydrothiophenyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxathiolanyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrahydropyranyl, pyranyl, dioxanyl, thianyl, thiopyranyl, morpholinyl, oxazinyl, or thiazinyl. In further embodiments, heteroaryl is furanyl, isoxazolyl, or thiophenyl.

[0062] In some embodiments, the compound is a compound of formula (I), a -OH, -COOH, -O-phosphate, -OC 1-6 Alkyl or -OC(=O)-C 1-6 Alkyl, -OC(=O)-C 1-4 Alkylene-NH (Fmoc or Boc), or -OC(=O)-NH-C(=O)-OC 1-10 (alkyl).

[0063] In some embodiments, the compound is a compound of formula (I), c are each independently a straight or branched chain C 1-6 Alkyl or straight or branched chain C 1-6In some embodiments, R c each independently represents a halogen, a straight-chain or branched-chain C 1-6 Alkyl, straight or branched chain C 1-6 Alkoxyl or -C 1-10 Alkenylene-YC 6-10 Heteroaryl (wherein Y is S and C 6-10 Heteroaryl is unsubstituted or C 1-15 Alkyl (preferably C 1-4 Alkyl), C 1-15 Alkenyl (preferably C 2-4 Alkyl), C 1-15 Alkoxy (preferably C 1-4 Alkoxy), -OH, -NH 2 , -NO 2 In a further embodiment, -C 1-10 Alkenylene-YC 6-10 Heteroaryl is

[0064] [ka] It is.

[0065] In some embodiments of Formula (I), compounds include, but are not limited to, the following or a pharma- ceutically acceptable salt thereof:

[0066] [Table 1] JPEG2025020168000010.jpg247161JPEG2025020168000011.jpg252161JPEG2025020168000012.jpg235161JPEG2025020168 000013.jpg239163JPEG2025020168000014.jpg250162JPEG2025020168000015.jpg238163JPEG2025020168000016.jpg25316 2JPEG2025020168000017.jpg249162JPEG2025020168000018.jpg249162JPEG2025020168000019.jpg247162JPEG2025020168 000020.jpg249162JPEG2025020168000021.jpg234162JPEG2025020168000022.jpg250162JPEG2025020168000023.jpg88162

[0067] The present disclosure covers all stereoisomers of the compounds of formula I, formula Ia, and formula Ib. The asymmetric centers present in the compounds of formula I, formula Ia, and formula Ib can all have (R) or (S) configurations, independently of one another. In the structural formulas of the present disclosure, when a bond to a chiral carbon is depicted as a straight line, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof, are encompassed by the formula. When a particular structure is described, its entantiomer (either (R) or (S) at the center) is intended. Similarly, when a compound name is described without a chiral designation of the chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore the individual enantiomers and mixtures thereof, are encompassed by the name.

[0068] The present disclosure includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers, for example mixtures of enantiomers and / or diastereomers in any ratio. Thus, the enantiomers of the subject matter of the present disclosure are in enantiomerically pure form, as both levorotatory and dextrorotatory antipodes, in the form of racemates, and in the form of mixtures of the two enantiomers in any ratio. In the case of cis / trans isomerism, the present disclosure includes both cis and trans forms, and mixtures of these forms in any ratio. The preparation of individual stereoisomers can be carried out, if necessary, by separation of the mixture by conventional methods, for example, by chromatography or crystallization, by the use of stereochemically uniform starting materials for synthesis, or by stereoselective synthesis. Optionally, derivatization can be carried out before the separation of the stereoisomers. Separation of the mixture of stereoisomers can be carried out at an intermediate stage during the synthesis of the compounds of formula (I), (Ia), or (Ib), or in the final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent that contains a stereocenter of known configuration. When compounds of the present disclosure can tautomerize, all individual tautomers and mixtures thereof are included within the scope of the present disclosure. The present disclosure includes all such isomers, as well as salts, solvates (such as hydrates), and solvated salts of such racemates, enantiomers, diastereomers, and tautomers, and mixtures thereof.

[0069] The compounds used in the methods of the present disclosure can be prepared using methods known to those skilled in the art.For example, the general synthetic scheme for preparing the compounds of formula (I) and the preparation procedures of the aforementioned compounds are disclosed in International Publication No. 2018053161(A1), which is incorporated herein by reference.

[0070] use The compounds of formula (I), formula (Ia), or formula (Ib), or pharma- ceutically acceptable salts thereof, may be useful in the treatment of diseases or disorders mediated by NLRP3, preferably selected from autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type I or type II diabetes and associated complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammatory-related disorders (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), sweat gland abscess, wound healing and scarring, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis). In a further embodiment, the treatment is selected by the disease and may be treated by inhibition of the NLRP3 inflammasome.In another embodiment, the disease is selected from the list above, preferably an inflammasome-related disease or disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, such as autoinflammatory fever syndrome (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorder (e.g., acute, chronic, e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, osteoarthritis), kidney-related disease (e.g., hyperoxaluria, lupus nephritis, type I diabetes, or type I diabetes), The present invention is selected from type I diabetes mellitus and associated complications (e.g., nephropathy, retinopathy, hypertensive nephropathy, hemodialysis-associated inflammation), neuroinflammatory-associated diseases (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular or metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland suppuration, acne), wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases or disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type I or type II diabetes and associated complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammatory related disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0071] In some embodiments, the compounds of Formula (I), Formula (Ia), or Formula (Ib) or pharma- ceutically acceptable salts thereof may be useful for the treatment of a disease or disorder mediated by NLRP3, preferably selected from neurological disorders, schizophrenia and schizoaffective disorder symptom domains (including negative, cognitive, depressive, positive, and general psychopathology symptom domains), depression, Tourette's syndrome, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), analgesia, memory and / or cognitive loss associated with a neurodegenerative disease or loss of neurological function characteristic of a neurodegenerative disease, mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, schizophrenia, pain, ataxia, seizures, anxiety, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), fragile X syndrome (FXS), autism, or attention deficit hyperactivity disorder (ADHD).

[0072] In particular, the RS-D7 compounds are useful for the treatment of a disease or disorder mediated by NLRP3, preferably selected from neurological disorders, schizophrenia and schizoaffective disorder symptom domains (including negative, cognitive, depressive, positive, and general psychopathology symptom domains), depression, Tourette's syndrome, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), analgesia, memory and / or cognitive loss associated with a neurodegenerative disease or loss of neurological function characteristic of a neurodegenerative disease, mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, schizophrenia, pain, ataxia, convulsions, anxiety, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), fragile X syndrome (FXS), autism, or attention deficit hyperactivity disorder (ADHD).

[0073] Pharmaceutical Compositions Comprising Benzimidazole Derivatives and Administration of Benzimidazole Derivatives A pharmaceutical composition or combination of the compounds used in the present disclosure can be in unit dosage form of about 1-1000 mg of active ingredient(s), or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 1-100 mg, or about 1-50 mg of active ingredient for a subject of about 50 to about 70 kg. The therapeutically effective dosage of the compounds, pharmaceutical compositions thereof, or combinations thereof will depend on the subject's species, weight, age, and the particular condition, disorder, or disease, or its severity, being treated. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of the disorder or disease.

[0074] The above dosage properties are demonstrable in in vitro and in vivo tests, advantageously using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and preparations thereof. The compounds of the present disclosure can be applied in vitro in the form of solutions, e.g. aqueous solutions, and in vivo either enterally (enterally), parenterally, advantageously intravenously, e.g. as a suspension, or in aqueous solution. In vitro dosages may range from about 10 3 molar to about 10 9 molar concentrations. In vivo therapeutically effective amounts may range between about 0.1 and 500 mg / kg, or between about 1 and 100 mg / kg, depending on the route of administration.

[0075] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) (or a pharma- ceutically acceptable salt or solvate thereof) and a pharma- ceutically acceptable carrier. The term "composition" as a pharmaceutical composition is intended to include a product comprising the active ingredient(s) and the inactive ingredient(s) that constitute the carrier (a pharma- ceutically acceptable excipient), as well as any product that is obtained directly or indirectly from the combination, complexation or aggregation of any two or more components, or from the dissociation of one or more components, or from any other type of reaction or interaction of one or more components. Thus, the pharmaceutical composition of the present disclosure includes any composition made by mixing a compound of formula (I), additional active ingredient(s), and a pharma- ceutically acceptable excipient.

[0076] The pharmaceutical compositions of the present disclosure comprise a compound represented by formula (I) (or a pharma- ceutically acceptable salt or solvate thereof) as an active ingredient, a pharma- ceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. Compositions include compositions suitable for oral, rectal, topical, and parenteral administration (including subcutaneous, intramuscular, and intravenous administration), although the most suitable route of administration in any given case will depend on the particular host and the characteristics and severity of the condition for which the active ingredient is to be administered. Pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy.

[0077] The active ingredient may be administered orally in solid dosage forms, such as capsules, tablets, troches, dragees, granules, and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions. The active ingredient may also be administered parenterally in sterile liquid dosage forms, such as dispersions, suspensions, or solutions. Other dosage forms may also be used to administer the active ingredient, such as ointments, creams, drops, transdermal patches, or powders for topical administration, eye drops (eye drops) or suspension preparations for eye drops, i.e., eye drops, aerosol sprays, or powder compositions for inhalation or intranasal administration, or creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0078] For topical application, the active ingredient or its pharmaceutical composition may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the active ingredient or its pharmaceutical composition include, but are not limited to, mineral oil, liquid petrolatum (petrolatum), white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, sugars such as lactose, and water. Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active ingredient or its pharmaceutical composition suspended or dissolved in one or more pharma- ceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0079] Depending on the particular condition, disorder, or disease being treated, additional therapeutic agents may be administered along with the active ingredient or pharmaceutical composition thereof. These additional agents may be administered sequentially in any order from the active ingredient or pharmaceutical composition thereof as part of a multiple dose regimen (continuous or intermittent administration). Alternatively, these agents may be mixed together with the active ingredient or pharmaceutical composition thereof and administered as part of a single dosage form (simultaneous or combined administration).

[0080] For oral administration, pharmaceutical compositions useful in the present disclosure may take the form of solutions, suspensions, tablets, pills, capsules, powders, granules, semisolids, sustained release formulations, elixirs, aerosols, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate, and calcium phosphate are used with various disintegrants such as starches, preferably potato starch or tapioca starch, and certain complex silicates, as well as binders such as polyvinylpyrrolidone, sucrose, gelatin, and acacia. Lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are also often very beneficial in the formation of tablets. Similar types of solid compositions are also used as fillers for soft and hard gelatin capsules, and preferred materials in this connection include lactose or milk sugar, and high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredients of the present disclosure or pharmaceutical compositions thereof can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents, and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0081] The term "parenteral" as used herein refers to methods of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intramedullary, and intraarticular injection and infusion. Pharmaceutical compositions for parenteral injection include pharma- ceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders to be reconstituted into sterile injectable solutions or dispersions immediately prior to use. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal injection purposes. In this connection, the sterile aqueous medium used can be readily obtained by standard techniques well known to those skilled in the art. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose, and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0082] Pharmaceutical compositions useful in the present disclosure may contain auxiliary agents, such as, but not limited to, preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial activity (prophylaxis) can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical forms can be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0083] A slower infusion rate for administration is particularly beneficial when intrathecal or epidural routes are used. Numerous implantable or wearable pumps are known in the art that are useful for delivering compounds at a prescribed rate.

[0084] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0085] For transdermal (eg, topical) administration, a dilute sterile aqueous or partially aqueous solution (usually in about 0.1-5% concentration) is prepared, otherwise similar to the parenteral solutions described above.

[0086] Pharmaceutical compositions useful in the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions may be prepared by techniques well known in the art of pharmaceutical formulation and may be prepared as a saline solution using benzyl alcohol or other appropriate preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0087] Compositions for rectal or vaginal administration may be prepared by mixing the active ingredient or a pharmaceutical composition thereof with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at room temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the drug.

[0088] Other pharma- ceutically acceptable carriers include, but are not limited to, non-toxic solid, semi-solid, or liquid fillers, diluents, encapsulating materials, or formulation auxiliary of any type, including, but not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, 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, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat.

[0089] Solid pharmaceutical excipients include, but are not limited to, starch, cellulose, talc, glucose, lactose, sucrose (cane sugar), gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, etc. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils including petroleum, animal, vegetable, or synthetic oils, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0090] Methods for preparing various pharmaceutical compositions having a certain amount of active ingredient are well known, or will be apparent to those skilled in the art in light of this disclosure. Other suitable pharmaceutical excipients, and their formulations, are described in Remington's Pharmaceutical Sciences (E. W. Martin, ed., Mack Publishing Company, 19th Edition, 1995).

[0091] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present disclosure to its fullest extent. Thus, the following examples are to be construed as merely illustrative and not limiting the scope of the present disclosure in any way. EXAMPLES

[0092] [Example 1] NLRP3 inflammasome assay Pathogen-associated molecular patterns (PAMPs) lipopolysaccharide (LPS) and danger-associated molecular patterns (DAMPs), including monosodium urate crystals (MSU) or adenosine triphosphate (ATP), are stimuli used to activate the NLRP3 inflammasome, triggering a cascade of downstream events, including activation of caspase-1 and subsequent conversion of pro-IL-1β to the proinflammatory cytokine IL-1β. Assays were performed with human promonocytic leukemia THP-1 cells.

[0093] method Human promonocytic leukemia THP-1 cells were cultured in RPMI and treated with phorbol 12-myristate 13-acetate (PMA). THP-1 cells sensitized to PMA were treated with LPS 50ng / mL for 2 hours, then pretreated with diarylsulfonylurea MCC950 (1uM) (Nature Medicine.21(3):248-55, 2015), RS-D7 (0.1uM, 1uM, and 5uM), 12083 (0.2uM, 1uM, and 5uM), 12127 (0.2uM, 1uM, and 5uM), 28093 (0.2uM, 1uM, and 5uM), or 12093 (0.2uM, 1uM, and 5uM) for 1 hour, and then stimulated with ATP 5mM for 20 minutes or MSU 400ug / ml for 5 hours. Culture medium was set up with RPMI medium containing MCC950, RS-D7, 12083, 12127, 28093, or 12093 and incubated for 2 hours (this step was only for ATP as activator). Supernatants of PMA-differentiated THP-1 cells were collected at given time points after stimulation, and IL-1β levels in cell culture supernatants were measured using an IL-1beta Human Uncoated ELISA kit (Invitrogen). Supernatants and cell lysates were also evaluated by immunoblotting. Immunoreactive signals were developed with Immobilon Crescendo Western HRP substrate, and digital images of membranes were detected by ImageQuant LAS4000mini (GE) according to the manufacturer's instructions.

[0094] According to the Western blot in Figure 1, LPS+MSU led to an increase in caspase-1 and IL-1β. MCC950, an NLRP3 inhibitor (positive control), inhibited the expression of caspase-1 and IL-1β. Treatment with RS-D7 showed a dose-dependent inhibition of caspase-1 and IL-1β. Since individual proteins were not inhibited by RS-D7, it is speculated that RS-D7 may inhibit the process of NLRP3 inflammasome assembly, which leads to a reduction in IL-1β.

[0095] According to the ELISA results in Figure 2, IL-1β 600pg / mL was released in LPS-treated and ATP-treated cells. Significantly lower IL-1β levels were detected in cells treated with MCC950. Compared with the LPS+ATP group or LPS+MSU group, significantly lower IL-1β levels were observed in cells treated with RS-D7 and various concentrations of 12083, 12127, 28093, and 12093. The reduction of IL-1β suggests that these compounds are effective NLRP3 inflammasome regulators.

[0096] [Example 2] In vivo efficacy of RS-D7 in the TgM83 mouse model of neuronal alpha-synucleinopathy associated with neurodegenerative disease method 2.1 Animal information Male TgM83 and its wild-type (WT) littermates were used in this example. TgM83 mice, homozygous for the human A53T-α-synuclein mutation driven by the prion promoter (A53T), were obtained from the Jackson laboratory (Bar Harbor, ME, United States, https: / / www.jax.org / strain / 004479), and were bred from an A53T-heterozygous mating on a mixed C57BL / 6J×C3H background to produce transgenic homozygotes (TgM83; A53T + / + B6;C3-Tg(Prnp-SNCA*A53T)83Vle / J) and non-transgenic (WT;A53T - / - ) littermates of mice (Giasson et al., 2002). Animals were also genotyped (from mouse tail DNA) using PCR analysis as previously described (Graham & Sidhu, 2010). Experiments were performed on TgM83 mice at the age of 12 months.

[0097] 2.2 Animal Welfare Compliance and Husbandry All animal procedures were performed in accordance with protocols approved by the Animal Care and Use Committee of National Taiwan University. All animals used in this example were housed in ventilated polysulfone cages (Alternative design Inc., Winthrop, Maine, USA) in the animal room of the Department of Psychology at National Taiwan University, with food and water available ad libitum. The room was maintained at 22±2°C and kept on a 12:12 light / dark cycle (lights on at 05:00). Animals were housed individually for at least 1 week prior to experimental testing, and all behavioral and pharmacological tasks were performed during the dark cycle. A minimum number of animals was used to meet the 3R reduction principle of animal use. Reasonable measures were taken to minimize any potential pain or discomfort that the animals used in this example may have experienced.

[0098] Dosage Form Mice were dosed at a constant volume of 10 mL per kg body weight. RS-D7 was freshly prepared before the experiment and discarded after use in the target animals.

[0099] 2.3 Experimental design and behavioral tasks The mice used in this example were divided into three groups, including a) WT littermate mice group with vehicle control (WT control), b) TgM83 mice group with vehicle control (TgM83 mice), and c) TgM83 mice group with RS-D7 (TgM83+RS-D7 30 mg / kg (PO)). There were 10 animals in each group. All animals were treated with vehicle (ddH) 20 min before the behavioral experiment began. 2 Mice were given a single dose of either RS-D7 (30 mg / kg, PO) or RS-D7 (30 mg / kg, PO). The open field task was performed in week 1, and the rotarod task was performed in week 2. Details of each behavioral task are described below.

[0100] 2.4 Open field task To assess spontaneous activity, each animal was placed in the center of an open-field apparatus (48 cm × 24 cm × 25 cm, Coulbourn Instruments, White Hall, PA, USA) under dim lighting conditions (60 lx). Locomotor activity parameters (total distance traveled) were monitored and recorded over an hourly period using a SMART video tracking system (San Diego Instruments, San Diego, CA).

[0101] 2.5 Rotarod task Mice were tested for motor coordination and motor skill learning as previously described (Brooks, Trueman, & Dunnett, 2012). On the training day, mice were trained three times for 5 min on the rotarod apparatus (LE8200, PanLab) at a constant speed of 4 rpm. 24 h after training, mice were tested on the rotarod at an accelerating speed (4-40 rpm within 5 min). Three test trials were performed on that test day. The latency of mice to fall off the rotating rod was automatically recorded by a stop plate.

[0102] 2.6 Experimental study of inflammatory cytokine treatment with RS-D7 in TgM83 mouse model To characterize the inflammatory response after RS-D7 treatment, the levels of inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), were investigated in the cerebellum of male TgM83 mice and WT littermate mice (n=5 each) using enzyme-linked immunosorbent assay (ELISA). All animals were sacrificed 20 min after RS-D7 treatment, and tissue samples were taken from the hippocampus of the brains of male WT littermate mice, TgM83 mice, and TgM83 mice with RS-D7 treatment (30 mg / kg, PO). These samples were cut on ice and stored at -80°C before use. ELISA experiments were performed for IL-1β (88-7013, Invitrogen, USA), IL-6 (88-7064, Invitrogen, USA), and TNF-α (88-7324, Invitrogen, USA) using commercial kits. The procedures followed the manufacturer's protocols. Standards and samples were run in triplicate. OD values ​​were read at 450 nm using a microplate reader (ThermoFisher Scientific, USA). Concentration calculations were performed using the standard curve method according to the manufacturer's protocols.

[0103] 2.7 Statistical analysis All data are expressed as the mean + SE of the mean (SEM). Data were analyzed using one-way ANOVA for behavioral outcomes. When F values ​​reached significant differences, post-hoc analysis was performed using Fisher's LSD test. Statistical analysis was performed by SPSS 13.0 (SPSS, Inc., Chicago, IL, USA) and a P value of <0.05 was considered statistically significant.

[0104] result To investigate the therapeutic potential of RS-D7 in the TgM83 mouse model, which mimics the related neurodegenerative disease neuronal alpha-synucleinopathy, TgM83 mice were treated with RS-D7 (30 mg / kg, PO) and subsequently tested using two motor-related behavioral experiments. The experiments included an open field test and a rotarod task, performed on two separate days, which together provide an assessment of the animals' locomotor activity and motor coordination.

[0105] In the open field test, significant differences in total distance traveled were observed among the three groups (WT controls: 21552 ± 1269, TgM83 mice: 15472 ± 942, and TgM83 + RS-D7 30 mg / kg (PO): 20479 ± 730 (cm, mean ± sem); F(2,27) = 10.429, P < 0.05). Fisher's LSD post hoc analysis (Figure 3) showed that TgM83 mice showed hypolocomotion activity compared to WT controls, with a difference of 6080 cm traveled in a given time period, and oral gavage of RS-D7 30 mg / kg was able to significantly rescue the observed hypolocomotion by increasing the distance traveled in a given time period by 5007 cm (all P < 0.05).

[0106] In the rotarod test, significant differences in the latency to fall on the rotarod were observed among the three groups (WT controls: 99.5 ± 7.5, TgM83 mice: 55.3 ± 10.4, and TgM83 + RS-D7 30 mg / kg (PO): 132.1 ± 16.1 (s, mean ± sem); F(2,27) = 10.502, P < 0.05, Figure 4). According to Fisher's LSD post-hoc analysis (Figure 4), compared to WT controls, TgM83 mice showed impaired motor coordination, expressed as 44.2 s less time it took the mice to fall off the rod. Oral gavage of RS-D7 30 mg / kg significantly improved the motor coordination deficit by increasing the latency to fall by 76.8 s (all P < 0.05).

[0107] In addition, it can be seen that RS-D7 treatment suppressed the inflammatory cytokine levels in the cerebellum of TgM83 mice. To explore the effect of RS-D7 on inflammatory responses in TgM83 mice, inflammatory cytokines including IL-1β, IL-6, and TNF-α were evaluated in the cerebellum using ELISA. As shown in Figure 5, significant differences were found in inflammatory cytokines from TgM83 mice in IL-1β (F(3,19)=11.729, P<0.05, Figure 5A), IL-6 (F(3,19)=12.189, P<0.05, Figure 5B), and TNF-α (F(3,19)=9.241, P<0.05, Figure 5C). Fisher's LSD post hoc analysis showed that, compared with the WT control group, the levels of IL-1β, IL-6, and TNF-α were all overexpressed by 2-fold in TgM83 mice, and oral gavage of 30 mg / kg of RS-D7 significantly inhibited the overexpression of IL-1β, IL-6, and TNF-α in TgM83 mice (all P < 0.05).

[0108] Since RS-D7 is a novel chemical entity, this example explores the therapeutic effect of RS-D7 in genetic mouse models of neurodegenerative diseases. A single acute oral gavage administration of RS-D7 at 30 mg / kg successfully rescued the observed motor defects, such as the suppression of locomotor activity and impaired motor coordination, in a male genetic α-synuclein aggregation mouse model (TgM83 mice). This example demonstrates the therapeutic effect of RS-D7 and its potential in treating neuronal alpha-synucleinopathy-related neurodegenerative diseases.

Claims

1. 1. A method for preventing and / or treating a disease or disorder mediated by NLRP3 in a subject, comprising: As an active ingredient, a compound of formula (I) 【Chemistry 1】 (In the formula, n is 0 or 1, X is -S-, -S(=O)-, or -NR n - and R n H or 【Chemistry 2】 and A is -CH, -CR c , or N, R a is -C(=O)OR a1 , -OR a2 , -OC(=O)R a3 , or -OC(=O)-T-OR a4 and R a1 is H or straight or branched chain C 1-15 is alkyl, R a2 is H, straight or branched chain C 1-15 an alkyl, phosphonate, diarylphosphonate, or O-protecting group; R a3 and R a4 are independently a protecting group, a straight or branched C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, -TC 3-10 Cycloalkyl, -T-NHR a3p , -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 Heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl, or -C 1-3 Alkylene-C 6-10 Aryl (where alkylene is -T-NHR a3p substituted with R a3p is H or an N-protecting group, R b is H, straight or branched chain C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl, or -T'-C 5-10 is heteroaryl, R c each independently represents a halogen, a straight-chain or branched-chain C 1-15 Alkyl, straight or branched chain C 1-15 Alkoxyl, unprotected or protected hydroxyl group, or -C 1-10 Alkylene-YC 6-10 Heteroaryl (wherein -Y- is -CH 2 -, -NH, -O-, or -S-; The symbol * represents the bond position; m is an integer from 0 to 4; -T- is absent or C 1-3 Alkylene or C 2-3 alkenylene, -T'- is C 1-3 Alkylene or C 2-3 alkenylene, Heteroaryl contains at least one heteroatom, each heteroatom being independently S, N, or O; alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene, and alkenylene are each independently unsubstituted or substituted with at least one substituent; The substituents are each independently a halogen, a protecting group, a protected or unprotected amino group, nitro, nitroso, a straight or branched chain C 1-15 Alkyl, or straight or branched chain C 1-15 Alkoxy or C 3-10 is cycloalkyl, R b When is H, tautomers are included; however, X is -S- or -S(=O)-, and R a -OR a2 and R a2 is H or linear or branched C 1-15 When A is alkyl, it is -CH or -CR c and X is -S- or -S(=O)-, and R a -C(=O)OR a1 If R b is a straight or branched chain C 6-15 Alkyl, straight or branched chain C 6-15 Alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl, or -T'-C 5-10 is heteroaryl, or a pharma- ceutically acceptable salt thereof) or a pharma- ceutically acceptable salt, solvate or prodrug thereof, in an effective amount to a subject.

2. 2. The method of claim 1, wherein the disease or disorder is selected from an inflammasome-associated disease or disorder, an immune disease, an inflammatory disease, an autoimmune or autoinflammatory disease, a liver-related disease or disorder, an inflammatory arthritis-related disorder, a kidney-related disease, a neuroinflammatory-related disease, a cardiovascular or metabolic disease or disorder, an inflammatory skin disease, wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration, or a cancer-related disease or disorder.

3. 3. The method of claim 2, wherein the disease or disorder is selected from autoinflammatory fever syndrome, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, alcoholic liver disease, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-associated inflammation, multiple sclerosis, brain infection, acute injury, neurodegenerative disease, Alzheimer's disease (AD), cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure, sweat gland abscess, acne, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis, multiple system atrophy (MSA), or dementia with Lewy bodies.

4. 4. The method of claim 3, wherein the disease or disorder is selected from cryopyrin-associated periodic syndrome, nephropathy, or retinopathy.

5. 2. The method of claim 1, wherein the disease or disorder is selected from a neurological disorder, schizophrenia and schizoaffective disorder symptom area, depression, Tourette's syndrome, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), analgesia, memory and / or cognitive loss associated with a neurodegenerative disease or loss of neurological function characteristic of a neurodegenerative disease, mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease (PD), schizophrenia, pain, ataxia, seizures, anxiety, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), fragile X syndrome (FXS), autism, or attention deficit hyperactivity disorder (ADHD).

6. 2. The method of claim 1, wherein n is 0.

7. 2. The method of claim 1, wherein m is an integer from 0 to 3.

8. n is 0, X is -S(=O), A is N, R a -OC(=O)R a3 Or -OC(=O)-T-OR a4 and R a3 Linear or branched chain C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, -TC 3-10 Cycloalkyl, -T-NHR a3p , -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 Heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl, or -C 1-3 Alkylene-C 6-10 Aryl (where alkylene is -T-NHR a3p substituted with R a4 Linear or branched chain C 1-15 Alkyl, straight or branched chain C 2-15 Alkenyl, -TC 3-10 Cycloalkyl, -T-NHR a3p , -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 Heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl, or -C 1-3 Alkylene-C 6-10 Aryl (where alkylene is -T-NHR a3p substituted with R a3p is H or an N-protecting group selected from Fmoc or Boc, or a pharma- ceutically acceptable salt thereof.

9. A is N, R b is H, m is 3, R c each independently represents a straight or branched chain C 1-15 Alkyl, straight or branched chain C 1-15 is alkoxyl, or a pharma- ceutically acceptable salt thereof.

10. R a But -OC(=O)R a3 , where R a3 adamantyl; unsubstituted or halogen-substituted, straight or branched chain C 1-10 Alkyl;C 1-4 Alkoxy; unsubstituted or C 1-10 Alkyl, Nitro, C 1-15 Alkoxy or halogen substituted -C 6-10 Aryl;C 3-10 Cycloalkyl;-C 3-10 Cycloalkenyl; straight or branched chain C 2-10 Alkenyl;-C 5-10 Heteroaryl;-C 1-3 Alkylene-C 3-10 Cycloalkyl;C 2-3 Alkenylene-C 6-10 Aryl (where C 6-10 Aryl is unsubstituted or substituted with halogen), -OC(=O)-OC 1-10 The method of claim 8, wherein the alkyl group is an alkyl group.

11. R a But -OC(=O)R a3 , where R a3 adamantyl; unsubstituted or halogen-substituted, straight or branched chain C 1-8 Alkyl;C 1-4 Alkoxy; unsubstituted or C 1-6 Alkyl, Nitro, C 1-4 Phenyl substituted with alkoxy or halogen; C 3-6 Cycloalkyl;-C 3-6 Cycloalkenyl; straight or branched chain C 2-6 Alkenyl;-C 5-6 Heteroaryl;-C 1-3 Alkylene-C 3-6 Cycloalkyl;C 2-3 alkenylene-phenyl, where phenyl is unsubstituted or substituted with halogen; -OC(=O)-OC 1-4 The method of claim 8, wherein the alkyl group is an alkyl group.

12. R a But -OC(=O)-C 1-6 Alkyl, -OC(=O)-C 1-3 Alkylene-NHFmoc, -OC(=O)-C 1-3 Alkylene-NHBoc or -OC(=O)-NH-C(=O)-OC 1-10 The method of claim 8, wherein the alkyl group is an alkyl group.

13. R c each independently represents a halogen, a straight-chain or branched-chain C 1-6 Alkyl, straight or branched chain C 1-6 Alkoxyl or -C 1-10 Alkenylene-YC 6-10 Heteroaryl (wherein Y is S and C 6-10 Heteroaryl is unsubstituted or C 1-15 Alkyl, C 1-15 Alkoxy, -OH, -NH 2 , -NO 2 9. The method of claim 8, wherein said aryl group is substituted with aryl, aryl or halogen.

14. X is -S-; A is N, R a -C(=O)OR a1 (In the formula, R a1 is H or straight or branched chain C 1-15 alkyl), or a pharma- ceutically acceptable salt thereof.

15. R a -C(=O)OH or -C(=O)OC 1-4 The method of claim 14, wherein the alkyl group is an alkyl group.

16. The compound is RS-D7: 5-O-desmethyl-omeprazole Esomeprazole: (S)-(-)-5-Methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzimidazole 21122: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl acetate) 21124: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylbenzoate) 26096: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl butyrate) 26097: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylcyclohexanecarboxylate) 26098: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-butylbenzoate) 21127: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3-methylbenzoate) 27076: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylhexanoate 27077: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl isobutyrate 27078: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylcyclohex-3-ene-1-carboxylate) 27079: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylcyclohex-3-enecarboxylate 28087: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-methylbenzoate) 28091: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-nitrobenzoate) 28092: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylcyclopropanecarboxylate) 28093: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-ethylbutanoate) 28094: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-phenylacetate) 28095: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3,5,5-trimethylhexanoate 28096: (2-(((5-Methoxy-4,6-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-ethoxybenzoate) 21123: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylpropionate) 21125: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-chlorobenzoate) 21126: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3-nitrobenzoate) 21128: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylheptanoate 21129: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-fluorobenzoate) 21130: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl(Z)-2-methylbut-2-enoate) 21131: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-chloropropanoate) 21132: tert-Butyl (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl) carbonate 12124: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl(Z)-but-2-enoate) 12125: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3-methylbut-2-enoate) 12122: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylfuran-2-carboxylate) 12123: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl acrylate) 12127: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-methylbutanoate) 12128: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3-cyclopentylpropanoate) 12129: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl(E)-3-(2-chlorophenyl)acrylate) 12130: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 6-bromohexanoate) 11021: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-fluorobenzoate) 11020: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-methoxybenzoate) 11022: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl(3r,5r,7r)-adamantane-1-carboxylate) 11023: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylisoxazole-5-carboxylate) 11030: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-(tert-butyl)benzoate) 11031: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3-chloro-4-fluorobenzoate) 25015: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl pivalate) 25016: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylpentanoate) 25017: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-nitrobenzoate) 25027: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylcyclobutanecarboxylate) 25028: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-ylthiophene-2-carboxylate) 25029: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-methylbutanoate) 25030: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3,3-dimethylbutanoate) 25031: (2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-methoxyacetate) and 25032: (Ethyl (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl)carbonate) 12082: Methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate 12083: 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylic acid 12084: Methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-carboxylate 12088: Methyl 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1-octyl-1H-benzo[d]imidazole-5-carboxylate 21098: Methyl 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazole-5-carboxylate 26065: Methyl 1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylate 21102: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid 21103: Methyl 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-carboxylate 21104: 2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid 26066: Methyl 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-pentyl-1H-benzo[d]imidazole-5-carboxylate 21105: 2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(2-(cyclohex-1-en-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxylic acid 26070: 1-(Furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylic acid 26071: Methyl 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(4-methoxybenzyl)-1H-benzo[d]imidazole-5-carboxylate 26072: Methyl 2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-(furan-2-ylmethyl)-3,4-dihydroquinazoline-7-carboxylate 21106: Methyl 3-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylate 12092: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazol-5-yl(((9H-fluoren-9-yl)methoxy)carbonyl)glycinate 12093: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazol-5-yl(tert-butoxycarbonyl)glycinate 21110: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-(3-methoxypropyl)-3,4-dihydroquinazoline-7-carboxylic acid 26076: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-pentyl-1H-benzo[d]imidazole-5-carboxylic acid 26077: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(4-methoxybenzyl)-1H-benzo[d]imidazole-5-carboxylic acid 12094: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]-imidazol-5-yl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-phenylacetate 13001: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-6-yl 2-((tert-butoxycarbonyl)amino)acetate 13084: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl diphenyl phosphate 26079: Methyl 3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylate 26089: 3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylic acid 26090: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-pentyl-3,4-dihydroquinazoline-7-carboxylic acid 26091: Methyl 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-pentyl-3,4-dihydroquinazoline-7-carboxylate 26092: Methyl 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-(4-methoxybenzyl)-3,4-dihydroquinazoline-7-carboxylate 21115: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid 21116: Methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylate 21117: 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylic acid 21118: Methyl 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazole-5-carboxylate 21119: 2-(((4-Methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazole-5-carboxylic acid 21120: 2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid 21121: 2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazole-5-carboxylic acid 22138: 5-Methoxy-2-((2-methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazole 22139: 5-Methoxy-2-((2-methoxy-3,6-dimethylbenzyl)sulfinyl)-1H-benzo[d]imidazole 22140: 2,2'-(((2-methoxy-4-methyl-1,3-phenylene)bis(methylene))bis(sulfanediyl))bis(5-methoxy-1H-benzo[d]imidazole) 21133: 2-((3-(bromomethyl)-2-((tert-butyldimethylsilyl)oxy)-6-methylbenzyl)thio)-5-methoxy-1H-benzo[d]imidazole and 22141: 2-((2-Methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazol-5-ol or a pharma- ceutically acceptable salt thereof.

17. R c each independently represents a halogen, a straight-chain or branched-chain C 1-6 Alkyl, straight or branched chain C 1-6 Alkoxyl or -C 1-10 Alkenylene-YC 6-10 Heteroaryl (wherein Y is S and C 6-10 Heteroaryl is unsubstituted or C 1-15 Alkyl, C 2-15 Alkenyl, C 1-15 Alkoxy, -OH, -NH 2 , -NO 2 16. The method of claim 15, wherein said alkyl group is substituted with aryl, aryl or halogen.

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