Pyrido-[3, 4-d] pyridazinamine derivatives useful as nlrp3 derivatives

Abstract

The present disclosure relates to inhibitors of NLRP3 of formula (I): # imgabs0 # or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof wherein ring A is a 5 to 8 membered monocyclic heterocycloalkyl group comprising at least one O ring atom, p is 0 or 1, and R1, R2, R3, R4 and X are as defined herein, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, it is useful for the treatment of diseases or conditions inhibited by said proteins.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Non-Provisional Application No. 17 / 704,983 filed on March 25, 2022, U.S. Provisional Application No. 63 / 420,930 filed on October 31, 2022, and U.S. Provisional Application No. 63 / 443,874 filed on February 7, 2023, the entire contents of each of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to inhibitors of NLR family pyrin domain 3 (NLRP3) proteins. The inhibitors described herein can be used to treat diseases and conditions associated with regulating NLRP3 proteins. In particular, the present invention concerns compounds and pharmaceutical compositions that inhibit NLRP3, methods of using the compounds and pharmaceutical compositions to treat diseases and conditions associated with NLRP3, and methods of synthesizing the compounds and compositions. Background Art

[0004] The innate immune response is mediated by different types of receptors called pattern recognition receptors (PRRs). PRRs recognize the presence of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Once engaged, these receptors trigger the activation of downstream inflammatory pathways that will help resolve the injury. However, in many cases, this activation can go uncontrolled and lead to disease.

[0005] Inflammasomes represent a class of PRRs that are key components of the innate immune response. Activation of inflammasomes triggers a cascade of events that release IL-1β, IL-18, and promote an inflammatory form of cell death called pyroptosis induced by gasdermin activation. Pyroptosis is a unique form of inflammatory cell death that results not only in the release of cytokines, but also in the release of other intracellular components that promote a broader immune response of both the innate and acquired immune systems. Therefore, inflammasome activation is a major regulator of the inflammatory cascade.

[0006] NLRP3 is the most characterized inflammasome and has been shown to be crucial in innate immunity and inflammatory responses. Although several other NLR complexes such as NLRC4 are activated under very specific circumstances, NLRP3 can be activated by a wide variety of stimuli and should be considered a sensor of homeostasis imbalance in the cell. Therefore, it is necessary for it to function accurately. In addition to playing a role in host immune defense, NLRP3 dysregulation has been associated with the pathogenesis of many inflammatory conditions. These include genetic diseases such as cryptopyrin-associated periodic syndrome (CAPS) caused by gain-of-function mutations in the NLRP3 gene, as well as many common neurological and systemic diseases. Importantly, preclinical studies have shown that NLRP3 overactivation plays a key role in a large number of inflammatory and degenerative diseases, including NASH, atherosclerosis and other cardiovascular diseases, Alzheimer's disease, Parkinson's disease, diabetes, gout, and many other autoinflammatory diseases. Therefore, there is an unmet need in the art to develop small molecules for regulating NLRP3 activity to treat various diseases and conditions. Summary of the invention

[0007] In one aspect, the present disclosure provides, inter alia, compounds of formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein:

[0010] A is a 5- to 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom;

[0011] R 1 is halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0012] R 2 is halogen or C1-C6 alkyl;

[0013] or R 1 and R 2 Together with the atoms to which they are attached, they form a 3- or 4-membered carbon ring;

[0014] R 3 is -OH, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0015] X is H, -OH, halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl; and

[0016] R 4 is H, C1-C6 alkyl or -C(O)(C1-C6 alkyl); and

[0017] p is 0 or 1,

[0018] wherein each instance of alkyl, alkane- or carbocyclic is independently substituted with 0, 1, 2 or 3 halogen atoms, and when R 3 When Cl is Not for

[0019] In some embodiments, the compound of formula (I) is not

[0020] In some embodiments, the compound has a Kpu,u>0.3.

[0021] In another aspect, the present disclosure provides, inter alia, suitable compounds selected from Table 1 or Table 2, and pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers or tautomers thereof.

[0022] In another aspect, the present disclosure provides, inter alia, suitable compounds selected from the group consisting of:

[0023] (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0024] 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0025] (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0026] (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0027] (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; and

[0028] (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0029] and pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers or tautomers thereof.

[0030] Another aspect of the present disclosure relates to a pharmaceutical composition comprising (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0031] Another aspect of the present disclosure relates to a pharmaceutical composition comprising 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0032] Another aspect of the present disclosure relates to a pharmaceutical composition comprising (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0033] Another aspect of the present disclosure relates to a pharmaceutical composition of (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0034] Another aspect of the present disclosure relates to a pharmaceutical composition comprising (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0035] Another aspect of the present disclosure relates to a pharmaceutical composition comprising (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0036] In some aspects, the present disclosure provides compounds obtainable by or by a process for preparing a compound as described herein (eg, a process comprising one or more steps described in Schemes 1 and 2).

[0037] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0038] In some aspects, the disclosure provides intermediates as described herein, which are useful in methods of preparing compounds as described herein (eg, the intermediates are selected from the intermediates described in Examples 1-11).

[0039] In some aspects, the present disclosure provides a method of treating or preventing a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0040] In some aspects, the present disclosure provides a method of treating a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0041] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or condition disclosed herein.

[0042] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition disclosed herein.

[0043] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or condition disclosed herein.

[0044] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition disclosed herein.

[0045] In some aspects, the present disclosure provides a method for treating or preventing a NLRP3-related disease or condition selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache / pain, and traumatic brain injury. The method comprises administering to a subject at least one therapeutically effective amount of a compound disclosed herein.

[0046] In some embodiments, the disease or disorder is inflammation, an autoimmune disease, cancer, an infection, a central nervous system disease or disorder, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft-versus-host disease, allodynia, or an NLRP3-related disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3.

[0047] In some embodiments, the central nervous system disease or disorder is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0048] In some embodiments, the kidney disease is acute kidney disease, chronic kidney disease, or a rare kidney disease.

[0049] In some embodiments, the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0050] In some embodiments, the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0051] In some embodiments, the NLRP3-associated disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3 is cryopyrin-associated autoinflammatory syndrome.

[0052] In some embodiments, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease.

[0053] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0054] In some aspects, the present disclosure provides a method of preparing a compound comprising one or more of the steps described herein.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. In the specification, unless the context clearly stipulates otherwise, the singular also includes the plural. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. It is not recognized that the references cited herein are prior art of the claimed invention. In the event of a conflict, this specification (including definitions) will prevail. In addition, materials, methods and embodiments are illustrative only and are not intended to be restrictive. In the event of a conflict between the chemical structure and the name of the compound disclosed herein, the chemical structure will prevail.

[0056] Other features and advantages of the disclosure will become apparent from the following detailed description and from the claims. DETAILED DESCRIPTION

[0057] The present disclosure relates to phthalazine derivatives, pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers (e.g., single stereoisomers, mixtures of stereoisomers, or racemic mixtures of stereoisomers), tautomers, prodrugs, and isotope-labeled compounds thereof, which can inhibit NLRP3 activity and are therefore useful in methods of treating the human or animal body. Certain compounds of the present invention exhibit surprising and unexpected superiority in brain penetration. The present disclosure also relates to methods for preparing these compounds, pharmaceutical compositions containing them, and their use in treating conditions involving NLRP3, such as inflammation, autoimmune diseases, cancer, infections, central nervous system diseases or conditions, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, psychological diseases, graft-versus-host disease, allodynia, or NLRP3-related diseases in subjects who have been determined to carry germline or somatic non-silent mutations in NLRP3.

[0058] definition

[0059] Unless otherwise stated, the following terms used in the specification and claims have the following meanings listed below.

[0060] As used herein, "alkyl", "C1, C2, C3, C4, C5 or C6 alkyl" or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl groups include moieties having one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for a straight chain, C3-C6 for a branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0061] The alkyl group may be an "optionally substituted alkyl," which refers to unsubstituted alkyl or alkyl having the specified substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0062] Other optionally substituted moieties (such as optionally substituted carbocycles or heterocycloalkyls) include both unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyls include those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0063] As used herein, the term "alkenyl" is included in length and possible substitutions similar to the above-mentioned alkyl, but contains an unsaturated aliphatic group of at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (for example, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, straight or branched alkenyl groups have six or less carbon atoms in their main chain (for example, for straight-chain C2-C6, for branched C3-C6). The term "C2-C6" includes alkenyl groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms.

[0064] As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0065] As used herein, the term "alkynyl" includes an unsaturated aliphatic group similar to the above-mentioned alkyl in length and possible substitution, but containing at least one triple bond. For example, "alkynyl" includes a straight chain alkynyl group (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and a branched chain alkynyl group. In certain embodiments, a straight chain or branched chain alkynyl group has six or less carbon atoms in its main chain (e.g., for a straight chain C2-C6, for a branched C3-C6). The term "C2-C6" includes an alkynyl group containing two to six carbon atoms. The term "C3-C6" includes an alkynyl group containing three to six carbon atoms. As used herein, "C2-C6 alkenylene joints" or "C2-C6 alkynylene joints" are intended to include C2, C3, C4, C5 or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0066] As used herein, the term "optionally substituted alkynyl" refers to unsubstituted alkynyl groups or alkynyl groups having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0067] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl) include both unsubstituted moieties and moieties with one or more of the specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0068] As used herein, the term "cyano" refers to a nitrile group (eg, -CN).

[0069] As used herein, the term "cycloalkyl" or "carbocycle" or "carbocyclyl" refers to a cycloalkyl radical having 3 to 30 carbon atoms (e.g., C3-C 12 、C3-C 10 The saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged or spiro) system of C3-C8 (C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl and adamantyl.

[0070] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more ring heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur (such as O, N, S, P or Se), e.g. 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 ring heteroatoms, or e.g. 1, 2, 3, 4, 5 or 6 ring heteroatoms, unless otherwise specified. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolyl, indolyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxirane, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxaze ... -5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane- 1,5'-furo[3,4-b]pyridinyl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6, 7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thienyl, etc. In the case of polycyclic heterocycloalkyls, only one ring of the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0071] As used herein, the term "optionally substituted heterocycloalkyl" refers to unsubstituted heterocycloalkyl groups having the specified substituents replacing one or more hydrogen atoms on one or more carbon or heteroatoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0072] As used herein, the term "hydroxy" or "hydroxyl" includes a group having -OH or -O - The group.

[0073] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0074] The term "haloalkyl" or "haloalkoxy" refers to the alkyl or alkoxy portion substituted with one or more halogen atoms.

[0075] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl groups covalently attached to an oxygen atom. Examples of alkoxy groups or alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy group may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0076] Unless otherwise clearly defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups, such as phenyl, biphenyl or naphthyl. In the case of containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group can be optionally substituted by one or more substituents, such as 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. The substituents themselves may be optionally substituted. In addition, when containing two or more fused rings, the aryl groups defined herein may have a saturated or partially unsaturated ring fused to a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoannulenyl, 10,11-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like.

[0077] Unless specifically defined otherwise, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, Se or B, the remaining ring atoms being C. Heteroaryl as defined herein also means a bicyclic heteroaromatic group, wherein the heteroatoms are selected from N, O, S, P, Se or B. Heteroaryl as defined herein also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se or B. Aromatic groups are optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thien-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazolyl, indazolyl, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furanyl, 2,3-c]pyridyl, imidazo[1,2-a]pyridyl, indazolyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thieno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indolyl, indolino, indolinononyl (indol inonyl), dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl , tetrazo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2 ,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl and their derivatives. In addition, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring, for example, a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring contains 0 to 4 heteroatoms selected from N, O, S, P, Se or B, and is optionally substituted with one or more oxo. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused to a saturated or partially unsaturated ring as described herein. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyridinyl pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, 7-oxabicyclo[2.2.1]heptyl or benzo[c][1,2]oxaborol-1(3H)-ol.

[0078] The cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted at one or more ring positions (e.g., a ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkyl The term "alkyl" refers to any of a group consisting of alkyl, alkyl, alkyl, alkylene ...

[0079] As used herein, unless otherwise specified, the expressions "one or more of A, B or C", "one or more A, B or C", "one or more of A, B and C", "one or more A, B and C", "selected from the group consisting of A, B and C", "selected from A, B and C", etc. are used interchangeably and all refer to selected from the group consisting of A, B and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof.

[0080] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then the substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which the substituent is bonded to the rest of the compound of a given formula, then the substituent may be bonded via any atom in the formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0081] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown as substituted with 0-2 R moieties, the group may be optionally substituted with up to two R moieties, and R is selected at each occurrence independently of the definition of R. In addition, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0082] It should be understood that the present disclosure provides methods for synthesizing compounds of any formula described herein.The present disclosure also provides detailed methods for synthesizing various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the examples.

[0083] It should be understood that throughout the specification, when a composition is described as having, including or comprising a particular component, it is contemplated that the composition is also substantially composed of or consists of the enumerated components. Similarly, where a method or process is described as having, including or comprising a particular process step, the process is also substantially composed of or consists of the enumerated process steps. In addition, it should be understood that the order of steps or the order in which certain actions are performed is not important, as long as the present invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

[0084] It should be understood that the synthetic methods disclosed herein can tolerate a variety of functional groups and therefore can use various substituted starting materials. The methods generally provide the desired final compound at or near the end of the overall method, although in some cases it may be necessary to further convert the compound into its pharmaceutically acceptable salt.

[0085] It should be understood that the compounds of the present disclosure can be prepared in a variety of ways by employing standard synthetic methods and procedures known to those skilled in the art, or which will be apparent to the skilled artisan in view of the teachings herein, using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or a few sources, classic texts such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated herein by reference, are useful and recognized reference textbooks on organic synthesis known to those skilled in the art.

[0086] Those of ordinary skill in the art will note that during the reaction sequence described herein and synthesis scheme, the order of some steps can be changed, such as the introduction and removal of blocking groups. Those of ordinary skill in the art will recognize that some groups may need to be protected from the impact of reaction conditions via the use of blocking groups. Blocking groups can also be used to distinguish similar functional groups in molecules. The list of blocking groups and how to introduce and remove these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley & Sons: New York, 1999.

[0087] It should be understood that any description of a method of treatment or prevention includes the use of a compound to provide such treatment or prevention as described herein, unless otherwise indicated. It should be further understood that any description of a method of treatment or prevention includes the use of a compound to prepare a medicament for treating or preventing such a disorder, unless otherwise indicated. Treatment or prevention includes treatment or prevention in humans or non-human animals, including rodents and other disease models.

[0088] It should be understood that, unless otherwise stated, any description of a method of treatment includes the use of a compound as described herein to provide such treatment. It should be further understood that, unless otherwise stated, any description of a method of treatment includes the use of a compound to prepare a medicament for treating such an illness. Treatment includes treating a human or non-human animal, including rodents and other disease models. As used herein, the term "subject" is interchangeable with the term "subject in need", both of which refer to a subject suffering from a disease or having an increased risk of developing the disease. "Subject" includes mammals. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or pig. In one embodiment, the mammal is a human. A subject in need may be a subject who has previously been diagnosed or identified as having a disease or condition disclosed herein. A subject in need may also be a subject suffering from a disease or condition disclosed herein. Alternatively, a subject in need may be a subject with an increased risk of developing such a disease or condition relative to the general population (i.e., a subject who is susceptible to developing such a condition relative to the general population). A subject in need may have a disease or condition disclosed herein that is refractory or resistant (i.e., a disease or condition disclosed herein that is not responsive or has not yet responded to treatment). A subject may be resistant at the beginning of treatment or may become resistant during treatment. In some embodiments, a subject in need has received all known effective therapies for a disease or condition disclosed herein and has failed. In some embodiments, a subject in need has received at least one prior therapy.

[0089] As used herein, the terms "treating" or "treatment" describe the management and care of a patient for the purpose of combating a disease, illness, or condition, and include the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, illness, or condition, or to eliminate the disease, illness, or condition. The term "treatment" may also include treating in vitro cells or animal models. It should be understood that references to "treating" or "treatment" include alleviation of established symptoms of a disease. Thus, "treating" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition in a person who may be susceptible to or susceptible to the condition, disorder, or condition but does not yet experience or display clinical or subclinical symptoms of the condition, disorder, or condition, (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) remitting or ameliorating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0090] It will be appreciated that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, may or may also be used to prevent related diseases, disorders or conditions, or to identify suitable candidates for such purposes.

[0091] As used herein, the terms "preventing," "prevent," or "protecting against" describe reducing or eliminating the onset of symptoms or complications of such a disease, disorder or condition.

[0092] It should be understood that those skilled in the art can refer to general reference texts for detailed descriptions of known techniques or equivalent techniques discussed herein. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd Edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th Edition (1990). These texts may also be referenced when making or using an aspect of the present disclosure.

[0093] It will be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0094] As used herein, the term "pharmaceutical composition" is a preparation containing a compound of the present disclosure, which is suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any one of a variety of forms, including, for example, a single pump or vial on a capsule, IV bag, tablet, aerosol inhaler. The amount of active ingredient (e.g., a preparation of a disclosed compound or its salt, hydrate, solvate or isomer) in a unit dose composition is an effective amount and varies according to the specific treatment involved. It will be appreciated by those skilled in the art that it is sometimes necessary to make conventional changes to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. The topical or transdermal dosage forms of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that are required.

[0095] As used herein, the term "pharmaceutically acceptable" refers to those compounds, anions, cations, materials, compositions, carriers and / or dosage forms that are within the scope of reasonable medical diagnosis; suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problems or complications; and commensurate with a reasonable benefit / risk ratio.

[0096] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition, which is generally safe, non-toxic and not biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. "Pharmaceutically acceptable excipient" as used in the specification and claims includes one and more than one such excipient.

[0097] It should be understood that the pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral administration, such as intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous applications may include the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates, and agents for adjusting tension, such as sodium chloride or dextrose. pH can be adjusted with acid or alkali, such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be packaged in ampoules, disposable syringes, or multidose vials made of glass or plastic.

[0098] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject by many well-known methods currently used for chemotherapy. For example, the compounds of the present disclosure can be injected into the bloodstream or body cavity or orally or applied through the skin with a patch. The selected dose should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or condition disclosed herein) and the health of the patient should preferably be closely monitored during and within a reasonable period after treatment.

[0099] As used herein, the term "therapeutically effective amount" refers to an amount of an agent that treats, ameliorates, or prevents an identified disease or disorder, or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the disorder; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0100] It will be appreciated that for any compound, the therapeutically effective amount can be estimated initially in cell culture assays, for example, of tumor cells, or in animal models, typically rats, mice, rabbits, dogs or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration to humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 / ED 50There is a need for pharmaceutical compositions that exhibit large therapeutic indices. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0101] Dosage and administration are adjusted to provide sufficient levels of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, drug combinations, reaction sensitivities and tolerance / response to therapy.

[0102] Pharmaceutical compositions containing the active compounds of the present disclosure can be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing methods. Pharmaceutical compositions can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, which contain excipients and / or adjuvants that help to process the active compounds into pharmaceutically useful preparations. Of course, suitable preparations are determined by the route of administration selected.

[0103] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that it is easy to inject. It must be stable under manufacturing and storage conditions, and must prevent the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or a dispersion medium, which contains, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Suitable fluidity can be maintained by, for example, using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by using a surfactant. The effect of preventing microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, isotonic agents, such as sugars, polyols such as mannitol and sorbitol, and sodium chloride are preferably included in the composition. By including an agent that delays absorption in the composition, such as aluminum monostearate and gelatin, the absorption of the injectable composition can be extended.

[0104] Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound with one or a combination of ingredients listed above into an appropriate solvent as required, followed by filtration sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other ingredients required from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods are vacuum drying and freeze drying, which produce a powder of the active ingredient plus any additional required ingredients from its previously sterile filtered solution.

[0105] Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be blended with an excipient and used in the form of tablets, lozenges or capsules. Oral compositions can also be prepared using a fluid carrier used as a mouthwash, wherein the fluid carrier containing the compound is applied orally and rinsed and spit out or swallowed. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel or corn starch; lubricants, such as magnesium stearate or Sterotes; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavorings, such as mint, methyl salicylate or orange flavoring.

[0106] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0107] Systemic administration can also be carried out by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants suitable for the barrier to be penetrated are used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be accomplished by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels or creams as known in the art.

[0108] The active compound can be prepared with a pharmaceutically acceptable carrier, which protects the compound from rapid elimination in vivo, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. The method for preparing such preparations will be apparent to those skilled in the art. The material can also be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeting infected cells, which have monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0109] It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the present disclosure are dictated by and directly dependent upon the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0110] In therapeutic applications, the dosage of the pharmaceutical composition used according to the present disclosure depends on the agent; the age, weight and clinical condition of the patient; and the experience and judgment of the clinician or practitioner administering the therapy; and other factors affecting the selected dosage. Generally, the dosage should be sufficient to cause the symptoms of the disease or condition disclosed herein to slow down and preferably disappear, and also preferably cause complete disappearance of the disease or condition. The dosage may be in the range of about 0.01 mg / kg per day to about 5000 mg / kg per day. The effective amount of a medicament is the amount of the medicament that provides an objectively identifiable improvement as indicated by a clinician or other qualified observer. Improvements in survival and growth indicate disappearance. As used herein, the term "dosage effective manner" refers to the amount of an active compound that produces a desired biological effect in a subject or cell.

[0111] It will be understood that the pharmaceutical compositions may be included in a container, pack, or dispenser together with instructions for administration.

[0112] It should be understood that for compounds of the present disclosure that are capable of further forming salts, all such forms are also contemplated within the scope of the claimed disclosure.

[0113] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure, wherein the parent compound is modified by preparing its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues such as mineral acid salts or organic acid salts of amines, acidic residues such as alkali metal salts or organic salts of carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed by non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, gluconic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinic acid, hydrabamine acid amic), hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, para-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid; and common amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0114] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzathine salt, tromethamine salt, ammonium salt, arginine salt, or lysine salt.

[0115] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions, or aluminum ions; or when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In salt form, it should be understood that the ratio of the compound to the cation or anion of the salt may be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0116] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same salt.

[0117] The compound or its pharmaceutically acceptable salt is administered orally, nasally, transdermally, pulmonary, inhaled, buccal, sublingual, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0118] The dosage regimen for using the compound is selected based on a variety of factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal and liver function; and the specific compound or salt thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, combat or arrest the progression of the condition. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to combat or arrest the progression of the condition.

[0119] Techniques for preparing and administering the disclosed compounds of the present disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0120] Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methods that can be used to practice the present disclosure. The examples do not limit the disclosure claimed. Based on the present disclosure, the skilled person can identify and adopt other components and methods that are useful for practicing the present disclosure.

[0121] In the synthetic schemes described herein, compounds may be drawn in one particular configuration for simplicity. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor excluding mixtures of isomers, tautomers, regioisomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

[0122] All publications and patent documents cited herein are incorporated herein by reference, as if each such publication or document specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents does not constitute any admission that any one is relevant prior art, nor does it constitute any admission of its content or date. Now that the invention has been described by way of a written description, those skilled in the art will recognize that the invention can be practiced in various embodiments, and the foregoing description and the following examples are for illustrative purposes rather than for the purpose of limiting the claims that follow.

[0123] As used herein, the phrase "compounds of the present disclosure" refers to those compounds disclosed both generically and specifically herein.

[0124] Compounds of the Disclosure

[0125] In one aspect, the present disclosure provides, inter alia, compounds of formula (I):

[0126]

[0127] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein:

[0128] A is a 5- to 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom;

[0129] R 1 is halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0130] R 2 is halogen or C1-C6 alkyl;

[0131] or R 1 and R 2 Together with the atoms to which they are attached, they form a 3- or 4-membered carbon ring;

[0132] R 3 is -OH, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0133] X is H, -OH, halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl; and

[0134] R 4 is H, C1-C6 alkyl or -C(O)(C1-C6 alkyl); and

[0135] p is 0 or 1,

[0136] wherein each instance of alkyl, alkane- or carbocycle is independently substituted with 0, 1, 2 or 3 halogen atoms; and when R 3 When Cl is Not for

[0137] In some embodiments, the compound of formula (I) is not or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0138] In some embodiments, the compound has formula (I), wherein p is 1; R 1 is C1-C6 alkyl or C1-C6 alkoxy; and R 2 It is a C1-C6 alkyl group.

[0139] In some embodiments, A is a 5- to 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom. In some embodiments, A is a 5- to 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains one O ring atom.

[0140] In some embodiments, A is a 5-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom. In some embodiments, A is a 5-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains one O ring atom.

[0141] In some embodiments, A is a 6-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom. In some embodiments, A is a 6-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains one O ring atom.

[0142] In some embodiments, A is a 7-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom. In some embodiments, A is a 7-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains one O ring atom.

[0143] In some embodiments, A is an 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom. In some embodiments, A is an 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains one O ring atom.

[0144] In some embodiments, p is 0 or 1.

[0145] In some embodiments, p is 0. In some embodiments, p is 1.

[0146] In some embodiments, R 1 is halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the alkyl or alkoxy is independently substituted by 0, 1, 2 or 3 halogen atoms.

[0147] In some embodiments, R 1 is halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the alkyl or alkoxy is substituted by 1, 2 or 3 halogen atoms.

[0148] In some embodiments, R 1 It is halogen, C1-C6 alkyl or C1-C6 alkoxy.

[0149] In some embodiments, R 1 It's a halogen.

[0150] In some embodiments, R 1 is F, Cl, Br or I.

[0151] In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 It's I.

[0152] In some embodiments, R 1 It is C1-C6 alkyl substituted by 0, 1, 2 or 3 halogens.

[0153] In some embodiments, R 1 It is C1-C6 alkyl substituted by 1, 2 or 3 halogens.

[0154] In some embodiments, R 1 It is a C1-C6 alkyl group.

[0155] In some embodiments, R 1 is methyl substituted with 0, 1, 2 or 3 halogens. 1 is ethyl substituted with 0, 1, 2 or 3 halogens. 1 is propyl substituted with 0, 1, 2 or 3 halogens. 1 is butyl substituted with 0, 1, 2 or 3 halogens. 1 is pentyl substituted with 0, 1, 2 or 3 halogens. 1 is hexyl substituted with 0, 1, 2 or 3 halogens. 1 is isopropyl substituted with 0, 1, 2 or 3 halogens. 1 is isobutyl substituted with 0, 1, 2 or 3 halogens. 1 is isopentyl substituted with 0, 1, 2 or 3 halogens.1 is isohexyl substituted with 0, 1, 2 or 3 halogens. 1 is sec-butyl substituted with 0, 1, 2 or 3 halogens. 1 is sec-pentyl substituted with 0, 1, 2 or 3 halogens. 1 is a secondary hexyl substituted with 0, 1, 2 or 3 halogens. 1 is tert-butyl substituted by 0, 1, 2 or 3 halogens.

[0156] In some embodiments, R 1 is methyl substituted with 1, 2 or 3 halogens. 1 is ethyl substituted with 1, 2 or 3 halogens. 1 is propyl substituted with 1, 2 or 3 halogens. 1 is butyl substituted with 1, 2 or 3 halogens. 1 is pentyl substituted with 1, 2 or 3 halogens. 1 is hexyl substituted with 1, 2 or 3 halogens. 1 is isopropyl substituted with 1, 2 or 3 halogens. 1 is isobutyl substituted with 1, 2 or 3 halogens. 1 is isopentyl substituted with 1, 2 or 3 halogens. 1 is isohexyl substituted with 1, 2 or 3 halogens. 1 is sec-butyl substituted with 1, 2 or 3 halogens. 1 is a secondary pentyl substituted with 1, 2 or 3 halogens. 1 is a secondary hexyl substituted with 1, 2 or 3 halogens. 1 It is tert-butyl substituted by 1, 2 or 3 halogens.

[0157] In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, each R 1In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is tert-butyl.

[0158] In some embodiments, R 1 It is C1-C6 alkoxy substituted by 0, 1, 2 or 3 halogens.

[0159] In some embodiments, R 1 It is a C1-C6 alkoxy group substituted by 1, 2 or 3 halogens.

[0160] In some embodiments, R 1 It is a C1-C6 alkoxy group.

[0161] In some embodiments, R 1 is C1 alkoxy substituted by 0, 1, 2 or 3 halogens. 1 is C2 alkoxy substituted with 0, 1, 2 or 3 halogens. 1 is C3 alkoxy substituted with 0, 1, 2 or 3 halogens. 1 is C4 alkoxy substituted with 0, 1, 2 or 3 halogens. 1 is C5 alkoxy substituted with 0, 1, 2 or 3 halogens. 1 It is C6 alkoxy substituted by 0, 1, 2 or 3 halogens.

[0162] In some embodiments, R 1 is C1 alkoxy substituted by 1, 2 or 3 halogens. 1 is C2 alkoxy substituted by 1, 2 or 3 halogens. 1 is C3 alkoxy substituted by 1, 2 or 3 halogens. 1 is C4 alkoxy substituted by 1, 2 or 3 halogens. 1 is C5 alkoxy substituted by 1, 2 or 3 halogens. 1 It is C6 alkoxy substituted by 1, 2 or 3 halogens.

[0163] In some embodiments, R 1 is C1 alkoxy. In some embodiments, R 1 is C2 alkoxy. In some embodiments, R 1 is C3 alkoxy. In some embodiments, R 1 is C4 alkoxy. In some embodiments, R 1 is C5 alkoxy. 1 It is a C6 alkoxy group.

[0164] In some embodiments, R 2 It is halogen or C1-C6 alkyl substituted by 0, 1, 2 or 3 halogens.

[0165] In some embodiments, R 2 It is halogen or C1-C6 alkyl substituted by 1, 2 or 3 halogens.

[0166] In some embodiments, R 2 It is halogen or C1-C6 alkyl.

[0167] In some embodiments, R 2 It's a halogen.

[0168] In some embodiments, R 2 is F, Cl, Br or I.

[0169] In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 It's I.

[0170] In some embodiments, R 2 It is C1-C6 alkyl substituted by 0, 1, 2 or 3 halogens.

[0171] In some embodiments, R 2 It is C1-C6 alkyl substituted by 1, 2 or 3 halogens.

[0172] In some embodiments, R 2 It is a C1-C6 alkyl group.

[0173] In some embodiments, R 2 is methyl substituted with 0, 1, 2 or 3 halogens. 2 is ethyl substituted with 0, 1, 2 or 3 halogens. 2 is propyl substituted with 0, 1, 2 or 3 halogens.2 is butyl substituted with 0, 1, 2 or 3 halogens. 2 is pentyl substituted with 0, 1, 2 or 3 halogens. 2 is hexyl substituted with 0, 1, 2 or 3 halogens. 2 is isopropyl substituted with 0, 1, 2 or 3 halogens. 2 is isobutyl substituted with 0, 1, 2 or 3 halogens. 2 is isopentyl substituted with 0, 1, 2 or 3 halogens. 2 is isohexyl substituted with 0, 1, 2 or 3 halogens. 2 is sec-butyl substituted with 0, 1, 2 or 3 halogens. 2 is sec-pentyl substituted with 0, 1, 2 or 3 halogens. 2 is a secondary hexyl substituted with 0, 1, 2 or 3 halogens. 2 is tert-butyl substituted by 0, 1, 2 or 3 halogens.

[0174] In some embodiments, R 2 is methyl substituted with 1, 2 or 3 halogens. 2 is ethyl substituted with 1, 2 or 3 halogens. 2 is propyl substituted with 1, 2 or 3 halogens. 2 is butyl substituted with 1, 2 or 3 halogens. 2 is pentyl substituted with 1, 2 or 3 halogens. 2 is hexyl substituted with 1, 2 or 3 halogens. 2 is isopropyl substituted with 1, 2 or 3 halogens. 2 is isobutyl substituted with 1, 2 or 3 halogens. 2 is isopentyl substituted with 1, 2 or 3 halogens. 2 is isohexyl substituted with 1, 2 or 3 halogens. 2 is sec-butyl substituted with 1, 2 or 3 halogens. 2 is a secondary pentyl substituted with 1, 2 or 3 halogens. 2 is a secondary hexyl substituted with 1, 2 or 3 halogens.2 It is tert-butyl substituted by 1, 2 or 3 halogens.

[0175] In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 It is tert-butyl.

[0176] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a 3- or 4-membered carbocyclic ring substituted with 0, 1, 2 or 3 halogen atoms.

[0177] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a 3- or 4-membered carbocyclic ring substituted by 1, 2 or 3 halogen atoms.

[0178] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a 3- or 4-membered carbon ring.

[0179] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a 3-membered carbocyclic ring substituted with 0, 1, 2 or 3 halogen atoms.

[0180] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a 3-membered carbocyclic ring substituted by 1, 2 or 3 halogen atoms.

[0181] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a 3-membered carbon ring.

[0182] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a 4-membered carbocyclic ring substituted with 0, 1, 2 or 3 halogen atoms.

[0183] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a 4-membered carbocyclic ring substituted by 1, 2 or 3 halogen atoms.

[0184] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a 4-membered carbon ring.

[0185] In some embodiments, p is 1, and R 1 and R 2 Each of is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, p is 1, and R 1 and R 2 Each of the above is independently C1-C6 alkyl or C1-C6 haloalkyl, wherein R 1 and R 2 are attached to the same carbon atom on ring A.

[0186] In some embodiments, p is 1, and R 1 and R 2 In some embodiments, p is 1, and R 1 and R 2 Each of which is methyl, wherein R 1 and R 2 are attached to the same carbon atom on ring A.

[0187] In some embodiments, R 3 is -OH, halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the alkyl or alkoxy is independently substituted by 0, 1, 2 or 3 halogens.

[0188] In some embodiments, R 3 is -OH, halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the alkyl or alkoxy is substituted by 1, 2 or 3 halogens.

[0189] In some embodiments, R 3 It is -OH, halogen, C1-C6 alkyl or C1-C6 alkoxy.

[0190] In some embodiments, R 3 It is -OH.

[0191] In some embodiments, R 3 It's a halogen.

[0192] In some embodiments, R 3 is Br. In some embodiments, R 3 is Cl. In some embodiments, R 3 is F. In some embodiments, R 3 It's I.

[0193] In some embodiments, R 3 Not halogen.

[0194] In some embodiments, R 3 It is a C1-C6 alkyl group or a C1-C6 alkoxy group.

[0195] In some embodiments, R 3 It is C1-C6 alkyl substituted by 0, 1, 2 or 3 halogens.

[0196] In some embodiments, R 3 It is C1-C6 alkyl substituted by 1, 2 or 3 halogens.

[0197] In some embodiments, R 3 It is a C1-C6 alkyl group.

[0198] In some embodiments, R 3 is methyl substituted with 0, 1, 2 or 3 halogens. 3 is ethyl substituted with 0, 1, 2 or 3 halogens. 3 is propyl substituted with 0, 1, 2 or 3 halogens. 3 is butyl substituted with 0, 1, 2 or 3 halogens. 3 is pentyl substituted with 0, 1, 2 or 3 halogens. 3 is hexyl substituted with 0, 1, 2 or 3 halogens. 3 is isopropyl substituted with 0, 1, 2 or 3 halogens. 3 is isobutyl substituted with 0, 1, 2 or 3 halogens. 2 is independently isopentyl substituted with 0, 1, 2 or 3 halogens. 3 is isohexyl substituted with 0, 1, 2 or 3 halogens. 3 is sec-butyl substituted with 0, 1, 2 or 3 halogens. 3is sec-pentyl substituted with 0, 1, 2 or 3 halogens. 3 is a secondary hexyl substituted with 0, 1, 2 or 3 halogens. 3 is tert-butyl substituted by 0, 1, 2 or 3 halogens.

[0199] In some embodiments, R 3 is methyl substituted with 1, 2 or 3 halogens. 3 is ethyl substituted with 1, 2 or 3 halogens. 3 is propyl substituted with 1, 2 or 3 halogens. 3 is butyl substituted with 1, 2 or 3 halogens. 3 is pentyl substituted with 1, 2 or 3 halogens. 3 is hexyl substituted with 1, 2 or 3 halogens. 3 is isopropyl substituted with 1, 2 or 3 halogens. 3 is isobutyl substituted with 1, 2 or 3 halogens. 2 is independently isopentyl substituted with 1, 2 or 3 halogens. 3 is isohexyl substituted with 1, 2 or 3 halogens. 3 is sec-butyl substituted with 1, 2 or 3 halogens. 3 is a secondary pentyl substituted with 1, 2 or 3 halogens. 3 is a secondary hexyl substituted with 1, 2 or 3 halogens. 3 It is tert-butyl substituted by 1, 2 or 3 halogens.

[0200] In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 2 In some embodiments, R 3 In some embodiments, R3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 It is tert-butyl.

[0201] In some embodiments, R 3 It is C1-C6 alkoxy substituted by 0, 1, 2 or 3 halogens.

[0202] In some embodiments, R 3 It is a C1-C6 alkoxy group substituted by 1, 2 or 3 halogens.

[0203] In some embodiments, R 3 It is a C1-C6 alkoxy group.

[0204] In some embodiments, R 3 is methoxy substituted with 0, 1, 2 or 3 halogens. 3 is ethoxy substituted with 0, 1, 2 or 3 halogens. 3 is propoxy substituted with 0, 1, 2 or 3 halogens. 3 is butoxy substituted with 0, 1, 2 or 3 halogens. 3 is pentyloxy substituted with 0, 1, 2 or 3 halogens. 3 is hexyloxy substituted by 0, 1, 2 or 3 halogens.

[0205] In some embodiments, R 3 is methoxy substituted with 1, 2 or 3 halogens. 3 is ethoxy substituted with 1, 2 or 3 halogens. 3 is propoxy substituted by 1, 2 or 3 halogens. 3 is butoxy substituted with 1, 2 or 3 halogens. 3 is pentyloxy substituted with 1, 2 or 3 halogens. 3 It is hexyloxy substituted by 1, 2 or 3 halogens.

[0206] In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R3 In some embodiments, R 3 It is hexyloxy.

[0207] In some embodiments, R 3 It is Cl, methyl, -CF3, -CHF2 or -OCHF2.

[0208] In some embodiments, R 3 It is -CF3, -CHF2 or -OCHF2.

[0209] In some embodiments, R 3 is -CF3. In some embodiments, R 3 is -CHF2. In some embodiments, R 3 Yes - OCHF2.

[0210] In some embodiments, X is H, -OH, halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl.

[0211] In some embodiments, X is -OH, halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl.

[0212] In some embodiments, X is H.

[0213] In some embodiments, X is halogen.

[0214] In some embodiments, X is Br, Cl, F, or I.

[0215] In some embodiments, X is Br. In some embodiments, X is Cl. In some embodiments, X is F. In some embodiments, X is I.

[0216] In some embodiments, X is -OH.

[0217] In some embodiments, X is -NH2. In some embodiments, X is -NH(C1-C6 alkyl).

[0218] In some embodiments, X is -NH(C1 alkyl). In some embodiments, X is -NH(C2 alkyl). In some embodiments, X is -NH(C3 alkyl). In some embodiments, X is -NH(C4 alkyl). In some embodiments, X is -NH(C5 alkyl). In some embodiments, X is -NH(C6 alkyl).

[0219] In some embodiments, X is -N(C1-C6 alkyl)2.

[0220] In some embodiments, X is -N(C1 alkyl)2. In some embodiments, X is -N(C2 alkyl)2. In some embodiments, X is -N(C3 alkyl)2. In some embodiments, X is -N(C4 alkyl)2. In some embodiments, X is -N(C5 alkyl)2. In some embodiments, X is -N(C6 alkyl)2.

[0221] In some embodiments, X is C1-C6 alkyl.

[0222] In some embodiments, X is methyl. In some embodiments, X is ethyl. In some embodiments, X is propyl. In some embodiments, X is butyl. In some embodiments, X is pentyl. In some embodiments, X is hexyl. In some embodiments, each X is isopropyl. In some embodiments, X is isobutyl. In some embodiments, X is isopentyl. In some embodiments, X is isohexyl. In some embodiments, X is sec-butyl. In some embodiments, X is sec-pentyl. In some embodiments, X is sec-hexyl. In some embodiments, X is tert-butyl.

[0223] In some embodiments, X is H or F.

[0224] In some embodiments, R 4 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -C(O)(C1-C6 alkyl).

[0225] In some embodiments, R 4 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -C(O)(C1-C6 alkyl).

[0226] In some embodiments, R 4 It's H.

[0227] In some embodiments, R 4 It is a C1-C6 alkyl group.

[0228] In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, each R 4 In some embodiments, R 4 In some embodiments, R4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 It is tert-butyl.

[0229] In some embodiments, R 4 It is -C(O)(C1-C6 alkyl).

[0230] In some embodiments, R 4 is -C(O)(C1 alkyl). 4 is -C(O)(C2 alkyl). 4 is -C(O)(C3 alkyl). 4 is -C(O)(C4 alkyl). 4 is -C(O)(C5 alkyl). 4 It is -C(O)(C6 alkyl).

[0231] In some embodiments, each instance of alkyl, alkane-, or carbocycle is independently substituted with 0, 1, 2, or 3 halogen atoms.

[0232] In some embodiments, each instance of alkyl is substituted with 0, 1, 2, or 3 halogen atoms.

[0233] In some embodiments, each instance of alkane- is substituted with 0, 1, 2, or 3 halogen atoms.

[0234] In some embodiments, each instance of the carbocycle is substituted with 0, 1, 2, or 3 halogen atoms.

[0235] In certain embodiments, the benzene ring system of formula (a):

[0236] With the formula:

[0237]

[0238] Wherein X is halogen or C1-C6 alkyl, such as -F, -Cl or -CH3. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, for example -Cl, -CHF2, -CF3, -CH3 or -OCHF2.

[0239] In certain embodiments, the amine ring system of formula (b):

[0240] With the formula:

[0241] In certain embodiments, the amine ring system of the formula:

[0242] With the formula:

[0243] In some embodiments, the compound of Formula (I) has Formula (Ia) or (Ib):

[0244] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof. In certain embodiments, the benzene ring system of formula (a) has the formula (a-1), (a-2) or (a-3), wherein X is hydrogen, halogen or C1-C6 alkyl, such as -H, -F, -Cl or -CH3. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, such as -Cl, -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl or C1-C6 alkoxy, such as -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is a C1-C6 alkyl group, such as -CHF2, -CF3 or -CH3. In certain embodiments, the amine ring system of formula (b) has formula (b-1). In certain embodiments, R 1 is -CH3, and R 2 It is -CH3.

[0245] In some embodiments, the compound of formula (I) has formula (II-a), (II-b) or (II-c):

[0246]

[0247] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof. In certain embodiments, X is a halogen or a C1-C6 alkyl, such as -F, -Cl or -CH3. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 3is halogen, C1-C6 alkyl or C1-C6 alkoxy, such as -Cl, -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl or C1-C6 alkoxy, such as -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is a C1-C6 alkyl group, such as -CHF2, -CF3 or -CH3. In certain embodiments, the amine ring system of formula (b) has formula (b-1). In certain embodiments, R 1 is -CH3, and R 2 It is -CH3.

[0248] In some embodiments, the compound of formula (I) has formula (II-d), (II-e), or (II-f):

[0249]

[0250] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof. In certain embodiments, X is a halogen or a C1-C6 alkyl, such as -F, -Cl or -CH3. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, such as -Cl, -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl or C1-C6 alkoxy, such as -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is a C1-C6 alkyl group, such as -CHF2, -CF3 or -CH3. In certain embodiments, the amine ring system of formula (b) has formula (b-1). In certain embodiments, R 1 is -CH3, and R 2 It is -CH3.

[0251] In some embodiments, the compound of Formula (I) has Formula (III-a), (III-b) or (III-c):

[0252]

[0253] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein m is an integer from 0 to 2, and n is an integer from 1 to 2.

[0254] In some embodiments of Formula (III-a), (III-b) or (III-c), m is 0, 1 or 2.

[0255] In some embodiments of Formula (III-a), (III-b) or (III-c), m is 1 or 2.

[0256] In some embodiments of Formula (III-a), (III-b), or (III-c), m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0257] In some embodiments of Formula (III-a), (III-b) or (III-c), n is 0, 1 or 2.

[0258] In some embodiments of Formula (III-a), (III-b) or (III-c), n is 1 or 2.

[0259] In some embodiments of Formula (III-a), (III-b), or (III-c), n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0260] In some embodiments of Formula (III-a), (III-b) or (III-c), when one of m and n is 0, the other of m and n is 1 or 2.

[0261] In some embodiments of Formula (III-a), (III-b), or (III-c), when one of m and n is 0, the other of m and n is 1.

[0262] In some embodiments of Formula (III-a), (III-b) or (III-c), when one of m and n is 0, the other of m and n is 2.

[0263] In certain embodiments of formula (III-a), (III-b) or (III-c), the benzene ring system of formula (a) has the formula (a-1), (a-2) or (a-3), wherein X is hydrogen, halogen or C1-C6 alkyl, such as -H, -F, -Cl or -CH3. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, such as -Cl, -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl or C1-C6 alkoxy, such as -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3is C1-C6 alkyl, such as -CHF2, -CF3 or -CH3. In certain embodiments, R 1 is -CH3, and R 2 It is -CH3.

[0264] In some embodiments, the compound of Formula (I) has Formula (III-d), (III-e), or (III-f):

[0265]

[0266] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein m is an integer from 0 to 2, and n is an integer from 1 to 2.

[0267] In certain embodiments of formula (III-d), (III-e) or (III-f), the benzene ring system of formula (a) has the formula (a-1), (a-2) or (a-3), wherein X is hydrogen, halogen or C1-C6 alkyl, such as -H, -F, -Cl or -CH3. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, such as -Cl, -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl or C1-C6 alkoxy, such as -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, such as -CHF2, -CF3 or -CH3. In certain embodiments, R 1 is -CH3, and R 2 is -CH3 (where p=1). In certain embodiments, R 1 is -CH3, and R 2 Does not exist (p=0 at this time).

[0268] In some embodiments, the compound of Formula (I) has Formula (IV-a), (IV-b) or (IV-c):

[0269]

[0270] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof. In certain embodiments, the benzene ring system of formula (a) has the formula (a-1), (a-2) or (a-3), wherein X is hydrogen, halogen or C1-C6 alkyl, such as -H, -F, -Cl or -CH3. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, such as -Cl, -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl or C1-C6 alkoxy, such as -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, such as -CHF2, -CF3 or -CH3. In certain embodiments, R 1 is -CH3, and R 2 It is -CH3.

[0271] In some embodiments, the compound of formula (I) has formula (IV-a1), (IV-b1), or (IV-c1):

[0272]

[0273] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof. In certain embodiments, the benzene ring system of formula (a) has the formula (a-1), (a-2) or (a-3), wherein X is hydrogen, halogen or C1-C6 alkyl, such as -H, -F, -Cl or -CH3. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, such as -Cl, -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl or C1-C6 alkoxy, such as -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 It is C1-C6 alkyl, such as -CHF2, -CF3 or -CH3.

[0274] In some embodiments, the compound of Formula (I) has Formula (Va), (Vb), or (Vc):

[0275]

[0276] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0277] In some embodiments, the compound of Formula (I) has Formula (V-a'), (V-b'), or (V-c'):

[0278]

[0279] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof. In certain embodiments, the benzene ring system of formula (a) has the formula (a-1), (a-2) or (a-3), wherein X is hydrogen, halogen or C1-C6 alkyl, such as -H, -F, -Cl or -CH3. In certain embodiments, R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, such as -Cl, -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl or C1-C6 alkoxy, such as -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, such as -CHF2, -CF3 or -CH3. In certain embodiments, R 1 is -CH3, and R 2 It is -CH3.

[0280] In some embodiments, the compound of Formula (I) has Formula (VI-a), (VI-b), (VI-c), (VI-d), (VI-e), (VI-f), (VI-g), or (VI-h):

[0281]

[0282] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof. In certain embodiments, the benzene ring system of formula (a) has the formula (a-1), (a-2) or (a-3), wherein X is hydrogen, halogen or C1-C6 alkyl, such as -H, -F, -Cl or -CH3. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, such as -Cl, -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3is C1-C6 alkyl or C1-C6 alkoxy, such as -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, such as -CHF2, -CF3 or -CH3. In certain embodiments, R 1 is -CH3, and R 2 It is -CH3.

[0283] In some embodiments, the compound of formula (I) has formula (VI-a1), (VI-b1), (VI-c1), (VI-d1), (VI-e1), (VI-f1), (VI-g1), or (VI-h1):

[0284]

[0285] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof. In certain embodiments, the benzene ring system of formula (a) has the formula (a-1), (a-2) or (a-3), wherein X is hydrogen, halogen or C1-C6 alkyl, such as -H, -F, -Cl or -CH3. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, such as -Cl, -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl or C1-C6 alkoxy, such as -CHF2, -CF3, -CH3 or -OCHF2. In certain embodiments, R 3 It is C1-C6 alkyl, such as -CHF2, -CF3 or -CH3.

[0286] In some embodiments, the compound is selected from the compounds described in Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0287] In some embodiments, the compound is selected from the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the compound is selected from the compounds described in Table 1, or a solvate thereof.

[0289] In some embodiments, the compound is selected from the compounds described in Table 1, or inclusion compounds thereof.

[0290] In some embodiments, the compound is selected from the compounds described in Table 1, or a hydrate thereof.

[0291] In some embodiments, the compound is selected from the compounds described in Table 1, or stereoisomers thereof.

[0292] In some embodiments, the compound is selected from the compounds described in Table 1, or tautomers thereof.

[0293] In some embodiments, the compound is selected from the compounds described in Table 1, or isotopically labeled compounds thereof.

[0294] In some embodiments, the compound is selected from the compounds described in Table 1, or a prodrug thereof.

[0295] In some embodiments, the compound is selected from the compounds described in Table 1. Arbitrary stereochemistry is indicated by an asterisk (*).

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound described in Table 1.

[0308] In some embodiments, the compound is a prodrug of a compound described in Table 1.

[0309] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, or a prodrug or a pharmaceutically acceptable salt thereof.

[0310] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the compound is an isotopic derivative of a prodrug of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0313] In some embodiments, the compound is selected from the compounds described in Table 2, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0314] In some embodiments, the compound is selected from the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the compound is selected from the compounds described in Table 2, or a solvate thereof.

[0316] In some embodiments, the compound is selected from the compounds described in Table 2, or inclusion complexes thereof.

[0317] In some embodiments, the compound is selected from the compounds described in Table 2, or a hydrate thereof.

[0318] In some embodiments, the compound is selected from the compounds described in Table 2, or stereoisomers thereof.

[0319] In some embodiments, the compound is selected from the compounds described in Table 2, or tautomers thereof.

[0320] In some embodiments, the compound is selected from the compounds described in Table 2, or isotopically labeled compounds thereof.

[0321] In some embodiments, the compound is selected from the compounds described in Table 2, or a prodrug thereof.

[0322] In some embodiments, the compound is selected from the compounds described in Table 2.

[0323] Arbitrarily assigned stereochemistry is indicated by an asterisk (*).

[0324]

[0325]

[0326] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound described in Table 2.

[0327] In some embodiments, the compound is a prodrug of a compound described in Table 2.

[0328] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2, or a prodrug or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0330] In some embodiments, the compound is an isotopic derivative of a prodrug of any one of the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2.

[0332] In some aspects, the present disclosure provides a compound that is an isotopic derivative (eg, an isotopically labeled compound) of any one of the compounds of the formulae disclosed herein.

[0333] In another aspect, the present disclosure provides, inter alia, a compound selected from:

[0334] (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0335] 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0336] (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0337] (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0338] (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; and

[0339] (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0340] In some embodiments, the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0341] In some embodiments, the compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0342] In some embodiments, the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0343] In some embodiments, the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0344] In some embodiments, the compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol.

[0345] In some embodiments, the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0346] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described herein.

[0347] In some aspects, the present disclosure provides a compound that is an isotopic derivative (also referred to herein as an isotopically labeled compound) of any one of the compounds of the formulae disclosed herein.

[0348] In some embodiments, the compound is an isotopic derivative of any one of the compounds described herein, as well as prodrugs and pharmaceutically acceptable salts thereof.

[0349] In some embodiments, the compound is an isotopic derivative of any one of the compounds described herein, and pharmaceutically acceptable salts thereof.

[0350] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds described herein, and pharmaceutically acceptable salts thereof.

[0351] In some embodiments, the compound is an isotopic derivative of any one of the compounds described herein.

[0352] It should be understood that any of a variety of art-recognized techniques can be used to prepare isotopic derivatives. For example, isotopic derivatives can generally be prepared by implementing the procedures disclosed in the schemes and / or examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0353] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0354] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0355] As used herein, the term "isotopic derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound disclosed herein is isotopically enriched or labeled with respect to one or more isotopes compared to a corresponding disclosed compound. In some embodiments, an isotopic derivative is selected from 2 H. 13 C. 14 C. 15 N. 18 O. 29 4. 31 P and 34 In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., a compound enriched with respect to one or more atoms thereof). 2 H). In some embodiments, the compound is 18 In some embodiments, the compound is 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compound or any combination thereof. In some embodiments, the compound is 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compound or any combination thereof.

[0356] It should be understood that various art-recognized techniques can be used to prepare 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 32 S. 34 S. 35 S and / or 36 For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein, by using 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 32 S. 34 S. 35 S and / or 36 S-labeled reagents are used to replace non-isotopically labeled reagents.

[0357] Containing the aforementioned 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 32 S. 34 S. 35 S and 36 The compounds of the present invention or pharmaceutically acceptable salts or solvates thereof containing one or more of the S atoms are within the scope of the present invention. 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 32 S. 34 S. 35 S and / or 36 S) substitutions may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0358] For the avoidance of doubt, it should be understood that throughout this specification, if a group is defined by "described herein," that group encompasses the first occurring and broadest definition as well as each and all specific definitions for that group.

[0359] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, sufficiently basic acid addition salts of the compounds of the present disclosure, for example, acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citrate methanesulfonate or maleate. In addition, suitable pharmaceutically acceptable salts of the compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts or salts with organic bases that provide pharmaceutically acceptable cations. For example, salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0360] It is to be understood that the compounds of any of the formulae disclosed herein and any pharmaceutically acceptable salt thereof encompass stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of the compounds.

[0361] In some embodiments, the compound of formula (I) is not:

[0362]

[0363]

[0364] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0365] As used herein, the term "isomerism" refers to compounds that have the same molecular formula but differ in the sequence of bonding of the atoms or the arrangement of the atoms in space. Isomers that differ in the arrangement of the atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers", and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture".

[0366] As used herein, the term "chiral center" refers to a carbon atom to which are bonded four different substituents.

[0367] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center may exist as individual diastereomers or as a mixture of diastereomers, referred to as a "diastereomeric mixture". When one chiral center is present, the stereoisomers may be characterized by the absolute configuration (R or S) of the chiral center. The absolute configuration refers to the arrangement of the substituents attached to the chiral center in space. The substituents attached to the chiral center under consideration are ordered according to the order rules of Cahn, Ingold, and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0368] As used herein, the term "geometric isomers" refers to diastereomers that exist due to hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans or Z and E, according to the Cahn-Ingold-Prelog rules, which indicate that the groups are located on the same or opposite sides of the double bond in the molecule.

[0369] It should be understood that the compounds of the present disclosure may be described as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral isomers or geometric isomers, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form, and it should be understood that not all isomers may have the same level of activity.

[0370] It should be understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof. It should also be understood that not all atropisomers may have the same level of activity.

[0371] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another isomeric form. This conversion causes the form migration of hydrogen atoms, accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In a solution where tautomerization may occur, the chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are mutually converted by tautomerization is called tautomerism. Among the various types of tautomerism that may be possible, two are often observed. In keto-enol tautomerism, electrons and hydrogen atoms are displaced simultaneously. Ring-chain tautomerism occurs as a result of the aldehyde group (-CHO) in the sugar chain molecule reacting with one of the hydroxyl groups (-OH) of the same molecule to make it appear as a cyclic (ring shape) form shown by glucose.

[0372] It should be understood that the compounds of the present disclosure can be described as different tautomers. It should also be understood that when a compound has a tautomeric form, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compound does not exclude any tautomeric form. It should be understood that certain tautomers may have a higher level of activity than other tautomers.

[0373] Compounds with the same molecular formula but different atomic bonding properties or order or arrangement of atoms in space are called "isomers". Isomers with different arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example when it is bonded to four different groups, there may be a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as right-handed or left-handed (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0374] Compounds of the present disclosure may have one or more asymmetric centers; such compounds may therefore be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in this specification and claims is intended to include individual enantiomers and racemic or other mixtures thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of racemic forms. Some of the compounds of the present disclosure may have geometric isomer centers (E and Z isomers). It should be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof having inflammasome inhibitory activity.

[0375] It should be understood that compounds of any formula described herein include the compounds themselves as well as salts thereof and solvates thereof, if applicable. For example, salts may be formed between anions on the substituted compounds disclosed herein and positively charged groups (e.g., amino groups). Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronide, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthylsulfonate, and acetate (e.g., trifluoroacetate).

[0376] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can be formed between cations and negatively charged groups (e.g., carboxylates) on the substituted compounds disclosed herein. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations, such as tetramethylammonium ions or diethylamine ions. Substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0377] It should be understood that the compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0378] As used herein, the term "solvate" means a solvent addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds tend to trap fixed molar ratios of solvent molecules in a crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with a molecule of a substance, wherein the water remains in its molecular state as H2O.

[0379] As used herein, the term "analog" refers to a compound that is structurally similar to another but has a slightly different composition (e.g., one atom is replaced by an atom of a different element, or in the case of a particular functional group, one functional group is replaced by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but different in structure or origin from a reference compound.

[0380] As used herein, the term "derivative" refers to compounds having a common core structure and substituted with various groups as described herein.

[0381] It is also understood that certain compounds of any of the formulas disclosed herein can exist in solvated as well as unsolvated forms (e.g., hydrated forms). Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It is understood that the present disclosure encompasses all such solvated forms having inflammasome inhibitory activity.

[0382] It is also understood that certain compounds of any of the formulas disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof having inflammasome inhibitory activity. It is well known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance Fourier transform infrared (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials is determined by Karl Fischer analysis.

[0383] Any one of the compounds of the formula disclosed herein can exist in a variety of different tautomeric forms, and mention includes all such forms. For the avoidance of doubt, when a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all other forms are still included in formula (I). The example of tautomeric form includes ketone, enol and enolate form, such as the following tautomeric pairs: ketone / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol and nitro / acid nitro.

[0384]

[0385] The compounds of any of the formulae disclosed herein can be administered in the form of prodrugs that decompose in the human or animal body to release the compounds of the present disclosure. Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compounds of the present disclosure. Prodrugs can be formed when the compounds of the present disclosure contain suitable groups or substituents to which property-modifying groups can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide groups in any of the formulae disclosed herein.

[0386] Therefore, the present disclosure includes those compounds of any of the formulae disclosed herein as defined above when obtainable by organic synthesis and when obtainable in the human or animal body by cleavage of its prodrug. Therefore, the present disclosure includes those compounds of any of the formulae disclosed herein produced by organic synthesis means, as well as such compounds produced in the human or animal body by metabolism of a precursor compound, i.e., the compounds of any of the formulae disclosed herein may be synthetically produced compounds or metabolically produced compounds.

[0387] Suitable pharmaceutically acceptable prodrugs of the compounds of any of the formulae disclosed herein are prodrugs that, based on sound medical judgment, are suitable for administration to the human or animal body without adverse pharmacological activity and without undue toxicity. Various forms of prodrugs have been described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs," by H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutical Design and Development. Sciences, 77, 285 (1988); f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems," ACSSymposium Series, Vol. 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design," Pergamon Press, 1987.

[0388] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having a hydroxyl group are, for example, esters or ethers thereof that can be cleaved in vivo. An in vivo cleavable ester or ether of a compound of any of the formulae disclosed herein containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in vivo in the human body or in an animal body to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable ester forming groups of hydroxyl groups include inorganic esters, such as phosphates (including phosphoramide cyclic esters). Other suitable pharmaceutically acceptable ester forming groups of hydroxyl groups include C1-C 10 Alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C 10Alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carbonylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinylmethyl, piperazine-1-ylmethyl and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ester-forming groups of hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0389] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having a carboxyl group are, for example, in vivo cleavable amides thereof, for example with amino groups such as C 1-4 Amides formed from amines of alkylamines (such as methylamine), (C1-C4 alkyl) 2-amines (such as dimethylamine, N-ethyl-N-methylamine or diethylamine), C1-C4 alkoxy-C2-C4 alkylamines (such as 2-methoxyethylamine), phenyl-C1-C4 alkylamines (such as benzylamine) and amino acids (such as glycine or its esters).

[0390] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides from the amino group include, for example, C1-C 10 Alkanoyl, such as acetyl, benzoyl, phenylacetyl and amides formed by substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinylmethyl, piperazin-1-ylmethyl and 4-(C1-C4alkyl)piperazin-1-ylmethyl.

[0391] The in vivo effects of the compounds of any of the formulae disclosed herein may be exerted in part by one or more metabolites that are formed in the human or animal body after administration of the compounds of any of the formulae disclosed herein. As described above, the in vivo effects of the compounds of any of the formulae disclosed herein may also be exerted by the metabolism of a precursor compound (prodrug).

[0392] A suitable general route for preparing the compounds of the present application is using Scheme A and can be depicted in Scheme 1 herein.

[0393] Solution 1

[0394]

[0395] Unless otherwise stated, the examples presented herein were synthesized according to the general procedure presented in Scheme 1.

[0396] Step 1 involves the S-reaction between an amine (i) and an aryl dichloride (ii). N Ar reaction to obtain the target chloroaryl intermediate (iii). Step two involves cross coupling between intermediate (iii) and the desired boronic acid or borate (iv), optionally followed by deprotection of the alkyl ether (e.g., methyl ether) on the benzene ring to produce the desired compound (v). Unless otherwise stated, amine (i), aryl dichloride (ii) and boronic acid or borate (iv) are commercially available or known in the chemical literature.

[0397] Another suitable general route for preparing compounds of the present disclosure is to use Scheme B in Scheme 2 herein.

[0398] Solution 2

[0399]

[0400] Step one involves opening of commercially available 3,4-pyridinedicarboxylic anhydride (vii) with a Grignard reagent to afford carboxylic acid (viii). Step two features chlorination followed by condensation with hydrazine to afford pyridazinol (ix). Step three then involves another chlorination to afford key intermediate (x), which in turn can undergo SNAr reaction with amine (i) in step four to form azaphthalazine (xi). Step five then features methyl ether deprotection to provide analog (xii).

[0401] Bioassay

[0402] Compounds designed, selected and / or optimized by the methods described above and herein, once produced, can be characterized using various assays known to those skilled in the art to determine whether the compound has biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they have the predicted activity, binding activity and / or binding specificity.

[0403] In addition, high throughput screening can be used to accelerate the analysis using such assays. As a result, the activity of the molecules described herein can be rapidly screened using techniques known in the art. General methods for performing high throughput screening are described in, for example, Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High throughput assays can use one or more different assay techniques, including but not limited to those described below.

[0404] Various in vitro or in vivo bioassays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo bioassays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, binding assays, cell assays (cell lines, primary cells, and whole blood), in vitro cell viability assays, and assays for measuring NLRP3 potency, unbound clearance, solubility, permeability, metabolic stability (e.g., in hepatocytes), and CYP inhibition, and time-dependent inhibition (TDI) assays (e.g., for reducing the risk of potential adverse in vivo drug-drug interactions).

[0405] In some embodiments, the biological assay is described in the Examples, Assay Methods section. In some embodiments, the Assay Methods section refers to Example 12.

[0406] For example, in some embodiments, the compounds of the present disclosure can be tested for their human-NLRP3 inhibitory activity using known procedures, such as the method reported in Coll et al. Nat Med. (2015) 21 (3): 248–255. See also the Examples, Assay Methods section. In some embodiments, the compounds of the present disclosure can be tested for their human NLRP3 potency using known procedures. See, for example, the human whole blood NLRP3 assay described in the Assay Methods section of the Examples. In some embodiments, the brain penetration of the compounds of the present disclosure can be further tested. See, for example, the kp and kpu,uNLRP3 assays described in the Assay Methods section of the Examples.

[0407] In other embodiments, the compounds of the present disclosure may be tested for unbound clearance (Clu) following known procedures, such as described in Miller et al., J. Med. Chem. (2020) 63: 12156-12170. For example, unbound clearance (Clu) can be calculated by dividing the total clearance ('CL', mL / min / kg) as measured in blood or plasma by the unbound fraction (fu) in plasma.

[0408] In still other embodiments, the permeability of the compounds of the present disclosure can be determined following known procedures, such as described in Wang et al. J Mass Spectrom. (2000) 35:71-76. For example, after measuring the compounds in the apical and basolateral compartments, the permeability across the cell membrane can be measured using Caco-2 or MDCK-MDR1 cell lines in Transwell plates and reported as 10 -6 Apparent permeability Papp AB in cm / s.

[0409] In other embodiments, the solubility of the compounds of the present disclosure can be determined following known procedures, such as described in Alsenz and Kansy, Advanced Drug Delivery Reviews (2007) 59: 546-567, and Wang et al. J Mass Spectrom. (2000) 35: 71-76. For example, the kinetic solubility in physiologically relevant media, such as phosphate buffer solution (PBS, pH 7.4) or simulated gastric fluid (SGF) can be measured using serial dilution and a two-hour incubation period, followed by filtration, and reported in μM by LC-MS / MS. Thermodynamic solubility in physiologically relevant media can be measured by LC-MS / MS after incubation for twenty-four hours, followed by filtration, and reported in mg / mL. Optimized solubility may be beneficial to the manufacture and further processing of compounds. In addition, optimized solubility allows for more effective in vivo analysis of compounds, including data collection around the safety, drug-drug interactions, efficacy, selectivity, metabolism, and permeability of the compounds.

[0410] Pharmaceutical composition

[0411] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulas described in Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, and one or more pharmaceutically acceptable carriers or diluents. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulas described in Table 2, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, and one or more pharmaceutically acceptable carriers or diluents. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, and one or more pharmaceutically acceptable carriers or diluents. In some embodiments, the pharmaceutical composition comprises one or more carriers, fillers, vehicles, excipients, solubilizers, chelating agents, or combinations thereof. In some embodiments, the disclosure provides a pharmaceutical composition comprising at least one compound described in Table 1. In some embodiments, the disclosure provides a pharmaceutical composition comprising at least one compound described in Table 2. In some embodiments, the disclosure provides a pharmaceutical composition comprising at least one compound described herein.

[0412] In some embodiments of the present disclosure, a pharmaceutical composition comprises a compound described in Table 1 and a pharmaceutically acceptable carrier.

[0413] In some embodiments of the present disclosure, a pharmaceutical composition comprises a compound described in Table 2 and a pharmaceutically acceptable carrier.

[0414] In some embodiments of the present disclosure, a pharmaceutical composition comprises a compound of Formula I as described herein and a pharmaceutically acceptable carrier.

[0415] In one embodiment of the present disclosure, a pharmaceutical composition comprises (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol as described herein and a pharmaceutically acceptable carrier.

[0416] In another embodiment of the present disclosure, a pharmaceutical composition comprises 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol as described herein and a pharmaceutically acceptable carrier.

[0417] In another embodiment of the present disclosure, a pharmaceutical composition comprises (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol as described herein and a pharmaceutically acceptable carrier.

[0418] In another embodiment of the present disclosure, a pharmaceutical composition comprises (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol as described herein and a pharmaceutically acceptable carrier.

[0419] In one embodiment of the present disclosure, a pharmaceutical composition comprises (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol as described herein and a pharmaceutically acceptable carrier.

[0420] In one embodiment of the present disclosure, a pharmaceutical composition comprises (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol as described herein and a pharmaceutically acceptable carrier.

[0421] The compounds of the present disclosure may be formulated for oral administration in forms such as tablets, capsules (each including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present disclosure may also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0422] The formulations of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include excipients selected from the group consisting of solubilizers, chelating agents, preservatives, tonicity agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0423] Any suitable solubilizing agent can be used. The example of solubilizing agent includes cyclodextrin, such as cyclodextrin selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylation-β-cyclodextrin, ethylation-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylation-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, random methylation-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0424] Any suitable chelating agent may be used.Examples of suitable chelating agents include chelating agents selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0425] Any suitable preservative may be used. Examples of preservatives include preservatives selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, bromotoluene, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, and butylparaben, and sorbic acid, and mixtures thereof.

[0426] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0427] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (carbopols, such as carbopol 934, carbopol 934P, carbopol 971, carbopol 974, and carbopol 974P), and mixtures thereof.

[0428] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9 or about 7.5 to about 8.0), the formulation may contain a pH adjusting agent. The pH adjusting agent is typically a mineral acid or a metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or alkaline pH adjusting agents are added to adjust the formulation to a target acceptable pH range. Thus, it may not be necessary to use both an acid and a base, and depending on the formulation, adding one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0429] The aqueous vehicle may also contain a buffer to stabilize the pH. When used, the buffer is selected from the group consisting of: a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or a salt thereof, including disodium tetraborate), a citrate buffer (such as citric acid, or a salt thereof, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0430] The preparation may further comprise a wetting agent. Suitable classes of wetting agents include wetting agents selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (Tyloxapol), polyoxyethylene 40 stearate, fatty acid glycol esters, fatty acid glycerides, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0431] Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be mixed with an excipient and used in the form of tablets, lozenges or capsules. Oral compositions can also be prepared using a fluid carrier used as a mouthwash, wherein the compound in the fluid carrier is orally administered and gargled and spit out or swallowed. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel or corn starch; lubricants, such as magnesium stearate or Sterotes; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavorings, such as mint, methyl salicylate or orange flavoring.

[0432] According to other aspects of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0433] The compositions of the present disclosure may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in a form suitable for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., as fine powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., as fine powders), or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as suppositories for rectal administration).

[0434] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweetening agents, flavoring agents and / or preservatives.

[0435] An effective amount of a compound of the disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with an inflammasome-associated disorder mentioned herein.

[0436] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and / or reduce the symptoms associated with an inflammasome-associated disorder mentioned herein.

[0437] According to well-known medical principles, the size of the dose of the compounds disclosed herein for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the disorder, the age and sex of the animal or patient and the route of administration.

[0438] How to use

[0439] In some aspects, the present disclosure provides a method of modulating NLRP3 activity (eg, in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0440] In some aspects, the present disclosure provides a method of modulating NLRP3 activity (eg, in vitro or in vivo) comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0441] In some aspects, the present disclosure provides a method of inhibiting NLRP3 activity (eg, in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0442] In some aspects, the present disclosure provides a method of inhibiting NLRP3 activity (eg, in vitro or in vivo) comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0443] In some aspects, the present disclosure provides a method of treating or preventing a disease or condition inhibited by NLRP3 as disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0444] In some aspects, the present disclosure provides a method of treating a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0445] In some aspects, the present disclosure provides a method of treating or preventing a disease or condition inhibited by NLRP3 as disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0446] In some aspects, the present disclosure provides a method of treating a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, the disease or condition is a disease or condition involving NLRP3 activity.

[0447] In some embodiments, the disease or disorder is inflammation, an autoimmune disease, cancer, an infection, a central nervous system disease or disorder, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft-versus-host disease, allodynia, or an NLRP3-related disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3.

[0448] In some aspects, the present disclosure provides a method for treating or preventing inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or a NLRP3-related disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0449] In some aspects, the present disclosure provides a method of treating inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or a NLRP3-related disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0450] In some aspects, the present disclosure provides a method for treating or preventing inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or a NLRP3-related disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0451] In some aspects, the present disclosure provides a method of treating inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or a NLRP3-related disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0452] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof for use in modulating NLRP3 activity (e.g., in vitro or in vivo).

[0453] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting NLRP3 activity (eg, in vitro or in vivo).

[0454] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting NLRP3 (eg, in vitro or in vivo).

[0455] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use as an antagonist of NLRP3 (eg, in vitro or in vivo).

[0456] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or condition disclosed herein.

[0457] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition disclosed herein.

[0458] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating NLRP3 activity (eg, in vitro or in vivo).

[0459] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating NLRP3 (eg, in vitro or in vivo).

[0460] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting NLRP3 activity (eg, in vitro or in vivo).

[0461] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting NLRP3 (eg, in vitro or in vivo).

[0462] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or condition disclosed herein.

[0463] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition disclosed herein.

[0464] In some aspects, the present disclosure provides uses of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for modulating NLRP3 activity (eg, in vitro or in vivo).

[0465] In some aspects, the present disclosure provides for use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for inhibiting NLRP3 activity (eg, in vitro or in vivo).

[0466] In some aspects, the present disclosure provides for use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for modulating NLRP3 (eg, in vitro or in vivo).

[0467] In some aspects, the present disclosure provides uses of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for inhibiting NLRP3 (eg, in vitro or in vivo).

[0468] In some aspects, the present disclosure provides for the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease or condition disclosed herein.

[0469] In some aspects, the present disclosure provides for the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating a disease or condition disclosed herein.

[0470] The effectiveness of the compounds of the present disclosure can be determined by industry accepted assays / disease models according to standard practice elucidating those described in the art and found within the current general knowledge.

[0471] In some embodiments, the disease or disorder is associated with an implicated NLRP3 activity.

[0472] In some embodiments, the disease or disorder is inflammation, an autoimmune disease, cancer, an infection, a central nervous system disease or disorder, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft-versus-host disease, allodynia, or an NLRP3-related disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3.

[0473] In some embodiments, the disease or disorder is inflammation.

[0474] In some embodiments, the disease or disorder is an autoimmune disease.

[0475] In some embodiments, the disease or condition is cancer.

[0476] In some embodiments, the disease or condition is an infection.

[0477] In some embodiments, the disease or disorder is a central nervous system disease or disorder.

[0478] In some embodiments, the disease or disorder is a metabolic disease.

[0479] In some embodiments, the disease or disorder is cardiovascular disease.

[0480] In some embodiments, the disease or disorder is a respiratory disease.

[0481] In some embodiments, the disease or disorder is kidney disease.

[0482] In some embodiments, the disease or disorder is liver disease.

[0483] In some embodiments, the disease or disorder is an ocular disease.

[0484] In some embodiments, the disease or disorder is a skin disorder.

[0485] In some embodiments, the disease or disorder is a lymphatic disease.

[0486] In some embodiments, the disease or disorder is a rheumatic disease.

[0487] In some embodiments, the disease or disorder is a mental illness.

[0488] In some embodiments, the disease or disorder is graft-versus-host disease.

[0489] In some embodiments, the disease or disorder is allodynia.

[0490] In some embodiments, the disease or disorder is a NLRP3-associated disease.

[0491] In some embodiments, the central nervous system disease or disorder is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0492] In some embodiments, the respiratory disease is steroid-resistant asthma.

[0493] In some embodiments, the respiratory disease is severe steroid-resistant asthma.

[0494] In some embodiments, the kidney disease is acute kidney disease, chronic kidney disease, or a rare kidney disease.

[0495] In some embodiments, the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0496] In some embodiments, the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0497] In some embodiments, the NLRP3-associated disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3 is cryopyrin-associated autoinflammatory syndrome.

[0498] In some embodiments, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease.

[0499] In some embodiments, the compound is a brain penetrant, eg, with a Kpu,u > 0.3.

[0500] Compounds with a Kpu,u less than or equal to 0.3 are not brain penetrants. In some embodiments, the compound is not a brain penetrant.

[0501] In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 10.

[0502] In some embodiments, the Kpu,u of the compound is greater than 0.3 to about 9. In some embodiments, the Kpu,u of the compound is greater than 0.3 to about 8. In some embodiments, the Kpu,u of the compound is greater than 0.3 to about 7. In some embodiments, the Kpu,u of the compound is greater than 0.3 to about 6. In some embodiments, the Kpu,u of the compound is greater than 0.3 to about 5. In some embodiments, the Kpu,u of the compound is greater than 0.3 to about 4. In some embodiments, the Kpu,u of the compound is greater than 0.3 to about 3. In some embodiments, the Kpu,u of the compound is greater than 0.3 to about 2. In some embodiments, the Kpu,u of the compound is greater than 0.3 to about 1.

[0503] In some embodiments, the Kpu,u of the compound is about 0.3. In some embodiments, the Kpu,u of the compound is about 0.4. In some embodiments, the Kpu,u of the compound is about 0.5.

[0504] In some embodiments, the Kpu,u of the compound is about 1. In some embodiments, the Kpu,u of the compound is about 1.5.

[0505] In some embodiments, the Kpu,u of the compound is about 2. In some embodiments, the Kpu,u of the compound is about 2.5.

[0506] In some embodiments, the Kpu,u of the compound is about 3. In some embodiments, the Kpu,u of the compound is about 3.5.

[0507] In some embodiments, the Kpu,u of the compound is about 4. In some embodiments, the Kpu,u of the compound is about 4.5.

[0508] In some embodiments, the Kpu,u of the compound is about 5. In some embodiments, the Kpu,u of the compound is about 5.5.

[0509] In some embodiments, the Kpu,u of the compound is about 6. In some embodiments, the Kpu,u of the compound is about 6.5.

[0510] In some embodiments, the Kpu,u of the compound is about 7. In some embodiments, the Kpu,u of the compound is about 7.5.

[0511] In some embodiments, the Kpu,u of the compound is about 8. In some embodiments, the Kpu,u of the compound is about 8.5.

[0512] In some embodiments, the Kpu,u of the compound is about 9. In some embodiments, the Kpu,u of the compound is about 9.5.

[0513] In some embodiments, the compound has a Kpu,u of about 10.

[0514] In certain embodiments, the compound is metabolically stable, e.g., has a half-life in mouse or human liver microsomes or hepatocytes of greater than 20 minutes, greater than 30 minutes, greater than 40 minutes, greater than 50 minutes, greater than 60 minutes, or between about 30 minutes to about 120 minutes.

[0515] Route of administration

[0516] The compounds of the present disclosure, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, tautomers, isotope-labeled compounds or prodrugs thereof, can be administered alone as a monotherapy, or can be administered together with one or more other substances and / or treatments. Such combined therapy can be achieved by administering the individual components of the treatment simultaneously, sequentially or separately.

[0517] For example, the effectiveness of a treatment may be enhanced by administering an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering a compound of the present disclosure with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0518] In the case where the compounds of the present disclosure are administered in combination with other therapeutic agents, the compounds of the present disclosure need not be administered via the same route as the other therapeutic agents, and may be administered by different routes (because of different physical and chemical characteristics). For example, the compounds of the present disclosure may be administered orally to produce and maintain good blood levels thereof, while another therapeutic agent may be administered intravenously. Initial administration may be performed according to established protocols known in the art, and then skilled clinicians may modify dosage, mode of administration, and time of administration based on the observed effects.

[0519] The specific choice of other therapeutic agents will depend on the diagnosis of the attending physician and their judgment of the individual's condition and the appropriate treatment regimen. According to this aspect of the disclosure, there is provided a combination for treating a disease involving inflammasome activity, comprising a compound of the disclosure as defined above, or a pharmaceutically acceptable salt thereof, and another suitable agent.

[0520] According to other aspects of the present disclosure, a pharmaceutical composition is provided, which comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof in combination with a suitable pharmaceutically acceptable diluent or carrier.

[0521] In any of the above-described pharmaceutical compositions, processes, methods, uses, medicaments and manufacturing features of the present disclosure, any of the alternative embodiments of the compounds of the present disclosure described herein also apply.

[0522] The compounds of the present disclosure, or pharmaceutical compositions comprising these compounds, may be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (ie, at the desired site of action).

[0523] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, using, for example, via an aerosol, such as through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a reservoir or depot, for example, subcutaneous or intramuscular.

[0524] Exemplary embodiments

[0525] Exemplary embodiment 1. A compound of formula (I):

[0526]

[0527] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein:

[0528] A is a 5- to 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom;

[0529] R 1 is halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0530] R 2 is halogen or C1-C6 alkyl;

[0531] or R 1 and R 2 Together with the atoms to which they are attached, they form a 3- to 4-membered carbon ring;

[0532] R3 is -OH, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0533] X is H, -OH, halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl; and

[0534] R 4 is H, C1-C6 alkyl or -C(O)(C1-C6 alkyl); and

[0535] p is 0 or 1,

[0536] wherein each instance of alkyl, alkane- or carbocycle is independently substituted with 0, 1, 2 or 3 halogen atoms, and

[0537] When R 3 When Cl is Not for

[0538] Exemplary embodiment 2. The compound according to exemplary embodiment 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, wherein A is a 5-membered monocyclic heterocycloalkyl group containing one O ring atom.

[0539] Exemplary embodiment 3. The compound as described in Exemplary embodiment 1 or Exemplary embodiment 2, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, wherein A is a 6-membered monocyclic heterocycloalkyl group containing one O ring atom.

[0540] Exemplary embodiment 4. The compound according to any one of exemplary embodiments 1-3, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein p is 1.

[0541] Exemplary embodiment 5. The compound as described in any one of exemplary embodiments 1-4, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein p is 1; R 1 is C1-C6 alkyl or C1-C6 alkoxy; and R 2 It is a C1-C6 alkyl group.

[0542] Exemplary embodiment 6. The compound as described in any one of exemplary embodiments 1-5, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein R 3Not halogen.

[0543] Exemplary embodiment 7. The compound as described in any one of exemplary embodiments 1-6, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein R 3 It is a C1-C6 alkyl group or a C1-C6 alkoxy group.

[0544] Exemplary embodiment 8. The compound as described in any one of exemplary embodiments 1-5, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein R 3 It is Cl, methyl, -CF3, -CHF2 or -OCHF2.

[0545] Exemplary embodiment 9. The compound as described in any one of exemplary embodiments 1-8, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein R 4 It's H.

[0546] Exemplary embodiment 10. The compound of any one of exemplary embodiments 1-9, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, wherein X is H or F.

[0547] Exemplary embodiment 11. A compound as described in any of the preceding exemplary embodiments, wherein the compound has formula (Ia) or (Ib):

[0548]

[0549] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0550] Exemplary embodiment 12. A compound as described in any of the preceding exemplary embodiments, wherein the compound has formula (II-a), (II-b), (II-c), (II-d), (II-e) or (II-f):

[0551]

[0552]

[0553] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0554] Exemplary embodiment 13. A compound as described in any of the preceding exemplary embodiments, wherein the compound has formula (III-a), (III-b) or (III-c):

[0555]

[0556] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein m is an integer from 0 to 2, and n is an integer from 1 to 2.

[0557] Exemplary embodiment 14. The compound according to any one of the preceding exemplary embodiments, wherein the compound has formula (III-d), (III-e) or (III-f):

[0558]

[0559] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein m is an integer from 0 to 2, and n is an integer from 1 to 2.

[0560] Exemplary embodiment 15. A compound as described in any of the preceding exemplary embodiments, wherein the compound has formula (IV-a), (IV-b) or (IV-c):

[0561]

[0562] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0563] Exemplary embodiment 16. The compound of any one of the preceding exemplary embodiments, wherein the compound has formula (IV-a1), (IV-b1) or (IV-c1):

[0564]

[0565] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0566] Exemplary embodiment 17. The compound of any one of exemplary embodiments 1-13, wherein the compound has formula (Va), (Vb), (Vc), (V-a'), (V-b') or (V-c'):

[0567]

[0568] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0569] Exemplary embodiment 18. A compound according to any one of exemplary embodiments 1-13, wherein the compound has formula (VI-a), (VI-b), (VI-c), (VI-d), (VI-e), (VI-f), (VI-g) or (VI-h):

[0570]

[0571]

[0572] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0573] Exemplary embodiment 19. The compound according to exemplary embodiment 1, which has the formula:

[0574]

[0575]

[0576]

[0577]

[0578] or a pharmaceutically acceptable salt or isotope-labeled compound thereof.

[0579] Exemplary embodiment 20. The compound according to exemplary embodiment 1, which has the formula:

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587] or a pharmaceutically acceptable salt or isotope-labeled compound thereof.

[0588] Exemplary embodiment 21. A compound having the formula:

[0589]

[0590] or a pharmaceutically acceptable salt or isotope-labeled compound thereof.

[0591] Exemplary embodiment 22. The compound according to exemplary embodiment 1, which has the formula:

[0592]

[0593]

[0594] or a pharmaceutically acceptable salt or isotope-labeled compound thereof.

[0595] Exemplary embodiment 23. The compound according to exemplary embodiment 1, wherein the compound is not or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

[0596] Exemplary embodiment 24. The compound according to exemplary embodiment 1, wherein the compound is not:

[0597]

[0598]

[0599] or a pharmaceutically acceptable salt or isotope-labeled compound thereof.

[0600] Exemplary embodiment 25. The compound of any one of exemplary embodiments 1-21, 23 and 24, wherein the compound has a Kpu,u greater than 0.3.

[0601] Exemplary embodiment 26. The compound of any one of exemplary embodiments 1-21, 23 or 24, wherein the compound has a Kpu,u of greater than 0.3 to about 10.

[0602] Exemplary embodiment 27. A pharmaceutical composition comprising a compound as described in any one of exemplary embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0603] Exemplary embodiment 28. A method of regulating NLRP3, the method comprising administering to a subject a compound as described in any one of Exemplary Embodiments 1-26, or a pharmaceutically acceptable salt, solvate, inclusion complex, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition as described in Exemplary Embodiment 27.

[0604] Exemplary embodiment 29. A method for treating or preventing a disease or condition, the method comprising administering to a subject a compound as described in any one of exemplary embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition as described in exemplary embodiment 27.

[0605] Exemplary embodiment 30. A compound as described in any one of exemplary embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition as described in exemplary embodiment 27, for use in treating or preventing a disease or disorder.

[0606] Exemplary embodiment 31. Use of a compound as described in any one of exemplary embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof in the manufacture of a medicament for treating or preventing a disease or disorder.

[0607] Exemplary embodiment 32. Use of the compound of any one of exemplary embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof for treating or preventing a disease or disorder.

[0608] Exemplary embodiment 33. The method, compound or use of any one of exemplary embodiments 29-32, wherein the disease or disorder is a NLRP3-related disease or disorder.

[0609] Exemplary embodiment 34. The method, compound or use of any one of exemplary embodiments 28-33, wherein the subject is a human.

[0610] Exemplary embodiment 35. The method, compound or use of any one of exemplary embodiments 28-34, wherein the disease or condition is inflammation, autoimmune disease, cancer, infection, central nervous system disease or condition, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or NLRP3-related disease.

[0611] Exemplary embodiment 36. The method, compound or use according to exemplary embodiment 35, wherein the central nervous system disease or disorder is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis or multiple sclerosis.

[0612] Exemplary embodiment 37. The method, compound or use according to exemplary embodiment 35, wherein the kidney disease is acute kidney disease, chronic kidney disease or a rare kidney disease.

[0613] Exemplary embodiment 38. The method, compound or use according to exemplary embodiment 35, wherein the skin disease is psoriasis, hidradenitis suppurativa (HS) or atopic dermatitis.

[0614] Exemplary embodiment 39. The method, compound or use according to Exemplary embodiment 35, wherein the rheumatic disease is dermatomyositis, Still's disease or juvenile idiopathic arthritis.

[0615] Exemplary embodiment 40. The method, compound or use of exemplary embodiment 35, wherein the NLRP3-related disease is in a subject determined to carry a germline or somatic non-silent mutation in NLRP3.

[0616] Exemplary embodiment 41. The method, compound or use of exemplary embodiment 40, wherein the NLRP3-associated disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3 is cryptopyrin-associated autoinflammatory syndrome.

[0617] Exemplary embodiment 42. The method, compound or use of exemplary embodiment 35, wherein the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome or neonatal-onset multisystem inflammatory disease.

[0618] Exemplary embodiment 43. A compound selected from:

[0619] (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0620] 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0621] (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0622] (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0623] (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; and

[0624] (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;

[0625] and a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer or prodrug of any of the foregoing.

[0626] Exemplary embodiment 44. A compound as described in exemplary embodiment 43, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0627] Exemplary embodiment 45. A compound as described in exemplary embodiment 43, wherein the compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0628] Exemplary embodiment 46. A compound as described in exemplary embodiment 43, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0629] Exemplary embodiment 47. A compound as described in exemplary embodiment 43, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0630] Exemplary embodiment 48. A compound as described in exemplary embodiment 43, wherein the compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0631] Exemplary embodiment 49. A compound as described in exemplary embodiment 43, wherein the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0632] Exemplary embodiment 50. A pharmaceutical composition comprising the compound as described in Exemplary embodiment 43, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0633] Exemplary embodiment 51. A pharmaceutical composition comprising the compound as described in Exemplary embodiment 44, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0634] Exemplary embodiment 52. A pharmaceutical composition comprising the compound as described in Exemplary embodiment 45, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0635] Exemplary embodiment 53. A pharmaceutical composition comprising the compound as described in Exemplary embodiment 46, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0636] Exemplary embodiment 54. A pharmaceutical composition comprising the compound as described in Exemplary embodiment 47, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0637] Exemplary embodiment 55. A pharmaceutical composition comprising the compound as described in Exemplary embodiment 48, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0638] Exemplary embodiment 56. A pharmaceutical composition comprising the compound as described in Exemplary embodiment 49, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0639] Exemplary embodiment 57. A method for treating or preventing a NLRP3-related disease or disorder, comprising administering to a subject at least one therapeutically effective amount of a compound as described in Exemplary Embodiment 43, or a pharmaceutically acceptable salt, solvate, inclusion complex, hydrate, stereoisomer, tautomer, isotope-labeled compound, or prodrug thereof.

[0640] Exemplary embodiment 58. A method as described in exemplary embodiment 57, wherein the NLRP3-related disease or condition is inflammation, autoimmune disease, cancer, infection, central nervous system disease or condition, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or an NLRP3-related disease in a subject who has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[0641] Exemplary embodiment 59. A method as described in Exemplary embodiment 58, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0642] Exemplary embodiment 60. A method as described in exemplary embodiment 58, wherein the compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0643] Exemplary embodiment 61. A method as described in exemplary embodiment 58, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0644] Exemplary embodiment 62. A method as described in exemplary embodiment 58, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0645] Exemplary embodiment 63. A method as described in exemplary embodiment 58, wherein the compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0646] Exemplary embodiment 64. A method as described in exemplary embodiment 58, wherein the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0647] Exemplary embodiment 65. A method for treating or preventing an NLRP3-related disease or disorder selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache / pain, and traumatic brain injury, the method comprising administering to a subject at least one therapeutically effective amount of a compound as described in exemplary embodiment 43, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0648] Exemplary embodiment 66. A method as described in Exemplary embodiment 65, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0649] Exemplary embodiment 67. A method as described in exemplary embodiment 65, wherein the compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0650] Exemplary embodiment 68. A method as described in exemplary embodiment 65, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0651] Exemplary embodiment 69. A method as described in Exemplary embodiment 65, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0652] Exemplary embodiment 70. A method as described in exemplary embodiment 65, wherein the compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0653] Exemplary embodiment 71. A method as described in exemplary embodiment 65, wherein the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof.

[0654] Exemplary embodiment 72. A method for treating or preventing an NLRP3-related disease or condition selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache / pain, and traumatic brain injury, the method comprising administering to a subject at least one therapeutically effective amount of a pharmaceutical composition as described in exemplary embodiment 50.

[0655] Exemplary embodiment A1. A compound selected from the group consisting of:

[0656] (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0657] 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0658] (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0659] (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;

[0660] (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; and

[0661] (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0662] Exemplary embodiment A2. A compound as described in Exemplary embodiment A1, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0663] Exemplary embodiment A3. A compound as described in exemplary embodiment A1, wherein the compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0664] Exemplary embodiment A4. A compound as described in Exemplary embodiment A1, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0665] Exemplary embodiment A5. A compound as described in Exemplary embodiment A1, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0666] Exemplary embodiment A6. A compound as described in exemplary embodiment A1, wherein the compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol.

[0667] Exemplary embodiment A7. A compound as described in exemplary embodiment A1, wherein the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0668] Exemplary embodiment A8. A pharmaceutical composition comprising the compound as described in Exemplary embodiment A1, and a pharmaceutically acceptable carrier.

[0669] Exemplary embodiment A9. A pharmaceutical composition comprising the compound as described in Exemplary embodiment A2, and a pharmaceutically acceptable carrier.

[0670] Exemplary embodiment A10. A pharmaceutical composition comprising the compound as described in Exemplary embodiment A3, and a pharmaceutically acceptable carrier.

[0671] Exemplary embodiment A11. A pharmaceutical composition comprising the compound as described in Exemplary embodiment A4, and a pharmaceutically acceptable carrier.

[0672] Exemplary embodiment A12. A pharmaceutical composition comprising the compound as described in Exemplary embodiment A5, and a pharmaceutically acceptable carrier.

[0673] Exemplary embodiment A13. A pharmaceutical composition comprising the compound as described in Exemplary embodiment A6, and a pharmaceutically acceptable carrier.

[0674] Exemplary embodiment A14. A pharmaceutical composition comprising the compound as described in Exemplary embodiment A7, and a pharmaceutically acceptable carrier.

[0675] Exemplary embodiment A15. A method for treating or preventing a NLRP3-related disease or disorder, comprising administering to a subject a therapeutically effective amount of at least one compound as described in Exemplary embodiment A1.

[0676] Exemplary embodiment A16. A method as described in exemplary embodiment A1, wherein the NLRP3-related disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or an NLRP3-related disease in a subject who has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[0677] Exemplary embodiment A17. The method of exemplary embodiment A16, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0678] Exemplary embodiment A18. A method as described in exemplary embodiment A16, wherein the compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0679] Exemplary embodiment A19. A method as described in exemplary embodiment A16, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0680] Exemplary embodiment A20. A method as described in exemplary embodiment A16, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0681] Exemplary embodiment A21. A method as described in exemplary embodiment A16, wherein the compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol.

[0682] Exemplary embodiment A22. A method as described in Exemplary embodiment A16, wherein the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0683] Exemplary embodiment A23. A method for treating or preventing a NLRP3-related disease or disorder selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache / pain, and traumatic brain injury, the method comprising administering to a subject at least one therapeutically effective amount of a compound as described in Exemplary Embodiment A1.

[0684] Exemplary embodiment A24. A method according to exemplary embodiment A23, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0685] Exemplary embodiment A25. A method as described in exemplary embodiment A23, wherein the compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0686] Exemplary embodiment A26. A method as described in Exemplary embodiment A23, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0687] Exemplary embodiment A27. A method as described in Exemplary embodiment A23, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0688] Exemplary embodiment A28. A method as described in exemplary embodiment A23, wherein the compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol.

[0689] Exemplary embodiment A29. A method as described in Exemplary embodiment A23, wherein the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0690] Exemplary embodiment A30. A method for treating or preventing a NLRP3-related disease or condition selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache / pain, and traumatic brain injury, the method comprising administering to a subject at least one therapeutically effective amount of a pharmaceutical composition as described in Exemplary embodiment A8.

[0691] Example

[0692] For illustrative purposes, neutral (free base) compounds described herein were synthesized and tested in the Examples. It should be understood that the neutral compounds disclosed herein can be converted to the corresponding pharmaceutically acceptable salts of the compounds using conventional techniques in the art (e.g., by saponification of esters to carboxylates, or by hydrolysis of amides to form the corresponding carboxylic acids, which are then converted to carboxylates).

[0693] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz and 300.3 K as indicated, unless otherwise stated; chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using a Bruker Avance 400 instrument with 8, 16 or 32 scans.

[0694] LC-MS chromatograms and spectra were recorded using a Shimadzu LCMS-2020. The injection volume was 0.7–8.0 μl, and the flow rate was typically 0.8 or 1.2 ml / min. The detection method was diode array (DAD) or evaporative light scattering (ELSD) with positive ion electrospray ionization. The MS range was 100–1000 Da. The solvents were gradients of water and acetonitrile, both containing modifiers (typically 0.01–0.04%) such as trifluoroacetic acid or ammonium carbonate.

[0695] abbreviation:

[0696] DCM Dichloromethane

[0697] DMF N,N-Dimethylformamide

[0698] DMSO Dimethyl sulfoxide

[0699] dppf 1,1′-bis(diphenylphosphino)ferrocene

[0700] ESI Electrospray ionization

[0701] EtOAc or EA Ethyl acetate

[0702] EtOH

[0703] FA Formic acid

[0704] h hour

[0705] Hex

[0706] HPLC High Performance Liquid Chromatography

[0707] IPA Isopropyl Alcohol

[0708] LCMS liquid chromatography-mass spectrometry

[0709] MeCN or ACN Acetonitrile

[0710] MeOH Methanol

[0711] min

[0712] mw microwave

[0713] m / z mass / charge

[0714] PE Petroleum Ether

[0715] Preparative HPLC Preparative High Performance Liquid Chromatography

[0716] rt room temperature

[0717] RT retention time

[0718] THF Tetrahydrofuran

[0719] Y yield

[0720] Example 1. 5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 1A), (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 1*) and (S)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 1B*)

[0721]

[0722] Example 1 follows Protocol A.

[0723] Step 1: Synthesis of 1-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-1-amine. 1,4-Dichloropyrido[3,4-d]pyridazine (250 mg, 1.25 mmol, 1 eq), DMF (3 mL) and Na2CO3 (423.91 mg, 4 mmol, 3.2 eq) were added to a 5 mL microwave tube at 130°C. The final reaction mixture was irradiated with microwave radiation at 130°C for 40 min. After completion of the reaction, the residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (MeCN) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in 1-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-1-amine (150 mg, mixture of two isomers) as yellow oils. LCMS: (ES, m / z): RT=0.735 min, m / z=279 [M+1] + .

[0724] Step 2: 5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 1A), (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 1*), and (S)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 1B*). A mixture of 1-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-1-amine (150 mg, 0.53 mmol, 1 eq), 4-chloro-2-hydroxyphenylboronic acid (120.59 mg, 0.69 mmol, 1.3 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (78.75 mg, 0.10 mmol, 0.2 eq), Na2CO3 (171.11 mg, 1.61 mmol, 3 eq), dioxane (6 mL) and H2O (1.2 mL) were added to a 25 mL round bottom flask at 80° C. The final reaction mixture was heated at 80° C. for 2 h. After the reaction was completed, the reaction mixture was concentrated, and the residue was purified by reverse phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, acetonitrile (MeCN) aqueous solution, 0% to 100% gradient in 30 min; detector, UV 254 nm). After the reaction was completed, the reaction mixture was concentrated, and the crude product was purified by preparative HPLC under the following conditions (2# SHIMADZU (HPLC-01): column, XBridge Prep Phenyl OBD Column, 19*250 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (25% MeCN increased to 45% in 12 min); detector, UV 254). This resulted in 5-chloro-2-(1-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol (3.2 mg, 1.5% yield) as a pale yellow crude solid and 5-chloro-2-(4-{[-4,4-dimethyloxolan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 1A) (32 mg, 15% yield) as a pale yellow crude solid.Then, 20 mg of 1% iodine was purified by HPLC under the following conditions (column, Chiral ART Cellulose-SA, 4.6*50 mm, 3 um; mobile phase, methyl tert-butyl ether (MtBE) (0.2% formic acid (FA)) and isopropyl: dichloromethane (IPA:DCM) = 1:1 (maintaining 50% IPA:DCM = 1:1 within 4 min); detector, UV 254). Chiral separation of 5-chloro-2-(4-{[-4,4-dimethyloxolan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 1A) afforded 5-chloro-2-(4-{[(3R)-4,4-dimethyloxolan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also referred to herein as (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol as a pale yellow solid. )(Compound 1*) (RT = 1.12 min, 5.4 mg, 2.69% yield) and 5-chloro-2-(4-{[(3S)-4,4-dimethyloxolan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also referred to herein as (S)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol) (Compound 1B*) (RT = 2.12 min, 6.0 mg, 3% yield) as a light yellow solid. Stereochemistry arbitrarily specified.

[0725] (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol. (Compound 1*) LCMS: (ES, m / z): RT = 0.605 min, m / z = 371.1 [M+1] + . 1 H NMR (400MHz, methanol-d4) δ9.77(d,J=1.0Hz,1H),8.87(d,J=5.7Hz,1H),7.59–7.50(m,1H),7.38(d,J=8.0Hz,1H),7.06(d,J=7.8Hz,2H) ,5.10–4.98(m,1H),4.47–4.30(m,1H),3.99–3.86(m,1H),3.75(d,J=8.4Hz,1H),3.68(d,J=8.4Hz,1H),1.32(s,3H),1.16(s,3H).

[0726] (S)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol. (Compound 1B*) LCMS: (ES, m / z): RT = 0.605 min, m / z = 371.1 [M+1] + . 1 H NMR (400MHz, methanol-d4) δ9.81–9.74(m,1H),8.87(d,J=5.7Hz,1H),7.57–7.51(m,1H),7.38(d,J=8.0Hz,1H),7.06(d,J=7.7Hz,2H), 5.13–4.98(m,1H),4.50–4.33(m,1H),4.00–3.87(m,1H),2.45(d,J=8.3Hz,1H),2.08(d,J=8.3Hz,1H),1.32(s,3H),1.16(s,3H).

[0727] Example 2. 5-Chloro-2-(4-{[(1S,2S)-2-hydroxycyclopentyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol) (Compound 3A), (S)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 3*) and (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 3B*)

[0728]

[0729] Example 2 follows Protocol B.

[0730] Step 1: Synthesis of (1S,2S)-2-((1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol. To a stirred solution of furano[3,4-c]pyridine-1,3-dione (30.0 g, 201.20 mmol, 1 eq) and tetrahydrofuran (300 mL) was added dropwise bromo(4-chloro-2-methoxyphenyl)magnesium (0.5 M in tetrahydrofuran (THF)) (241 mL, 120 mmol, 0.6 eq) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at 25 °C under nitrogen atmosphere for 2 h. The reaction progress was monitored by LCMS. The reaction was quenched by adding water (150 mL) at 0 °C. The precipitated solid was collected by filtration and washed with water (3x50 mL). This resulted in 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (20 g, 34.1% yield) as a light brown solid. LCMS (ES, m / z): RT = 0.662 min, m / z = 292.0 [M+1] + .

[0731] Step 2: Synthesis of 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine-4-ol. 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (5 g, 17.1 mmol, 1 eq) and SOCl2 (50 mL) were added to a 250 mL round-bottom flask. The resulting mixture was stirred at 70 ° C for 2 h. The reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (DCM) (50 mL) and added to a solution of NH2NH2.H2O (3.43 g, 68.6 mmol, 4 eq), methanol (MeOH) (50 mL) at 0 ° C. The resulting mixture was stirred at 70 ° C in an oil bath for 3 h. The reaction progress was monitored by LCMS. The precipitated solid was collected by filtration. The crude product (4 g, 90% purity) was purified by preparative HPLC under the following conditions (2# SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD Column, 19*250 mm, 10 μm; mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (maintaining 39% MeCN within 17 min); detector, UV 254 / 220 nm. This produced 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2.0 g, 40.6% yield) as an off-white solid. LCMS: (ES, m / z): RT=0.723 min, m / z=288.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.90(s,1H),9.50(s,1H),8.94(d,J=5.5Hz,1H),7 .41(d,J=8.0Hz,1H),7.33(d,J=1.9Hz,1H),7.23–7.15(m,2H),3.75(s,3H).

[0732] Step 3: Synthesis of 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine. 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine-4-ol (2.5 g, 8.69 mmol, 1 eq.) and POCl3 (40 mL) and pyridine (4 mL) were added to a 250 mL round-bottom flask. The resulting mixture was stirred at 100 °C for 3 h. The reaction progress was monitored by LCMS. The reaction was quenched with 500 mL of sodium bicarbonate (aq.) and 500 mL of EtOAc at 0 °C. The resulting mixture was extracted with EtOAc (3x500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (1.5 g, 56.4% yield) as a brown solid. LCMS (ES, m / z): RT = 0.845 min, m / z = 306.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ9.84–9.68(m,1H),9.12(d,J=5.7Hz,1H),7.60–7.56(m,1 H),7.51(d,J=8.1Hz,1H),7.41(d,J=1.9Hz,1H),7.32–7.25(m,1H),3.74(s,3H).

[0733] Step 4: Synthesis of 1-(4-chloro-2-methoxyphenyl)-N-(3,3-dimethyltetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazine-4-amine. 4-Chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (200 mg, 0.65 mmol, 1 eq) and 3,3-dimethyloxane-4-amine (101.28 mg, 7.84 mmol, 1.2 eq), triethylamine (TEA) (198.32 mg, 1.96 mmol, 3 eq) and dimethyl sulfoxide (DMSO) (5 mL) were added to a 40 mL vial at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. The reaction progress was monitored by LCMS. The resulting mixture was used directly in the next step without further purification. LCMS: (ES, m / z): RT=0.684min, m / z=399[M+1]+ .

[0734] Step 5: Synthesis of 5-chloro-2-(4-{[(1S,2S)-2-hydroxycyclopentyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol) (Compound 3A), (S)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 3*), and (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 3B*). To a 20 vial was added the reaction mixture from Step 4, sodium (ethylsulfanyl) (1054.30 mg, 12.53 mmol, 25 equiv) and DMSO (8 mL) at room temperature. The resulting mixture was stirred for 2h at 120 ° C. under a nitrogen atmosphere. The reaction progress was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeCN (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions (column, C18 gel; mobile phase, MeCN aqueous solution (10mmol / L NH4HCO3), 0% to 100% gradient in 30min; detector, UV254nm), producing a product as an off-white solid. The product (90mg, 98.2% purity) was prepared by preparative HPLC under the following conditions (preparative HPLC-064: column, CHIRALPAK IG, 2*25cm, 5um; mobile phase, Hex and MeOH:DCM=1:1 (50% MeOH:DCM=1:1 was maintained in 23min); detector, UV 254 nm) to afford 5-chloro-2-(4-{[(4R)-3,3-dimethyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also referred to herein as (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol) (Compound 3B*) as an off-white solid (RT = 1.50 min, 27.8 mg, 14. 3% yield) and 5-chloro-2-(4-{[(4S)-3,3-dimethyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also referred to herein as (S)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol) (Compound 3*) as off-white solids (RT = 3.28 min, 24.4 mg, 12.5% ​​yield). Stereochemistry arbitrarily specified.

[0735] 5-Chloro-2-(4-{[(4R)-3,3-dimethyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 3B*). LCMS: (ES, m / z): RT=0.553 min, m / z=385.2 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),9.89(s,1H),8.86(d,J=5.6Hz,1H),7.38–7.20(m,3H),7.03(d,J=7.4Hz,2H),4.81–4.70(m, 1H), 4.05–3.89 (m, 1H), 3.54–3.42 (m, 2H), 3.25 (d, J = 11.3Hz, 1H), 1.99–1.90 (m, 1H), 1.75–1.66 (m, 1H), 1.14 (s, 3H), 0.87 (s, 3H).

[0736] 5-Chloro-2-(4-{[(4S)-3,3-dimethyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 3*). LCMS: (ES, m / z): RT=0.671 min, m / z=385.2 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),9.88(s,1H),8.86(d,J=5.6Hz,1H),7.40–7.17(m,3H),7.03(d,J=7.5Hz,2H),4.80–4.72(m,1H ),4.05–3.96(m,1H),3.56–3.41(m,2H),3.23(s,1H),2.01–1.92(m,J=12.2,4.8Hz,1H),1.73–7.65(m,1H),1.13(s,3H),0.87(s,3H).

[0737] Example 3. 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 5A), (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 5) and (S)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 5B)

[0738]

[0739] Example 3 follows Protocol A.

[0740] 1-Chloro-N-(5,5-dimethyloxacyclopentane-3-yl)pyrido[3,4-d]pyridazin-4-amine (120 mg, 0.430 mmol, 1 eq), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (201 mg, 0.860 mmol, 2 eq), Pd(dppf)Cl2 (94.5 mg, 0.130 mmol, 0.300 eq), dioxane (2 mL) and H2O (0.4 mL) were added to a 8 mL sealed tube at 80°C. The resulting mixture was stirred at 80°C for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1) to give a crude product (140 mg), which was purified by preparative HPLC (column: Xselect CSH C18 OBD Column 30*150mm 5m,n; mobile phase A: water (10mmol / L NH4HCO3; mobile phase B: MeCN; flow rate: 60mL / min; gradient: 34% B to 34% B, 34% B in 11min; wavelength: 254nm; RT1 (min): 10.2) to give a mixture of compounds 5A and 5B (65 mg), which was purified by preparative chiral-HPLC (column: CHIRAL ART Amylose-SA, 2*25cm, 5m; mobile phase A: hexane (Hex) HPLC, mobile phase B: MeOH:DCM=1:1, HPLC; flow rate: 20mL / min; gradient: 20% B to 20% B in 15min B; wavelength: 220 / 254nm) was further purified to give (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 5) (28.4 mg, 18.8% yield) (RT (min): 9.63) and (S)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 5B) (23.7 mg, 15.7% yield) (RT (min): 13.52). The absolute stereochemistry was determined by X-ray crystallography.

[0741] (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 5). LCMS (ES, m / z): RT = 1.23 min, m / z = 351.1 [M+H] + . 1H NMR (400MHz, methanol-d4) δ9.70(d,J=1.0Hz,1H),8.85(d,J=5.7Hz,1H),7.57(m,J =5.7,1.0Hz,1H),7.28(d,J=7.7Hz,1H),6.91–6.83(m,2H),5.05–4.97(m,1H ),4.41(m,J=9.1,6.7Hz,1H),3.92(m,J=9.1,5.9Hz,1H),2.45(m,J=12.8,8. 1Hz, 1H), 2.40 (s, 3H), 2.08 (m, J = 12.7, 6.8Hz, 1H), 1.45 (s, 3H), 1.35 (s, 3H).

[0742] (S)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 5B) LCMS (ES, m / z): RT = 1.23 min, m / z = 351.1 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ9.70(d,J=1.0Hz,1H),8.85(d,J=5.7Hz,1H),7.57(m,J =5.7,1.0Hz,1H),7.28(d,J=7.7Hz,1H),6.91–6.83(m,2H),5.07–4.97(m,1H ),4.41(m,J=9.1,6.6Hz,1H),3.92(m,J=9.1,5.8Hz,1H),2.45(m,J=12.8,8. 0Hz, 1H), 2.40 (s, 3H), 2.08 (m, J = 12.7, 6.8Hz, 1H), 1.45 (s, 3H), 1.35 (s, 3H).

[0743] Table A shows schemes for preparing compounds of the present disclosure, and Table B provides NMR data.

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752] Example 4. 5-(Difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 9A), (S)-5-(Difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 9*) and (R)-5-(Difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 9B*)

[0753]

[0754] Example 4 follows Protocol A.

[0755] Step 1.1-bromo-4-(difluoromethoxy)-2-methoxybenzene synthesis. 4-bromo-3-methoxyphenol (5g, 24.62mmol, 1 equivalent), acetonitrile (MeCN) (10mL), diethyl bromodifluoromethylphosphonate (13.15g, 49.25mmol, 2 equivalents) and KOH (2.76g, 49.25mmol, 2 equivalents), H2O (10mL) were added to a 100mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 1h. The reaction was monitored by gas chromatography / mass spectrometry (GCMS). The reaction was quenched with water (10mL) at 0°C. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layer was washed with brine (1x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (PE / EA) (4:1) to give the title compound (3.9 g, 61.3% yield). LCMS, ESI: RT = 1.35 min, m / z = 253 [M+H] + .

[0756] Step 2. Synthesis of (4-(difluoromethoxy)-2-methoxyphenyl)boronic acid. To a stirred solution of 1-bromo-4-(difluoromethoxy)-2-methoxybenzene (2200 mg, 8.69 mmol, 1 eq) in dioxane (25 mL) was added triethylamine (2639.37 mg, 26.08 mmol, 3 eq) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5563.40 mg, 43.47 mmol, 5 eq) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 0.5 h. To the above mixture was added Pd(OAc)2 (195.19 mg, 0.86 mmol, 0.1 eq.) and 2-(dicyclohexylphosphino)biphenyl, (2-biphenyl)dicyclohexylphosphine (Cy-JohnPhos) (609.44 mg, 1.73 mmol, 0.2 eq.) in dioxane (2 mL) at room temperature. The resulting mixture was stirred for another 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude title compound, which was used directly in the next step. LCMS, ESI: RT = 0.75 min, m / z = 219 [M+H] + .

[0757] Step 3.1-Chloro-N-(5,5-dimethyloxacyclopentane-3-yl)pyrido[3,4-d]pyridazine-4-amine synthesis. 1,4-dichloropyrido[3,4-d]pyridazine (800 mg, 3.99 mmol, 1 equivalent), 5,5-dimethyloxacyclopentane-3-amine (552.79 mg, 4.79 mmol, 1.2 equivalents), Na2CO3 (1270.94 mg, 11.99 mmol, 3 equivalents) and dimethylformamide (10 mL) were added to a 20 mL sealed tube. The final reaction mixture was irradiated with microwave radiation for 30 min at 130 ° C. The reaction was monitored by LCMS. The reaction was repeated 5 times. The combined resulting mixture was filtered and the filter cake was washed with EtOAc (3x20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (2#SHIMADZU (HPLC-01): column, XBridge Prep PhenylOBD Column, 19*250mm, 5μm; mobile phase, water (50mmol / L NH4HCO3) and acetonitrile (MeCN) (12% MeCN increased to 22% within 10min, maintained at 22% within 2min); detector, UV254nm) to obtain 1-chloro-N-(5,5-dimethyloxacyclopentane-3-yl)pyrido[3,4-d]pyridazin-4-amine (2g, 32.3% yield). LCMS, ESI: RT = 0.73min, m / z = 279.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.83(d,J=1.0Hz,1H),9.07(d,J=5.6Hz,1H),8.07(d,J=5.8Hz,1H),7.88(dd,J=5.6,0.9Hz,1H), 4.85-4.77(m,1H),4.20-4.16(m,1H),3.78-3.74(m,1H),2.30-2.25(m,1H),1.98-1.93(m,1H),1.34(s,3H),1.24(s,3H).

[0758] Step 4. Synthesis of 1-(4-(difluoromethoxy)-2-methoxyphenyl)-N-(5,5-dimethyltetrahydrofuran-3-yl)pyrido[3,4-d]pyridazin-4-amine. To a stirred solution of 1-chloro-N-(5,5-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine (1400 mg, 5.02 mmol, 1 eq) and 4-(difluoromethoxy)-2-methoxyphenylboronic acid (3284.18 mg, 15.06 mmol, 3 eq) in dioxane (12 mL) and water (2.4 mL) was added Na2CO3 (1596.36 mg, 15.06 mmol, 3 eq) and Pd(dppf)Cl2 (735.02 mg, 1 mmol, 0.2 eq) at room temperature. The resulting mixture was stirred at 80°C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, acetonitrile (MeCN) in water, 40% to 50% gradient in 10 min; detector, UV 254 nm) to give the title compound (1.20 g, 57% yield). LCMS, ESI: RT = 0.66 min, m / z = 417.1 [M + H] + .

[0759] Step 5. Synthesis of 5-(difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol. To a stirred solution of 1-(4-(difluoromethoxy)-2-methoxyphenyl)-N-(5,5-dimethyltetrahydrofuran-3-yl)pyrido[3,4-d]pyridazin-4-amine (1100 mg, 2.64 mmol, 1 eq) in dimethylformamide (10 mL) was added (ethylsulfanyl)sodium (666.53 mg, 7.92 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 120 °C for 1 h. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (3x5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Xselect CSH C18 OBD Column 30*150mm5μm,n; mobile phase A: water (0.05% trifluoroacetic acid (TFA)), mobile phase B: MeCN; flow rate: 60mL / min; gradient: 18% B to 28% B, 28% B in 10min; wavelength: 254nm; RT (min): 8.4) to give the title compound (Compound 9A) (751.6mg, 55.1% yield). LCMS, ESI: RT = 0.67min, m / z = 403.1 [M+H] + ; 1H NMR (400 MHz, methanol-d4) δ 10.01 (d, J = 1.0 Hz, 1H), 9.15 (d, J = 5.5 Hz, 1H), 7.72 (dd, J = 5.6, 1.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.24-6.73 (m, 3H), 4.85-4.76 (m, 1H), 4.36-4.32 (m, 1H), 4.11-4.07 (m, 1H), 2.53-2.48 (m, 1H), 2.18-2.13 (m, 1H), 1.46 (s, 3H), 1.37 (s, 3H). Compound 9* was then separated from Compound 9B* by chiral HPLC, and the stereochemistry was assigned based on extrapolation from the stereochemistry assignments of Compound 5 and Compound 5B.

[0760] Separation of (S)-5-(difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 9*). Preparative chiral HPLC (column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% trifluoroacetic acid (TFA)), mobile phase B: EtOH:DCM=1:1; flow rate: 20 mL / min; gradient: 60% B to 60% B in 11 min; wavelength: 220 / 254 nm; RT (min): 6.39; 1 H NMR (400MHz, methanol-d4) δ9.99(d,J=1.3Hz,1H),9.14(d,J=5.5Hz,1H),7.72–7.71(m,1H),7.47(d,J=8.4Hz,1H),7.17–6.76(m,3H),4.83–4.7 5(m,1H),4.35–4.31(m,1H),4.09–4.06(m,1H),2.53–2.47(m,1H),2.17–2.13(m,6.0Hz,1H),1.46(s,3H),1.37(s,3H); LCMS:403.5[M+H] + .

[0761] Separation of (R)-5-(difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 9B*). Preparative chiral HPLC (column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% TFA), mobile phase B: EtOH:DCM=1:1; flow rate: 20 mL / min; gradient: 60% B to 60% B in 11 min; wavelength: 220 / 254 nm; RT (min): 9.83;1 H NMR (400MHz, methanol-d4) δ10.03–9.98(m,1H),9.14–9.13(m,1H),7.72–7.71(m,1H),7.47(d,J=8.4Hz,1H),7.16–6.79(m,3H),4.83–4. 75(m,1H),4.35–4.31(m,1H),4.10–4.06(m,1H),2.53–2.47(m,1H),2.18–2.13(m,1H),1.46(s,3H),1.37(s,3H); LCMS:403.5[M+H] + .

[0762] Example 5. 2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 10A), (S)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 10*) and (R)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 10B*)

[0763]

[0764] Example 5 follows Scheme B.

[0765] Step 1. Synthesis of 4-(2-methoxy-4-methylbenzoyl)pyridine-3-carboxylic acid. Furano[3,4-c]pyridine-1,3-dione (10 g, 67.06 mmol, 1 eq.), THF (100 mL) and bromo(2-methoxy-4-methylphenyl)magnesium (9 g, 40.24 mmol, 0.6 eq.) were added dropwise to a 250 mL 3-necked round-bottom flask at -78 °C. The resulting mixture was stirred for 1 h at room temperature under a nitrogen atmosphere. The reaction progress was monitored by LCMS. The reaction was quenched by adding ice / water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (6 g, 33% yield). LCMS: (ES, m / z): RT=0.570min, m / z=272[M+1] + .

[0766] Step 2.1-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazine-4-ol synthesis. 4-(2-methoxy-4-methylbenzoyl)pyridine-3-carboxylic acid (2g, 7.37mmol, 1 equivalent) and SOCl2(20mL) were added to a 250mL round-bottom flask. The resulting mixture was stirred at 70°C for 2h, and the reaction was monitored by TLC. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was dissolved in DCM (50mL) and added to a solution of hydrazine hydrate (1.70g, 33.99mmol, 4.61 equivalents) and EtOH (10mL) at 0°C. The resulting mixture was stirred for 3h at 70°C in an oil bath. The reaction progress was monitored by LCMS. The precipitated solid was collected by filtration. The crude product (2.0 g, 80% purity) was purified by preparative HPLC ((preparative HPLC-059): column, CHIRAL ART Cellulose-SC, 2*25 cm, 5 um; mobile phase, Hex (0.5% 2M NH3-MeOH) and MeOH:DCM=1:1 (maintaining 60% MeOH:DCM=1:1 within 10 min); detector, UV 254) to obtain the title compound (1.30 g, 66% yield). LCMS: (ES, m / z): RT=0.880 min, m / z=268 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.75(s,1H),9.49(d,J=0.9Hz,1H),8.93(d,J=5.5Hz,1H),7.25(d,J=7 .6Hz,1H),7.17(d,J=5.5,0.9Hz,1H),7.06(s,1H),6.98–6.91(m,1H),3.70(s,3H),2.43(s,3H).

[0767] Step 3. Synthesis of 4-(2-methoxy-4-methylbenzoyl)pyridine-3-carboxylic acid. 1-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazine-4-ol (800 mg, 2.99 mmol, 1 eq.), POCl3 (10 mL) and pyridine (1 mL) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred at 110 ° C under a nitrogen atmosphere for 2 h. The reaction progress was monitored by LCMS. The reaction was quenched by adding to an aqueous solution of NaHCO3 (500 mL) and ethyl acetate (EtOAc) (500 mL) at 0 ° C. The resulting mixture was extracted with EtOAc (3x500 mL). The combined organic layers were washed with H2O (1x500 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (300 mg, 35.1% yield). LCMS: (ES, m / z): RT=0.837min, m / z=286[M+1]+ 。 1H NMR(300MHz,DMSO-d6)δ9.74(d,J=1.0Hz,1H),9.10(d,J=5.7Hz,1H),7.59–7.46(m,1H),7 .35(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.08–6.95(m,1H),3.69(s,3H),2.47(s,3H).

[0768] Step 4. Synthesis of N-(6,6-dimethyloxan-3-yl)-1-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazine-4-amine. To a stirred solution of 4-chloro-1-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazine (149.6 mg, 0.525 mmol, 1 eq) in DMSO (4.5 mL) was added 6,6-dimethyloxan-3-amine (81.39 mg, 0.630 mmol, 1.2 eq) and triethylamine (TEA) (159.4 mg, 1.58 mmol, 3 eq). The resulting mixture was stirred at 80 ° C for 2 h. The reaction was monitored by LCMS. After the reaction was completed, the resulting mixture was concentrated under vacuum and purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, aqueous MeCN (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to give the title compound (180 mg, 77.5% yield). LCMS: (ES, m / z): RT = 0.663 min, m / z = 378 [M+H] + .

[0769] Step 5. Synthesis of 2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 10A), (S)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 10*), and (R)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 10B*). To a stirred solution of N-(6,6-dimethyloxane-3-yl)-1-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazine-4-amine (50 mg, 0.026 mmol, 1 eq) in DMF (1.5 mL) was added (ethylsulfanyl)sodium (166.3 mg, 1.98 mmol, 15 eq). The resulting mixture was stirred at 120 °C for 1 h. The reaction was monitored by LCMS. After the reaction was complete, the resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with EtOAc (2 x 10 mL) and concentrated under vacuum. The product was purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 33% B to 43% B, 43% B in 10 min; wavelength: 254 nm; RT1 (min): 9.5) to give the title compound (Compound 10A). Compound 10* was then separated from Compound 10B* via chiral HPLC. Stereochemistry was arbitrarily specified.

[0770] Separation of (S)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 10*). Column: Lux 5um Celluloes-3, 2.12*25cm, 5μm; Mobile phase A: Hexane (0.2% formic acid (FA)), Mobile phase B: MeOH:EtOH=1:1; Flow rate: 20mL / min; Gradient: 15% B to 15% B in 12.5min; Wavelength: 220 / 254nm; RT (min): 2.81; (13.3mg, 27.6% yield). LCMS: (ES, m / z): RT=1.372min, m / z=365[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ9.74 (s, 1H), 9.65 (s, 1H), 8.85 (dd, J = 5.8, 2.2Hz, 1H), 7.5 3(d,J=7.6Hz,1H),7.32(d,J=5.7Hz,1H),7.20(d,J=7.6Hz,1H),6.81(q,J=7.7,6.7 Hz,2H),4.39(s,1H),3.91–3.82(m,1H),3.53(dd,J=11.1,9.6Hz,1H),2.34(s,3H), 1.97–1.85(m,2H),1.76–1.68(m,1H),1.64–1.53(m,1H),1.28(s,3H),1.22(s,3H).

[0771] (R)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 10B*). Column: Lux 5um Celluloes-3, 2.12*25cm, 5μm; Mobile phase A: Hexane (0.2% FA), Mobile phase B: MeOH:EtOH=1:1; Flow rate: 20mL / min; Gradient: 15% B to 15% B in 12.5min; Wavelength: 220 / 254nm; RT (min): 3.82; (5.4mg, 11.2% yield). LCMS: (ES, m / z): RT=1.36min, m / z=365[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.75 (s, 1H), 9.64 (s, 1H), 8.85 (d, J = 5.6Hz, 1H), 7.53 (d ,J=7.6Hz,1H),7.32(d,J=5.6Hz,1H),7.20(d,J=7.6Hz,1H),6.84–6.76(m,2H),4 .39(s,1H),3.87(dd,J=11.4,4.7Hz,1H),3.53(t,J=10.5Hz,1H),2.34(s,3H),1. 95–1.87(m,2H),1.76–1.67(m,1H),1.64–1.52(m,1H),1.28(s,3H),1.22(s,3H).

[0772] Example 6. 2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (Compound 11A), (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (Compound 11*) and (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (Compound 11B*)

[0773]

[0774] Example 6 follows Protocol A.

[0775] Step 1. Synthesis of 1-chloro-N-(2,2-dimethyloxacyclohexane-4-yl)pyrido[3,4-d]pyridazine-4-amine. 2,2-dimethyloxacyclohexane-4-amine (2 g, 15.5 mmol, 1 eq), Na2CO3 (4921 mg, 46.44 mmol, 3 eq) and DMF (20 mL) were added to a 100 mL sealed tube. The final reaction mixture was irradiated with microwave radiation at 130 ° C for 1 h. The reaction progress was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with DMF (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN aqueous solution, 10% to 60% gradient in 30 min; detector, UV 254 nm) to give the title compound (1.80 g, 39.3% yield). LCMS: (ES, m / z): RT=0.93min, m / z=293.0[M+H]+.

[0776] Step 2. Synthesis of 2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (Compound 11A), (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (Compound 11*), and (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (Compound 11B*). 1-Chloro-N-(2,2-dimethyloxacyclohexane-4-yl)pyrido[3,4-d]pyridazine-4-amine (250 mg, 0.85 mmol, 1 eq), Na2CO3 (271.51 mg, 2.56 mmol, 3 eq), Pd(dppf)Cl2 (187.44 mg, 0.25 mmol, 0.3 eq), dioxane (2.5 mL) and H2O (0.5 mL) were added to a 20 mL vial. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. The reaction progress was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, aqueous MeCN, gradient from 30% to 60% in 10 min; detector, UV 254 nm) to give the crude product compound 11A (200 mg, 80% purity), which was purified by preparative HPLC (column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and MeCN (35% MeCN increased to 45% in 10 min); detector, UV 254 nm) to give purified compound 11A (120 mg, 98% purity), which was purified by chiral preparative HPLC (column, CHIRALPAKID, 2*25 cm, 5 um; mobile phase, hexane (0.2% formic acid) and ethanol (EtOH) (maintaining 10% EtOH in 20 min); detector, UV 254 nm). 254nm) to give (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (26.5mg, 7.25% yield) (Compound 11*) with a RT of 1.66min; and (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (24.3mg, 5.33% yield) (Compound 11B*) with a RT of 2.37min.The stereochemistry is arbitrarily specified.

[0777] (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (Compound 11*): LCMS: (ES, m / z): RT=1.21 min, m / z=419.0 [M+H] + ; 1 H NMR (400MHz, methanol-d4) δ9.71(d,J=1.0Hz,1H),8.86(d,J=5.7Hz,1H),7.60(d,J=7.9Hz,1H),7.52–7.46(m,1H),7.37–7.31(m,1H),7.28(d,J=1.7Hz, 1H),4.86–4.75(m,1H),3.99–3.88(m,1H),3.91–3.82(m,1H),2.24–2.10 (m,2H),1.75–1.64(m,1H),1.67–1.58(m,1H),1.41(s,3H),1.32(s,3H).

[0778] (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (Compound 11B*): LCMS: (ES, m / z): RT=1.21 min, m / z=419.0 [M+H] + ; 1 H NMR (400MHz, methanol-d4) δ9.71(d,J=1.0Hz,1H),8.86(d,J=5.7Hz,1H),7.59(d,J=7.9Hz,1H),7.52–7.46(m,1H),7.37–7.31(m,1H) ,7.28(d,J=1.7Hz,1H),4.86–4.74(m,1H),3.99–3.81(m,2H),2.24–2.10(m,2H),1.75–1.58(m,2H),1.41(s,3H),1.32(s,3H).

[0779] Example 7. 5-(Difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 16A), (S)-5-(Difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 16*) and (R)-5-(Difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 16B*)

[0780]

[0781] Example 7 follows Protocol A.

[0782] Step 1.1-bromo-4-(difluoromethyl)-2-methoxybenzene synthesis. Diethylaminosulfur trifluoride (DAST) (3.75 g, 23.25 mmol, 5 equivalents) was added to a stirred solution of 4-bromo-3-methoxybenzaldehyde (1 g, 4.65 mmol, 1 equivalent) in DCM (10 mL). The resulting mixture was stirred for 2 h at room temperature under air atmosphere. The reaction was quenched with ice water (20 mL) at 0 ° C. The water layer was extracted with EtOAc (3x10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / petroleum ether (DCM / PE) (1: 1) to give the title compound (1.03 g, 93% yield).

[0783] Step 2. Synthesis of (4-(difluoromethyl)-2-methoxyphenyl)boronic acid. A solution of 1-bromo-4-(difluoromethyl)-2-methoxybenzene (400 mg, 1.68 mmol, 1 eq.) in dioxane (10 mL) was treated with triethylamine (512.27 mg, 5.04 mmol, 3 eq.) for 30 min at room temperature under a nitrogen atmosphere, followed by the addition of Pd(OAc)2 (37.88 mg, 0.17 mmol, 0.1 eq.) and 2-(dicyclohexylphosphino)biphenyl, (2-biphenyl)dicyclohexylphosphine (Cy-JohnPhos) (118.29 mg, 0.33 mmol, 0.2 eq.). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was quenched with ice / water (10 mL) at 0 °C. The aqueous layer was extracted with EtOAc (50 mL x 3). The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum to give the title compound (1 g crude), which was used directly in the next step without further purification. GCMS: m / z = 202.06.

[0784] Step 3. Synthesis of 1-[4-(difluoromethyl)-2-methoxyphenyl]-N-(2,2-dimethyloxan-4-yl)pyrido[3,4-d]pyridazin-4-amine. To a stirred solution of 2-[4-(difluoromethyl)-2-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (135.86 mg, 0.47 mmol, 1 eq) in 1,4-dioxane (9 mL) and H2O (1.8 mL) was added Na2CO3 (152.05 mg, 1.43 mmol, 3 eq) and Pd(dppf)Cl2 (104.97 mg, 0.14 mmol, 0.3 eq). The resulting mixture was stirred at 80°C under nitrogen atmosphere for 2 h. The reaction was diluted with water (20 mL) at 0°C. The aqueous layer was extracted with EtOAc (3x50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN aqueous solution, 10% to 50% gradient in 10 min; detector, UV 254 nm) to obtain the title compound (176 mg, 88.8% yield). LCMS: (ES, m / z): RT=0.65min, m / z=415.40[M+H]+; 1H NMR (400MHz, DMSO-d6) δ9.78(s,1H),8.84(d,J=5.60Hz,1H),7.67(d,J=6.90Hz,1H),7.52(d,J=7.70Hz,1H),7.40(s,1H),7.34(d,J=7 .9Hz,1H),7.21–7.12(m,1H),6.44(q,J=7.0Hz,1H),3.76(d,J=5.50Hz,3H),3.74(s,2H),1.91(d,J=12.90Hz,4H),1.27–1.14(m,6H).

[0785] Step 4. Synthesis of 5-(difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 16A), (S)-5-(difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 16*), and (R)-5-(difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 16B*). To a stirred solution of 1-[4-(difluoromethyl)-2-methoxyphenyl]-N-(2,2-dimethyloxan-4-yl)pyrido[3,4-d]pyridazine-4-amine (150 mg, 0.36 mmol, 1 eq) in DMF (1.5 mL) was added sodium ethanethiolate (EtSNa) (457 mg, 5.43 mmol, 15 eq). The final reaction mixture was stirred at 120 ° C for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with EtOAc (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, aqueous MeCN (10 mmol / L NH4HCO3), gradient from 25% to 45% in 10 min; detector, UV 254 nm) to give compound 16A (43 mg, 96% purity, 88.8% yield), which was purified by preparative chiral HPLC (column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: Hex (0.2% FA), mobile phase B: IPA:DCM=1:1; flow rate: 20 mL / min; gradient: 30% B to 30% in 15 min. B; wavelength: 254 / 220 nm; RT1 (min): 10.29) was further purified to give (R)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 16B*) (16.5 mg, 11.4% yield) at RT of 14.32 min and (S)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 16*) (18.5 mg, 12.3% yield) at RT of 10.29 min. Stereochemistry was arbitrarily specified.

[0786] (R)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol. (Compound 16B*): LCMS: (ES, m / z): RT = 1.12 min, m / z = 401.20 [M+H]+; 1 HNMR (400MHz, DMSO-d6) δ10.14(s,1H),9.78(s,1H),8.85(d,J=5.6Hz,1H),7.66(s,1H),7.46(d,J=7.60Hz,1H),7.29(d,J=5. 6Hz,1H),7.24–6.91(m,3H),4.85–4.59(m,1H),3.79–3.69(m,2H),2.03(s,2H),1.65–1.47(m,2H),1.30(s,3H),1.22(s,3H).

[0787] (S)-5-(Difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 16*): LCMS: (ES, m / z): RT=1.12 min, m / z=401.20 [M+H]+; 1 HNMR (400MHz, DMSO-d6) δ10.14(s,1H),9.78(s,1H),8.85(d,J=5.6Hz,1H),7.66(s,1H),7.46(d,J=7.60Hz,1H),7.29(d,J=5. 6Hz,1H),7.24–6.91(m,3H),4.85–4.59(m,1H),3.79–3.69(m,2H),2.03(s,2H),1.65–1.47(m,2H),1.30(s,3H),1.22(s,3H).

[0788] Example 8. 5-Chloro-2-(4-((3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18B*), 5-chloro-2-(4-(((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18C*), 5-chloro-2-(4-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 5-Chloro-2-(4-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18A*), 5-Chloro-2-(4-(((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18D*)

[0789]

[0790]

[0791] Example 8 follows Protocol B.

[0792] Step 1: Synthesis of 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid. To a stirred solution of furano[3,4-c]pyridine-1,3-dione (30.0 g, 201.20 mmol, 1 eq.) and tetrahydrofuran (300 mL) was added dropwise bromo(4-chloro-2-methoxyphenyl)magnesium (0.5 M in THF) (241 mL, 120 mmol, 0.60 eq.) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 25 °C under a nitrogen atmosphere. The reaction progress was monitored by LCMS. The reaction was quenched by adding water (150 mL) at 0 °C. The precipitated solid was collected by filtration and washed with water (3x50 mL). This produced the title compound (20 g, 34.1% yield). LCMS (ES, m / z): RT=0.662 min, m / z=292.0 [M+1] + .

[0793] Step 2: Synthesis of 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine-4-ol. 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (5 g, 17.1 mmol, 1 eq) and SOCl2 (50 mL) were added to a 250 mL round-bottom flask. The resulting mixture was stirred at 70 ° C for 2 h. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was dissolved in DCM (50 mL) and added to a solution of NH2NH2.H2O (3.43 g, 68.6 mmol, 4 eq), MeOH (50 mL) at 0 ° C. The resulting mixture was stirred at 70 ° C in an oil bath for 3 h. The reaction progress was monitored by LCMS. The precipitated solid was collected by filtration. The crude product (4 g, 90% purity) was purified by preparative HPLC (2# SHIMADZU (HPLC-01): column, XBridge Shield RP18 OBD Column, 19*250 mm, 10 μm; mobile phase, water (10 mmol / L NH4HCO3) and MeCN (maintaining 39% MeCN within 17 min); detector, UV 254 / 220 nm) to obtain the title compound (2.0 g, 40.6% yield). LCMS: (ES, m / z): RT = 0.723 min, m / z = 288.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.90(s,1H),9.50(s,1H),8.94(d,J=5.5Hz,1H),7 .41(d,J=8.0Hz,1H),7.33(d,J=1.9Hz,1H),7.23–7.15(m,2H),3.75(s,3H).

[0794] Step 3: Synthesis of 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine. 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine-4-ol (2.5 g, 8.69 mmol, 1 eq.) and POCl3 (40 mL) and pyridine (4 mL) were added to a 250 mL round-bottom flask. The resulting mixture was stirred at 100 ° C for 3 h. The reaction progress was monitored by LCMS. The reaction was quenched with 500 mL of sodium bicarbonate (aq.) and 500 mL of EtOAc at 0 ° C. The resulting mixture was extracted with EtOAc (3x500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (1.50 g, 56.4% yield). LCMS (ES, m / z): RT=0.845min, m / z=306.0[M+1] + . 1H NMR(400MHz,DMSO-d6)δ9.84–9.68(m,1H),9.12(d,J=5.7Hz,1H),7.60–7.56(m,1 H),7.51(d,J=8.1Hz,1H),7.41(d,J=1.9Hz,1H),7.32–7.25(m,1H),3.74(s,3H).

[0795] Step 4: Synthesis of 1-(4-chloro-2-methoxyphenyl)-N-(3-methyltetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazine-4-amine. 3-Methyloxane-4-amine hydrochloride (200 mg, 1.31 mmol, 3 eq), DMSO (3 mL), 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (134.60 mg, 0.44 mmol, 1 eq) and DIEA (170.48 mg, 1.31 mmol, 3 eq) were added to a 20 mL vial at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. The reaction progress was monitored by LCMS. The residue was purified by reverse phase flash chromatography (column, C18 gel; mobile phase, aqueous MeCN, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give the title compound (150 mg, 88.7% yield) as a mixture of cis and trans stereoisomers. LCMS: (ES, m / z): RT=0.688 min, m / z=385 [M+1]+.

[0796] Step 5: Synthesis of 5-chloro-2-(4-((3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18B*). To a 20 mL vial was added a cis / trans mixture of (1-(4-chloro-2-methoxyphenyl)-N-(3-methyltetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine (90 mg, 0.24 mmol, 1 eq), DMSO (3 mL) and (ethylsulfanyl)sodium (204.14 mg, 2.43 mmol, 10 eq) at room temperature. The resulting mixture was stirred at 120 °C under nitrogen atmosphere for 1 h. The reaction progress was monitored by LCMS. The residue was purified by reverse phase flash chromatography (column, C18 gel; mobile phase, aqueous MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give a crude mixture of stereoisomers (70 mg, 90% purity).

[0797] Step 6: Separation of cis diastereomers: 5-chloro-2-(4-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18*), 5-chloro-2-(4-{3-methyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18'*) and 5-chloro-2-(4-(((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18D*). The crude mixture was purified using chiral preparative HPLC under the following conditions: column, Chiral ART Cellulose-SA, 2*25 cm, 5 um; mobile phase, Hex (0.2% FA) and EtOH:DCM=1:1 (maintaining 30% EtOH:DCM=1:1 in 15.5 min); detector, UV 254 nm. This resulted in 5-chloro-2-(4-{[(3R,4R)-3-methyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also known as 5-chloro-2-(4-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol) (Compound 18*) (9.30 mg, 10.3% yield, RT=1.47 on 4.6*50 mm column) as a light yellow solid and 5-chloro-2-(4-{3-methyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also known as 5-chloro-2-(4-{3-methyloxan-4-yl]amino}pyrido[3 ,4-d]pyridazin-1-yl)phenol) (Compound 18'*) as an assumed mixture of trans isomers (30 mg, 34.6% yield, RT=2.39 on a 4.6*50 mm column) and 5-chloro-2-(4-{[(3S,4S)-3-methyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also known as 5-chloro-2-(4-(((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol) (Compound 18D*) (7.50 mg, 8.3% yield, RT=3.11 on a 4.6*50 mm column) as a light yellow solid (cis and trans isomers and arbitrary specified stereochemistry).

[0798] 5-Chloro-2-(4-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18*): LCMS: (ES, m / z): RT=0.631 min, m / z=371 [M+1]+;1 H NMR (400MHz, methanol-d4) δ9.72(d,J=1.0Hz,1H),8.86(d,J=5.7Hz,1H),7.52(d,J=5.7Hz,1H),7.45–7.32(m,1H),7.05(d,J=7.3Hz,2H),4.43–4.31( m,1H),4.11–3.93(m,2H),3.72–3.57(m,1H),3.30–3.15(m,1H),2.23–2 .12(m,1H),2.12–1.97(m,1H),1.85–1.61(m,1H),0.99(d,J=6.6Hz,3H).

[0799] 5-Chloro-2-(4-(((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18D*): LCMS: (ES, m / z): RT=1.202 min, m / z=371 [M+1]+; 1 H NMR (400 MHz, methanol-d4) δ 9.72 (d, J = 1.0 Hz, 1H), 8.86 (d, J = 5.7 Hz, 1H), 7.56–7.45 (m, 1H), 7.45–7.36 (m, 1H), 7.14–6.99 (m, 2H), 4.43–4.31 (m, 1H), 4.10–3.94 (m, 2H), 3.70–3.59 (m, 1H), 3.31–3.16 (m, 1H), 2.25–2.14 (m, 1H), 2.14–1.94 (m, 1H), 1.80–1.60 (m, 1H), 1.00 (d, J = 6.6 Hz, 3H). Step 7:

[0800] Separation of trans diastereomers: 5-chloro-2-(4-(((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18C*) and 5-chloro-2-(4-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18A*). The assumed trans mixture (30 mg, 98% purity) was separated by chiral preparative HPLC under the following conditions: column, Chiral ART Cellulose-SA, 2*25 cm, 5 um; mobile phase, Hex (0.2% FA) and EtOH:DCM=1:1 (maintaining 30% EtOH:DCM=1:1 within 18.2 min); detector, UV 254 nm. This produced 5-chloro-2-(4-{[(3R,4S)-3-methyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also known as 5-chloro-2-(4-(((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol) (Compound 18C*) (13.9 mg, 39.6% yield, RT = 4.880 on 4.6*50 mm column) ) and 5-chloro-2-(4-{[(3S,4R)-3-methyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also known as 5-chloro-2-(4-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol) (Compound 18A*) (14.0 mg, 40.0% yield, RT=3.50 on a 4.6*50 mm column). Stereochemistry arbitrarily assigned.

[0801] 5-Chloro-2-(4-(((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18C*): LCMS: (ES, m / z): RT=1.032 min, m / z=371 [M+1]+; 1H NMR (400MHz, methanol-d4) δ9.78(d,J=1.0Hz,1H),8.86(d,J=5.7Hz,1H),7.42–7.33(m,1H),7.38(d,J=8.0Hz,1H),7.11–7.01(m,2H),4.74–4.66(m,1 H),4.11–4.02(m,1H),3.86–3.72(m,2H),3.66(d,J=2.7Hz,1H),2.58–2 .47(m,1H),2.29–2.12(m,1H),1.83–1.72(m,1H),1.13(d,J=7.1Hz,3H).

[0802] 5-Chloro-2-(4-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 18A*): LCMS: (ES, m / z): RT=1.032 min, m / z=371 [M+1]+; 1 H NMR (400MHz, methanol-d4) δ9.78(d,J=1.0Hz,1H),8.86(d,J=5.7Hz,1H),7.59–7.48(m,1H),7.38(d,J=7.9Hz,1H),7.10–6.97(m,2H),4.79–4.52(m ,1H),4.07(d,J=11.9Hz,1H),3.86–3.71(m,2H),3.70–3.56(m,1H),2. 53(s,1H),2.25–2.14(m,1H),1.86–1.71(m,1H),1.13(d,J=7.1Hz,3H).

[0803] Additional compounds provided below in Table C followed the schemes and examples described herein.

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817] Example 9. 2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethylphenol (Compound 24*) and 2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethylphenol (Compound 24B*)

[0818] Scheme 9A

[0819]

[0820] Option 9B

[0821]

[0822] Scheme 9C

[0823]

[0824] Example 9 follows Protocol A.

[0825] Step 1: 1,4-dichloropyrido [3,4-d] pyridazine (500 mg, 2.50 mmol, 1 eq.), 5,5-dimethyloxacyclopentane-3-amine (201.53 mg, 1.75 mmol, 0.7 eq.), Na2CO3 (802.39 mg, 7.50 mmol, 3 eq.) and DMF (5 mL) were added to a 20 ml sealed tube. The final reaction mixture was irradiated with microwave radiation at 130 ° C for 30 min. The reaction was repeated four times. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with methanol (MeOH). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (MeCN) aqueous solution, 10% to 80% gradient in 25 min; detector, UV 254 nm to give the crude product, which was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (23% to 35% in 8 min); detector, UV254 nm to give 1-chloro-N-(5,5-dimethyloxacyclopentane-3-yl)pyrido[3,4-d]pyridazine-4-amine as a mixture of R and S stereoisomers (1.2 g, 28% yield). LCMS: (ES, m / z): RT=0.62min, m / z=279.0[M+H] + .

[0826] Step 2: The stereoisomeric mixture from step 1 was purified by chiral HPLC under the following conditions: column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3 in methanol), mobile phase B: isopropanol / dichloromethane (1:1); flow rate: 20 mL / min; gradient: 70% B to 70% in 14.5 min B; wavelength: 254 / 220nm; RT1 (min) ((R)-1-chloro-N-(5,5-dimethyltetrahydrofuran-3-yl)pyrido [3,4-d] pyridazin-4-amine): 4.81; RT2 (min): 11.33 (S)-1-chloro-N-(5,5-dimethyltetrahydrofuran-3-yl)pyrido [3,4-d] pyridazin-4-amine; sample solvent: methanol / dichloromethane (1:1); injection volume: 1mL, to obtain (R)-1-chloro-N-(5,5-dimethyltetrahydrofuran-3-yl)pyrido [3,4-d] pyridazin-4-amine (Intermediate A*) (120 mg, 39% yield; LCMS: (ES, m / z): RT = 0.78 min, m / z = 279.1 [M+H] +) and (S)-1-chloro-N-(5,5-dimethyltetrahydrofuran-3-yl)pyrido[3,4-d]pyridazin-4-amine (Intermediate B*) (121 mg, 39% yield; LCMS: (ES, m / z): RT = 0.78 min, m / z = 279.1 [M+H] + ), with arbitrarily specified stereochemistry.

[0827] Step 3: Add 2-bromo-3,5-dimethylphenol (600 mg, 2.98 mmol, 1 eq.) and dioxane (6 mL), triethylamine (905.92 mg, 8.95 mmol, 3 eq.) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1909.55 mg, 14.92 mmol, 5 eq.) to a 20 mL vial. Stir the resulting mixture at room temperature under nitrogen atmosphere for 30 min. Add palladium (II) acetate (Pd(OAc)2) (67 mg, 0.29 mmol, 0.1 eq.) and 2-(dicyclohexylphosphino)biphenyl (Cy-JohnPhos) (209.18 mg, 0.59 mmol, 0.2 eq.) to the above mixture. Stir the resulting mixture at 80 °C under nitrogen atmosphere for 1 h. Monitor the reaction progress by GCMS. Quench the reaction with water (10 mL). The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-hydroxy-4,6-dimethylphenylboronic acid (800 mg, 81% yield), which was used directly in the next step without further purification.

[0828] Step 4. To an 8 mL vial was added 2-hydroxy-4,6-dimethylphenylboronic acid (214.37 mg, 1.29 mmol, 3 eq.) and Intermediate A* (120 mg, 0.43 mmol, 1 eq.), water (0.2 mL), Na2CO3 (138.19 mg, 1.29 mmol, 3 eq.), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (Pd(dppf)Cl2 CH2Cl2) (94.50 mg, 0.12 mmol, 0.3 eq.) and dioxane (1 mL). The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, gradient from 10% to 50% in 10 min; detector, UV254 nm, to give the crude product (70 mg), which was purified by preparative HPLC under the following conditions: column: XBridge ShieldRP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 35% B, 35% B in 10 min; wavelength: 254 nm; RT1 (min): 9.5 to give 2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethylphenol (Compound 24*) (41.90 mg, 27% yield). Stereochemistry is arbitrarily assigned. LCMS: (ES, m / z): RT1 = 1.43 min, m / z = 365.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.81(d,J=0.9Hz,1H),9.21(d,J=2.3Hz,1H),8.82(d ,J=5.6Hz,1H),7.84–7.82(m,1H),7.13–7.03(m,1H),6.65(d,J=6.9Hz,2H), 4.98–4.88(m,1H),4.30–4.18(m,1H),3.87–3.71(m,1H),2.38–2.26(m,4H), 2.05–1.90(m,1H),1.87(d,J=3.1Hz,3H),1.37(d,J=3.2Hz,3H),1.26(s,3H).

[0829] Step 5. To an 8 mL vial was added 2-hydroxy-4,6-dimethylphenylboronic acid (214.37 mg, 1.29 mmol, 3 eq), Intermediate B* (120 mg, 0.43 mmol, 1 eq), water (0.2 mL), Na2CO3 (138.19 mg, 1.29 mmol, 3 eq), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (Pd(dppf)Cl2 CH2Cl2) (94.50 mg, 0.12 mmol, 0.3 eq) and dioxane (1 mL). The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, gradient from 10% to 50% in 10 min; detector, UV254 nm, to give the crude product (70 mg), which was purified by preparative HPLC under the following conditions: column: XBridge ShieldRP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 35% B, 35% B in 10 min; wavelength: 254 nm; RT1 (min): 9.5 to give 2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethylphenol (Compound 24B*) (40.4 mg, 26% yield). Stereochemistry is arbitrarily assigned. LCMS: (ES, m / z): RT1 = 1.43 min, m / z = 365.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.81(d,J=0.9Hz,1H),9.21(d,J=2.3Hz,1H),8.82(d ,J=5.6Hz,1H),7.84–7.82(m,1H),7.13–7.03(m,1H),6.65(d,J=6.9Hz,2H), 4.98–4.88(m,1H),4.30–4.18(m,1H),3.87–3.71(m,1H),2.38–2.26(m,4H), 2.05–1.90(m,1H),1.87(d,J=3.1Hz,3H),1.37(d,J=3.2Hz,3H),1.26(s,3H).

[0830] Example 10. 5-Chloro-2-(4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 25A*), 5-Chloro-2-(4-(((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 25B* ), 5-chloro-2-(4-(((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 25C*) and 5-chloro-2-(4-(((2R,4S)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 25D*)

[0831] Scheme 10A

[0832]

[0833] Example 10 follows Protocol B.

[0834] Step 1: At -78 ° C, furano [3,4-c] pyridine -1,3-dione (3g, 20.12mmol, 1 equivalent), tetrahydrofuran (THF) (30mL) and bromo (4-chloro-2-methoxyphenyl) magnesium (0.5mol / L) (24.16mL, 12.07mmol, 0.6 equivalent) were added to a 250mL 3-necked round-bottom flask. The resulting mixture was stirred for 2h at room temperature under a nitrogen atmosphere. The reaction progress was monitored by LCMS. The reaction was quenched by adding ice water (300mL) at 0 ° C. The resulting mixture was concentrated under vacuum. The precipitated solid was collected by filtration and washed with water (3x 20mL) and dried under vacuum to give 4- (4-chloro-2-methoxybenzoyl) pyridine-3-carboxylic acid (2.5g, 43% yield). LCMS: (ES, m / z): RT=0.633min, m / z=292.0[M+1] + .

[0835] Step 2: 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (2.5 g, 8.56 mmol, 1 eq.) and SOCl2 (25 mL) were added to a 250 mL round-bottom flask. The resulting mixture was stirred at 70 ° C for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (DCM) (30 mL) and added to a solution of NH2NH2.H2O (80%) (2.39 g, 34.24 mmol, 4 eq.) in methanol (MeOH) (50 mL) at 0 ° C. The resulting mixture was stirred at 80 ° C in an oil bath for 1 h. The reaction progress was monitored by LCMS. The precipitated solid was collected by filtration. The crude product (2 g, 73% purity) was purified by preparative HPLC under the following conditions (2# SHIMADZU (HPLC-01)): column, XBridgeShield RP18 OBD Column, 19*250 mm, 10 μm; mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (maintained 41% in 19 min); detector, UV 254 / 220 nm, to give 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (1.2 g, 49% yield). LCMS: (ES, m / z): RT=0.678 min, m / z=288.0 [M+1] + .

[0836] Step 3: 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine-4-ol (1.2 g, 4.16 mmol, 1 eq.) and POCl3 (25 mL) and pyridine (2.5 mL) were added to a 250 mL round-bottom flask. The resulting mixture was stirred at 110 ° C for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was diluted with ethyl acetate (EtOAc) (20 mL). The resulting mixture was slowly poured into a mixture of EtOAc (1 L) and saturated sodium bicarbonate (aq.) (1 L) at 0 ° C. The aqueous layer was extracted with EtOAc (2x1 L). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (800 mg, 63% yield). LCMS: (ES, m / z): RT=0.801min, m / z=306.0[M+1] + .

[0837] Step 4. 4-Chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (200 mg, 0.65 mmol, 1 eq.), 2-methyloxan-4-amine (150.48 mg, 1.30 mmol, 2 eq.), triethylamine (198.32 mg, 1.95 mmol, 3 eq.) and DMSO (6 mL) were added to a 20 mL sealed tube at room temperature. The resulting mixture was stirred at 80 °C under air atmosphere for 12 h. The reaction was monitored by LCMS. The crude product, a mixture of cis and trans stereoisomers of 5-chloro-2-{4-[(2-methyloxan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol, was used directly in the next step without further purification. LCMS: RT = 0.85 min, m / z = 385 [M+H] + .

[0838] Step 5. Sodium ethanethiolate (EtSNa) (654.78 mg, 7.80 mmol, 15 equiv) was added directly to the reaction solution from step 4. The resulting mixture was stirred at 120°C under air atmosphere for 1 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 15% to 18% gradient in 15 min; detector, UV 254nm and 220nm to give a mixture of cis and trans isomers of 5-chloro-2-{4-[(2-methyloxan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (150 mg, 78% yield). The crude product (150 mg) was purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 μm; mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: methanol; flow rate: 20 mL / min; gradient: 40% B to 45% B in 8 min; wavelength: 254 nm; RT1 (min): 10) to give 5-chloro-2-{4-[(2-methyloxan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (120 mg, 99% purity) as a mixture of cis and trans isomers. LCMS: RT=0.62 min, m / z=371 [M+H] + .

[0839] Step 6. A mixture of isomers of 5-chloro-2-{4-[(2-methyloxan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (120 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAKIG, 2*25 cm, 5 μm; mobile phase A: hexane (0.2% formic acid), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: 50% B to 50% in 20 min B; wavelength: 220 / 254nm; RT1(min): 8.115; (mixture of compounds 25A* and 25B*); RT2(min): 12.895 (compound 25C*); RT3(min): 18.241 (compound 25D*); sample solvent: methanol / dichloromethane = 1:1; injection volume: 0.7mL), to obtain a mixture of compounds 25A* and 25B* (55mg, 98% purity), compound 25C* (11.2mg, 99.8% purity) and compound 25D* (10.6mg, 99.9% purity); arbitrarily specified stereochemistry.

[0840] Compound 25C*: LCMS: RT = 0.61 min, m / z = 371 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ9.80(d,J=1.0Hz,1H),8.87(d,J=5.6Hz,1H),7.53(dd,J=5.7,1.0Hz,1H),7.38(d,J=8.0Hz,1H),7.10–7.02(m,2H),4 .73–4.66(m,1H),4.11–3.86(m,3H),2.18(d,J=13.9Hz,1H),2.12–1.97(m,2H),1.58(ddd,J=14.0,10.0,4.0Hz,1H),1.35(d,J=6.3Hz,3H).

[0841] Compound 25D*: LCMS: RT = 0.62 min, m / z = 371 [M+H] + . 1H NMR (400MHz, methanol-d4) δ9.80(d,J=1.0Hz,1H),8.87(d,J=5.7Hz,1H),7.53(dd,J=5.7,1.0Hz,1H),7.38(d,J=8.0Hz,1H),7.10–7.02(m,2H),4 .73–4.66(m,1H),4.11–3.86(m,3H),2.18(d,J=13.9Hz,1H),2.12–1.97(m,2H),1.76(ddd,J=14.0,10.0,4.0Hz,1H),1.26(d,J=6.3Hz,3H).

[0842] Step 7: A mixture of compounds 25A* and 25B* (55 mg) was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: hexane (0.2% formic acid), mobile phase B: ethanol; flow rate: 20 mL / min; gradient: 35% B to 35% B in 16.5 min; wavelength: 254 / 220 nm; RT1 (min): 1.179 (compound 25A*); RT2 (min): 4.19 (compound 25B*); sample solvent: methanol; injection volume: 0.6 mL) to give compound 25A* (14.7 mg, 98% purity) and compound 25B* (15.5 mg, 99% purity); arbitrarily specified stereochemistry.

[0843] Compound 25A*: LCMS: RT = 0.91 min, m / z = 371 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ9.69(d,J=1.0Hz,1H),8.85(d,J=5.7Hz,1H),7.51(dd,J =5.7,1.0Hz,1H),7.38(d,J=8.0Hz,1H),7.09–7.02(m,2H),4.63–4.52(m,1H), 4.13–4.05(m,1H),3.73–3.62(m,2H),2.30–2.22(m,1H),2.18(d,J=13.3Hz,1H ), 1.72 (qd, J = 12.3, 4.7 Hz, 1H), 1.44 ( q, J = 11.6 Hz, 1H), 1.27 ( d, J = 6.2 Hz, 3H).

[0844] Compound 25B*: LCMS: RT = 0.91 min, m / z = 371 [M+H] + . 1H NMR (400MHz, methanol-d4) δ9.72(d,J=1.0Hz,1H),8.68(d,J=5.7Hz,1H),7.54(dd, J=5.7,1.0Hz,1H),7.38(d,J=7.9Hz,1H),7.09–7.02(m,2H),4.63–4.53(m,1H ),4.13–4.04(m,1H),3.73–3.62(m,2H),2.30–2.22(m,1H),2.21–2.13(m,1H) ,1.72(qd,J=12.3,4.6Hz,1H), 1.44(q,J=11.7Hz,1H), 1.24(d,J=6.2Hz,3H).

[0845] Example 11. Synthesis of 3-chloro-2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 26*) and 3-chloro-2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (Compound 26B*)

[0846] Scheme 11A

[0847]

[0848] Scheme 11B

[0849]

[0850] Example 11 followed Protocol A.

[0851] Step 1. At room temperature, chloro-meta-cresol (3g, 21.04mmol, 1 equivalent), acetonitrile (20mL), K2CO3 (8.72g, 63.12mmol, 3 equivalents) and iodomethane (MeI) (8.96g, 63.12mmol, 3 equivalents) were added to a 40mL vial. The resulting mixture was stirred at 80°C for 2h. The reaction was monitored by LCMS. The reaction was quenched with water (20mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (3x 50mL). The combined organic layer was washed with brine (1x 20mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (18:1) to give 1-chloro-3-methoxy-5-toluene (3.1g, 94% yield). LCMS: RT=1.04min, m / z=157.0[M+H] + .

[0852] Step 2. At -78 ° C, N2 atmosphere, in a 100-mL three-round-bottom flask, tert-butyl lithium solution (1.6M in hexane, 20mL, 1.7 equivalents) was added dropwise to a solution of 1-chloro-3-methoxy-5-toluene (3g, 19.16mmol, 1 equivalent) in tetrahydrofuran (THF) (5mL). The reaction mixture was stirred at -78 ° C for 1h. Then a solution of triisopropyl borate (5.40g, 28.73mmol, 1.50 equivalents) in THF (10mL) was added dropwise, and the mixture was stirred for another 2h at -20 ° C. The reaction was monitored by LCMS. The reaction was quenched with saturated NH4Cl (10mL), and the mixture was then extracted with ethyl acetate (EtOAc) (2x30mL). The combined organic extracts were washed with brine (30mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether / ethyl acetate 3:1) to give 2-chloro-6-methoxy-4-methylphenylboronic acid (780 mg, 20% yield). LCMS: RT = 0.78 min, m / z = 201.0 [M+H] + .

[0853] Step 3. To an 8 mL vial was added 2-chloro-6-methoxy-4-methylphenylboronic acid (287.60 mg, 1.40 mmol, 4 equiv), dioxane (1.5 mL), H2O (0.3 mL), Intermediate A* from Example 9 (100 mg, 0.36 mmol, 1 equiv), Na2CO3 (114.06 mg, 1.08 mmol, 3 equiv) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (Pd(dppf)2Cl2CH2Cl2) (79.2 mg, 0.11 mmol, 0.3 equiv) at room temperature. The resulting mixture was stirred at 80°C under N2 atmosphere for 2 h. The reaction was monitored by LCMS. The reaction was quenched with water (5 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile aqueous solution, 10% to 50% gradient in 20 min; detector, UV 254 nm to give 1-(2-chloro-6-methoxy-4-methylphenyl)-N-[(3R)-5,5-dimethyloxolan-3-yl]pyrido[3,4-d]pyridazin-4-amine (80 mg, 56% yield). LCMS: RT = 1.01 min, m / z = 399.0 [M + H] + . 1H NMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.84 (d, J = 5.5 Hz, 1H), 7.97 (d, J = 5.8 Hz, 1H), 7.12–7.01 (m, 3H), 5.00–4.87 (m, 1H), 4.30–4.17 (m, 1H), 3.87–3.70 (m, 1H), 3.64 (s, 3H), 2.44 (s, 3H), 2.39–2.26 (m, 1H), 2.06–1.91 (m, 1H), 1.37 (s, 3H), 1.26 (s, 3H). Stereochemistry is arbitrarily specified.

[0854] Step 4. To an 8 mL vial was added 1-(2-chloro-6-methoxy-4-methylphenyl)-N-[(3R)-5,5-dimethyloxolan-3-yl]pyrido[3,4-d]pyridazin-4-amine (80 mg, 0.20 mmol, 1 eq), DMSO (1 mL) and sodium (ethylsulfanyl) (168.69 mg, 2.01 mmol, 10 eq) at room temperature. The resulting mixture was stirred at 120° C. for 2 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, gradient from 10% to 40% in 10 min; detector, UV 254 / 220 nm to give a crude product (70 mg, 90% purity), which was purified by preparative HPLC under the following conditions (column: Xselect CSH F-Phenyl OBD Column, 19*250 mm, 5 μm; mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 20% B to 25% B in 8 min; wavelength: 254 nm; RT1 (min): 8 min; to give compound 26A* (25 mg, 25% yield). LCMS: RT1=1.08 min, m / z=385.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),10.02(s,1H),9.03(s,1H),7.29(s,1H),6.98(s,1H),6.84(s,1H),4.87(d, J=7.8Hz,1H),4.26–4.17(m,1H),3.91(m,2H),2.35(s,3H),2.10–1.98(m,1H),1.38(d,J=2.5Hz,3H),1.26(s,3H).

[0855] Step 5. Intermediate B* from Example 9 (80.0 mg, 0.29 mmol, 1 eq), dioxane (0.5 mL), H2O (0.1 mL), 2-chloro-6-methoxy-4-methylphenylboronic acid (173 mg, 0.86 mmol, 3 eq), Na2CO3 (91.3 mg, 0.86 mmol, 3 eq) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (Pd(dppf)2Cl2CH2Cl2) (63 mg, 0.09 mmol, 0.3 eq) were added to an 8 mL vial at room temperature. The resulting mixture was stirred at 60°C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The reaction was quenched with water (5 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 20 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 15% to 40% gradient in 20 min; detector, UV 220 / 254 nm. This produced 1-(2-chloro-6-methoxy-4-methylphenyl)-N-[(3S)-5,5-dimethyloxolan-3-yl]pyrido[3,4-d]pyridazin-4-amine (40.4 mg, 26% yield). LCMS, ESI: RT = 0.73 min, m / z = 399.0 [M+H] + ; 1 H NMR (300 MHz, DMSO-d6) δ 9.84 (d, J = 1.0 Hz, 1H), 8.84 (d, J = 5.6 Hz, 1H), 8.00 (d, J = 5.9 Hz, 1H), 7.14-7.03 (m, 3H), 4.93 (q, J = 6.9 Hz, 1H), 4.32-4.13 (m, 1H), 3.87-3.72 (m, 1H), 3.64 (d, J = 1.0 Hz, 3H), 2.44 (s, 3H), 2.39-2.21 (m, 1H), 2.08-1.86 (m, 1H), 1.36 (s, 3H), 1.26 (s, 3H). Stereochemistry is arbitrarily assigned.

[0856] Step 6. 1-(2-chloro-6-methoxy-4-methylphenyl)-N-[(3S)-5,5-dimethyloxolan-3-yl]pyrido[3,4-d]pyridazin-4-amine (80 mg, 0.20 mmol, 1 eq), dimethylformamide (DMF) (1 mL) and (ethylsulfanyl)sodium (168.69 mg, 2.01 mmol, 10 eq) were added to an 8 mL vial at room temperature. The resulting mixture was stirred at 120 °C for 2 h. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with DMF (4 mL). After filtration, the filtrate was concentrated under reduced pressure. The filtrate was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep Phenyl OBD Column, 19*250mm, 5μm; mobile phase, water (10mmol / L NH4HCO3) and acetonitrile (30% to 40% in 10min); detector, UV 220 / 254nm, to obtain compound 26B* (20mg, 20% yield). LCMS, ESI: RT=0.85min, m / z=385.0[M+H] + ; 1 H NMR (400MHz, methanol-d4) δ9.82(s,1H),8.93(s,1H),7.38(d,J=5.4Hz,1H),6.97(s,1H),6.81(s,1H),4.97(d,J=6.2Hz,1H),4. 45–4.30(m,1H),4.06–3.91(m,1H),2.52–2.43(m,1H),2.40(s,3H),2.16–2.06(m,1H),1.46(d,J=2.4Hz,3H),1.36(s,3H).

[0857] Example 12. Biological Activities of Compounds of the Disclosure

[0858] The biological activity of the compounds of the present disclosure was determined using the assays described herein.

[0859] Human whole blood – NLRP3

[0860] Heparin lithium coated tubes are used to collect blood from volunteers. Using 90 μl per well, blood samples are distributed on 96-well plates. By adding 5 μl LPS (O26: B6; Sigma L-2654), priming was performed at a final concentration of 1 μg / ml in a humidified incubator at 37 ° C, 5% CO2 for 4.5 hours. Thirty minutes before NLRP3 activation, 5 μl 20X compound solution or vehicle (2% DMSO) was added to each well, and the plate was incubated on an oscillator (450 rpm) in a humidified incubator at 37 ° C, 5% CO2. Then 3.3 μl 31X ATP solution was added to each well for activation. At the end of 30 minutes of stimulation, the plate was centrifuged (800 g, 10 min, room temperature), and the plasma from each well was frozen at -80 ° C. According to the manufacturer's instructions, the IL-1β level in the supernatant was analyzed using mesoscalediscovery assay (MSD K151TUK). Human whole blood was drawn from healthy volunteers after written informed consent was obtained.

[0861] Brain levels (kp and kpu,u) – NLRP3

[0862] After oral administration of the compound, the ratio of total brain to plasma in vivo was assessed in CD1 mice. Blood was collected at several time points up to 24h and transferred to a plastic microcentrifuge tube containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 4000g for 5 minutes at 4°C to obtain plasma, then immediately frozen and stored at -75 ± 15°C before analysis. At about 1 minute, animals were terminally anesthetized with an elevated concentration of CO2 gas. At the selected time point, the whole brain was removed from the skull, rinsed in cold PBS to remove blood, wiped dry with clean gauze, then frozen in liquid nitrogen and stored at -75 ± 15°C before analysis. During analysis, brain samples were homogenized with PBS at a ratio of 1:3 of tissue weight (g) to PBS volume (mL). After separation on a HALO 160A ES-C18, 2.7 μm 2.1×50 mm column, plasma and brain drug levels were quantified by LC / MS / MS on an AB Sciex Triple Quad 5500+ instrument. Quantification was performed using calibration curves prepared in blank plasma or blank brain homogenate. Software WinNonlin (Phoenix TM ) is used to calculate the concentration versus time data (including AUC inf and AUC last ) for pharmacokinetic analysis. The Kp ratio (total brain concentration relative to total plasma concentration) was calculated as (AUC tot,br ) / (AUC tot,pl ).

[0863] Unbound brain exposure was estimated as Kpuu , which is the free brain / free plasma concentration ratio (C u,br / C u,pl ). C u,br / C u,pl The ratio was determined by using the in vitro F u,br and F u,pl Autologous total brain plasma ratio (C tot,br / C tot,pl ) obtained.

[0864] Plasma protein binding and brain homogenate protein binding are measured by equilibrium dialysis in HT dialysis plates. The dialysis membrane is soaked in ultrapure water for 60 minutes to separate the bands, then soaked in 20% ethanol for 20 minutes, and finally soaked in dialysis buffer for 20 minutes. The dialysis device is assembled according to the manufacturer's instructions. Each cell receives 150 μL of plasma or brain homogenate labeled with 1mM compound, and dialyzed with an equal volume of dialysis buffer (PBS). The dialysis plate is sealed and incubated at 100 rpm for 6 hours in an incubator at 37°C and 5% CO2. At the end of the incubation, after separation on XSelect Hss T3 2.5μ (2.1×30mm) columns, the compound concentrations in the two chambers are measured by LC-MS / MS on Triple QuadTM 5500 of AB Inc. The free fraction (Fu) is calculated as (peak area ratio buffer chamber / peak area ratio plasma chamber).

[0865] Kp uu Calculated as (AUC tot,br x F u,br ) / (AUC tot,pl x F u,pl ).

[0866] Activity data

[0867] Table D assigns each compound a code to indicate potency in the human whole blood (hWB) NLRP3 assay: A or B. Depending on the code, A indicates IC 50 Value ≤1.0μM; B represents IC 50 Values ​​> 1.0 μM. The corresponding raw activity data are also included.

[0868] The table below also assigns a code for the kp and kpu,u values ​​for each compound: A or B. Depending on the code, A indicates a value >0.3 and B indicates a value ≤0.3. The kp value was calculated by measuring the whole brain drug level (AUC) in mice dosed PO at 20 mpk at 24 h and dividing by the plasma AUC. The kpu,u was then calculated after correcting this kp value for mouse plasma protein binding and mouse brain homogenate binding. Kpu,u values ​​>0.3 are brain penetrant and Kpu,u values ​​less than or equal to 0.3 are non-brain penetrant. ND = Not Determined. The corresponding raw kp and kpu,u data are also included.

[0869]

[0870]

[0871]

[0872] Comparative Examples

[0873] The compounds described in the present disclosure are useful for treating diseases and / or conditions mediated by NLRP3 proteins and are structurally related to compounds previously disclosed in U.S. Patent Application No. 17 / 528,928 as inhibitors of the same NLRP3 protein. However, the brain levels of these active pharmaceutical ingredients were unexpected and therefore not contemplated in the US 17 / 528,928 application. Therefore, the unexpected ability of compounds 1*, 2*, 3*, 4*, 5 and 6 of the present invention to penetrate the brain-blood barrier constitutes a novel invention.

[0874] In addition, as shown in Table D above, the inhibitors of the NLPR3 protein described in U.S. Application No. 17 / 528,928 exhibited this unexpected activity and were not significant. It was found that the selected NLPR3 inhibitors of the present disclosure exhibited stronger brain penetration properties in a head-to-head comparison with the compounds of the USSN 17 / 528,928 application, and their NLPR3 inhibitory activity in the blood was similar, as exemplified in Table D. As more clearly illustrated by the above table, compounds 1*, 2, 3*, 4*, 5 and 6 of the present disclosure exhibited unexpected "A" brain levels compared to compound 7* (Comparative Example 1, compound 89 of USSN 17 / 528,928) and compound 8 (Comparative Example 2, compound 96 of USSN 17 / 528,928), the latter two of which each exhibited "B" brain levels and had no brain penetration, thereby making the compounds of the present application more useful for treating NLPR3-mediated CNS diseases.

[0875] It has further been found that R 3Halogen moieties, such as chloro groups, are used to increase the solubility of compounds of formula (I) (wherein the alkyl or alkane- is independently substituted with 0, 1, 2 or 3 halogen atoms) while still maintaining a Kpu,u greater than 0.3. See, for example, Table E below. Compare, for example, compounds with chloro R 3 Partial comparison of Example 3 (Compound 105 of USSN 17 / 528,928) with Compounds 9*, 9B* and 5 in phosphate buffer solution (PBS, pH 7.4): Compounds 9* and 9B* both resulted in self-chloro R 3 Partially moved to -OCHF2R 3 The solubility of the part increased by 7 times; compound 5 led to the self-chlorination of R 3 Partially moved to -CH3R 3 The solubility of the moiety increased by 27 times; and each of them maintained good brain permeability. 3 moieties, such as compound 21* (meta-fluorine moiety), compound 26* (meta-chloro moiety), and compound 24* (meta-CH3 group) resulted in further increases in solubility; compare compound 21* (37-fold increase), compound 26* (42-fold increase), and compound 24* (43-fold increase) with Comparative Example 3. Compounds that do not have brain penetration but have improved properties such as solubility can be used to treat systemic (non-CNS) NLPR3-mediated diseases.

[0876]

[0877]

[0878] Equivalent

[0879] The details of one or more embodiments of the present disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure, the desired methods and materials are described herein. Other features, objects and advantages of the present disclosure will be apparent from the specific embodiments and the claims. In the specification and the appended claims, singular forms include plural references unless the context clearly provides otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

[0880] The foregoing description is presented for purposes of illustration only and is not intended to limit the disclosure to the precise form disclosed except as limited by the appended claims.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein: A is a 5- to 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom; R 1 is halogen, C1-C6 alkyl or C1-C6 alkoxy; R 2 is halogen or C1-C6 alkyl; or R 1 and R 2 Together with the atoms to which they are attached, they form a 3- to 4-membered carbon ring; R 3 is -OH, halogen, C1-C6 alkyl or C1-C6 alkoxy; X is H, -OH, halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl; and R 4 is H, C1-C6 alkyl or -C(O)(C1-C6 alkyl); and p is 0 or 1, wherein each instance of alkyl, alkane- or carbocycle is independently substituted with 0, 1, 2 or 3 halogen atoms, and When R 3 When Cl is Not for 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, wherein A is a 5-membered monocyclic heterocycloalkyl containing one O ring atom.

3. A compound as claimed in claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug thereof, wherein A is a 6-membered monocyclic heterocycloalkyl containing one O ring atom.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein p is 1.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein p is 1; R 1 is C1-C6 alkyl or C1-C6 alkoxy; and R 2 It is a C1-C6 alkyl group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein R 3 Not halogen.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein R 3 It is a C1-C6 alkyl group or a C1-C6 alkoxy group.

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein R 3 It is Cl, methyl, -CF3, -CHF2 or -OCHF2.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein R 4 It's H.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein X is H or F.

11. A compound as claimed in any one of the preceding claims, wherein the compound has formula (Ia) or (Ib): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

12. A compound as claimed in any one of the preceding claims, wherein the compound has formula (II-a), (II-b), (II-c), (II-d), (II-e) or (II-f): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

13. A compound as claimed in any one of the preceding claims, wherein the compound has formula (III-a), (III-b) or (III-c): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein: m is an integer from 0 to 2; and n is an integer of 1 to 2.

14. A compound as claimed in any one of the preceding claims, wherein the compound has formula (III-d), (III-e) or (III-f): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, wherein: m is an integer from 0 to 2; and n is an integer of 1 to 2.

15. A compound as claimed in any one of the preceding claims, wherein the compound has formula (IV-a), (IV-b) or (IV-c): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

16. A compound as claimed in any one of the preceding claims, wherein the compound has formula (IV-a1), (IV-b1) or (IV-c1): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

17. The compound of any one of claims 1-13, wherein the compound has formula (Va), (Vb), (Vc), (V-a'), (V-b') or (V-c'): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

18. The compound of any one of claims 1-13, wherein the compound has formula (VI-a), (VI-b), (VI-c), (VI-d), (VI-e), (VI-f), (VI-g) or (VI-h): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

19. The compound of claim 1 having the formula: 1A 5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3A 5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 4A 5-Chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylbenzene phenol; 9A 5-(Difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 10A 2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 11A 2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 12A 6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3-methylphenol; 13A 2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 14A 2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 15A 2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 16A 5-(Difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 17A 5-(Difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 18B 5-Chloro-2-(4-((3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 19A 2-(4-((4-oxaspiro[2.4]heptane-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 20A 5-(Difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 21A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5-methylphenol; 22A 2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; or a pharmaceutically acceptable salt or isotope-labeled compound thereof.

20. The compound of claim 1, which is: 1* -5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl) phenol; 1B (S)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3B* (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3* (S)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 4* (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 4B* (R)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5 (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 5B (S)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 9B* (R)-5-(difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 9* (S)-5-(difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 10* (S)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazine-1- 4-Methylphenol; 10B* (R)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazine-1- 4-Methylphenol; 11* (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- 4-(4-(6-fluoromethyl)phenol; 11B* (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- 4-(4-(6-fluoromethyl)phenol; 12* (R)-6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3-methylphenol; 12B* (S)-6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3-methylphenol; 13B* (R)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- 4-Methylphenol; 13* (S)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 14B* (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 14* (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 15* (S)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 15B* (R)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 16B* (R)-5-(difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 16* (S)-5-(difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 17* (S)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido [3,4-d]pyridazin-1-yl)phenol; 17B* (R)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido [3,4-d]pyridazin-1-yl)phenol; 18A* 5-Chloro-2-(4-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 18* 5-Chloro-2-(4-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 18C* 5-Chloro-2-(4-(((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 18D* 5-Chloro-2-(4-(((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 19B* (S)-2-(4-((4-oxaspiro[2.4]heptane-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 19* (R)-2-(4-((4-oxaspiro[2.4]heptane-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 20B* (R)-5-(difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido [3,4-d]pyridazin-1-yl)phenol; 20* (S)-5-(Difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido [3,4-d]pyridazin-1-yl)phenol; 21* 2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5-methylphenol; 21B* 2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5-methylphenol; 22B* (S)-2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1- 4-(4-(6-fluoromethyl)phenol; 22* (R)-2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; or a pharmaceutically acceptable salt or isotope-labeled compound thereof.

21. A compound having the formula: 2 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 6A 2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; or a pharmaceutically acceptable salt or isotope-labeled compound thereof.

22. The compound of claim 1 having the formula: 24* 2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethylphenol; 24B* 2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5- Xylenol; 25A* 5-Chloro-2-(4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine -1-yl)phenol; 25B* 5-Chloro-2-(4-(((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 25C* 5-Chloro-2-(4-(((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine -1-yl)phenol; 25D* 5-Chloro-2-(4-(((2R,4S)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine -1-yl)phenol; 26* 3-Chloro-2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1- 4-Methylphenol; 26B* 3-Chloro-2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1- 4-Methylphenol; or a pharmaceutically acceptable salt or isotope-labeled compound thereof.

23. The compound of claim 1, wherein the compound is not or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof.

24. The compound of claim 1, wherein the compound is not: 1A 5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)benzene phenol; 3A 5-Chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- 1-Hydroxyphenol; 4A 5-Chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- 1-Hydroxyphenol; or 5A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methyl phenol, or a pharmaceutically acceptable salt or isotope-labeled compound thereof.

25. The compound of any one of claims 1-21, 23 and 24, wherein the Kpu,u of the compound is greater than 0.

3.

26. The compound of any one of claims 1-21, 23 or 24, wherein the compound has a Kpu,u of greater than 0.3 to about 10.

27. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, and one or more pharmaceutically acceptable carriers.

28. A method for regulating NLRP3, the method comprising administering to a subject a compound as described in any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, inclusion complex, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition as described in claim 27.

29. A method for treating or preventing a disease or condition, the method comprising administering to a subject a compound as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition as described in claim 27.

30. A compound as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition as described in claim 27, for use in treating or preventing a disease or condition.

31. Use of a compound as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof in the manufacture of a medicament for treating or preventing a disease or condition.

32. Use of a compound as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope-labeled compound or prodrug thereof for treating or preventing a disease or disorder.

33. The method, compound or use of any one of claims 29-32, wherein the disease or disorder is a NLRP3-associated disease or disorder.

34. The method, compound or use of any one of claims 28-33, wherein the subject is a human.

35. The method, compound or use of any one of claims 29-34, wherein the disease or condition is inflammation, autoimmune disease, cancer, infection, central nervous system disease or condition, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or NLRP3-related disease.

36. The method, compound or use of claim 35, wherein the central nervous system disease or disorder is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis or multiple sclerosis.

37. The method, compound or use of claim 35, wherein the kidney disease is acute kidney disease, chronic kidney disease or a rare kidney disease.

38. The method, compound or use of claim 35, wherein the skin disease is psoriasis, hidradenitis suppurativa (HS) or atopic dermatitis.

39. The method, compound or use of claim 35, wherein the rheumatic disease is dermatomyositis, Still's disease or juvenile idiopathic arthritis.

40. The method, compound or use of claim 35, wherein the NLRP3-associated disease is in a subject identified as carrying a germline or somatic non-silent mutation in NLRP3.

41. The method, compound or use of claim 40, wherein the NLRP3-associated disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3 is cryptopyrin-associated autoinflammatory syndrome.

42. The method, compound or use of claim 41, wherein the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome or neonatal-onset multisystem inflammatory disease.

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