Pyrido-[3,4-d]pyridazinamine derivatives useful as NLRP3 inhibitors

Abstract

The present disclosure provides a compound of formula (I): or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein ring A is a 5-8 membered monocyclic heterocycloalkyl containing at least one O ring atom, p is 0 or 1, and R 1 , R 2 , R 3 , R 4 and X are as defined herein and are useful in the treatment of diseases and disorders inhibited by said protein.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Non-provisional Application No. 17 / 704,983, filed March 25, 2022, U.S. Provisional Application No. 63 / 420,930, filed October 31, 2022, and U.S. Provisional Application No. 63 / 443,874, filed February 7, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] Field of the Disclosure The present disclosure relates to inhibitors of NLR family pyrin domain-containing 3 (NLRP3) protein. The inhibitors described herein are useful for treating diseases and disorders associated with the regulation of NLRP3 protein. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit NLRP3, methods of using the compounds and pharmaceutical compositions to treat diseases and disorders associated with NLRP3, and methods of synthesizing the compounds and compositions. [Background technology]

[0003] 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 bound, these receptors trigger the activation of downstream inflammatory pathways that help resolve damage. However, in many cases, this activation can be uncontrolled, leading to disease.

[0004] Inflammasomes represent a class of PRRs that are crucial components of the innate immune response. Inflammasome activation triggers a cascade of events that releases IL-1β, IL-18, and promotes an inflammatory form of cell death called pyroptosis, induced by activation of gasdermins. Pyroptosis is a unique form of inflammatory cell death that results in the release of not only cytokines but also other intracellular components that promote a broader immune response of both the innate and adaptive immune systems. Thus, inflammasome activation is a major regulatory inflammatory cascade.

[0005] NLRP3 is the best characterized inflammasome and has been shown to be important for innate immunity and inflammatory responses. While some other NLR complexes, such as NLRC4, are activated under very specific circumstances, NLRP3 can be activated by many stimuli and should be considered as a sensor of homeostatic imbalance within the cell. Its precise function is therefore essential. In addition to playing a role in host immune defense, dysregulation of NLRP3 has been linked to the pathogenesis of many inflammatory disorders. These include inherited diseases such as cryopyrin-associated periodic syndromes (CAPS), which are caused by gain-of-function mutations in the NLRP3 gene, as well as many common neurological and systemic diseases. Importantly, hyperactivation of NLRP3 has been preclinically demonstrated to play a key role in many inflammatory and degenerative diseases, including NASH, atherosclerosis and other cardiovascular diseases, Alzheimer's disease, Parkinson's disease, diabetes, gout, and many other autoinflammatory diseases. Thus, there is an unmet need in the art to develop small molecules to modulate NLRP3 activity to treat various diseases and disorders. Summary of the Invention

[0006] In one aspect, the present disclosure relates to, inter alia, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein: A is a 5-8 membered monocyclic heterocycloalkyl, wherein said 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 form a 3- or 4-membered carbocyclic 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)(C C 1-C6 alkyl); and p is 0 or 1; wherein each instance of alkyl, alk-, or carbocyclic is independently substituted with 0, 1, 2, or 3 halogen atoms; and R 3 If is Cl, then [ka] teeth, [ka] isn't it.

[0007] In some embodiments, the compound of formula (I) is [ka] isn't it.

[0008] In some embodiments, the compound has a Kpu,u of greater than 0.3.

[0009] In another aspect, the present disclosure provides, inter alia, suitable compounds selected from Tables 1 or 2, and pharma- ceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, or tautomers thereof.

[0010] In another aspect, the present disclosure relates to a compound, particularly a compound selected from the following: (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; and (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol and pharma- ceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, or tautomers thereof.

[0011] 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 pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent or carrier.

[0012] 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 pharma- ceutically acceptable salt thereof and a pharma-ceutically acceptable diluent or carrier.

[0013] Another aspect of the present disclosure relates to a pharmaceutical composition comprising (R)-5-chloro-2-(4-((3,3-dimethyltetrahydrofuran-3H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent or carrier.

[0014] Another aspect of the present disclosure relates to a pharmaceutical composition comprising (S)-5-chloro-2-(4-((4,4-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent or carrier.

[0015] 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-methoxyphenol, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent or carrier.

[0016] 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 pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable diluent or carrier.

[0017] In some aspects, the disclosure provides compounds obtainable by or obtained by a method of preparing a compound described herein (e.g., a method comprising one or more steps described in Schemes 1 and 2).

[0018] In some aspects, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent or carrier.

[0019] In some aspects, the disclosure provides an intermediate described herein that is suitable for use in the method of preparing a compound described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-11).

[0020] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder 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 pharma- ceutical acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0021] In some aspects, the present disclosure provides a method of treating a disease or disorder 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 pharma- ceutical acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0022] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[0023] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease or disorder disclosed herein.

[0024] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0025] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0026] In some embodiments, the present disclosure provides a method for treating or preventing an NLRP3-related disease or disorder selected from Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache / pain, and traumatic brain injury, comprising administering to a subject a therapeutically effective amount of at least one of the compounds disclosed herein.

[0027] In some embodiments, the disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychiatric disease, graft-versus-host disease, allodynia, or an NLRP3-associated disease (in a subject identified as carrying a germline or somatic non-silent mutation in NLRP3).

[0028] In some embodiments, the disease or disorder of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0029] In some embodiments, the renal disease is an acute renal disease, a chronic renal disease, or a rare renal disease.

[0030] In some embodiments, the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0031] In some embodiments, the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0032] In some embodiments, the NLRP3-associated disease in a subject identified as carrying a germline or somatic non-silent mutation in NLRP3 is cryopyrin-associated autoinflammatory syndrome.

[0033] In some embodiments, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease.

[0034] In some aspects, the disclosure provides methods of preparing the disclosed compounds.

[0035] In some aspects, the disclosure provides methods for preparing compounds comprising one or more of the steps described herein.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification, the singular form includes the plural form unless the context clearly indicates otherwise. In carrying out or testing this disclosure, methods and materials similar or equivalent to those described herein can be used, but suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted as prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure will control.

[0037] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] The present disclosure relates to phthalazine derivatives, their pharma- ceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers (e.g., single stereoisomers, mixtures of stereoisomers, or racemic mixtures of stereoisomers), tautomers, prodrugs, and isotopically labeled compounds that 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 advantages in terms of brain penetration. The present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions containing them, and to their use in treating disorders involving NLRP3, such as inflammation, autoimmune diseases, cancer, infectious diseases, diseases or disorders of the central nervous system, metabolic diseases, cardiovascular diseases, respiratory diseases, renal diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, psychiatric diseases, graft-versus-host disease, allodynia, or NLRP3-associated diseases (in subjects identified as carrying germline or somatic non-silent mutations in NLRP3).

[0039] definition Unless otherwise defined, the following terms used in the specification and claims have the meanings set forth below.

[0040] 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 include, but are not limited to, moieties having 1-6 carbon atoms, such as methyl, ethyl, n-propyl, I-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in other embodiments, a straight chain or branched alkyl has 4 or fewer carbon atoms.

[0041] An alkyl group can also be an "optionally substituted alkyl," which refers to an unsubstituted alkyl or an alkyl having 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, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, 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, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0042] Other optionally substituted moieties (such as optionally substituted carbocyclic or heterocycloalkyl) include both unsubstituted moieties and moieties with 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.

[0043] As used herein, the term "alkenyl" includes unsubstituted aliphatic groups of similar length and possible substitution to the alkyls described above, but containing at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, a straight or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkenyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3 to 6 carbon atoms.

[0044] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having 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, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, 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, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0045] As used herein, the term "alkynyl" includes unsubstituted aliphatic groups of similar length and possible substitution to the alkyls described above, but containing at least one triple bond. For example, "alkynyl" includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, a "C2-C6 alkenylene linker" or a "C2-C6 alkynylene linker" is intended to include a C2, C3, C4, C5, or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0046] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having 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, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, 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, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0047] 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 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.

[0048] As used herein, the term "cyano" refers to a nitrile radical (eg, --CN).

[0049] As used herein, the term "cycloalkyl" or "carbocyclic" or "carbocyclyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro) system having 3 to 30 carbon atoms (e.g., C3-C 12 , C3-C 10 , or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.

[0050] 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 (e.g., O, N, S, P, or Se), for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 ring heteroatoms, or for example, 1, 2, 3, 4, 5, or 6 ring heteroatoms (independently selected from the group consisting of nitrogen, oxygen, and sulfur, unless otherwise specified).Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, and 1,4-diazepanyl. , 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 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]hexanyl, 3-azabicyclo[3.1.0]hexan-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]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanylmethyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and the like.In the case of polycyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl need be non-aromatic (eg, 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0051] As used herein, the term "optionally substituted heterocycloalkyl" refers to an unsubstituted heterocycloalkyl having 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, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, 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, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0052] As used herein, the term "hydroxy" or "hydroxyl" refers to -OH or -O - The formula includes groups having the formula:

[0053] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0054] The terms "haloalkyl" or "haloalkoxyl" refer to the alkyl or alk-portion of an alkoxyl that is substituted with one or more halogen atoms.

[0055] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, 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, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0056] Unless otherwise specifically stated, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group may be attached at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be optionally substituted at any point of attachment with one or more substituents (e.g., 1 to 5 substituents). 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 may themselves be optionally substituted. Additionally, when containing two or more fused rings, aryl groups as defined herein may have a saturated or partially unsaturated ring fused to a fully unaromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, 10,11-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like.

[0057] Unless otherwise specified, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being C. Heteroaryl, as defined herein, also means a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, S, P, Se, or B. Salerheteroaryl, 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 radicals are optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, thiazole ... riazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, Indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quina Zolinyl, tetrazolo[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]triazolyl pyrazolo[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 derivatives thereof. Additionally, when containing two or more fused rings, heteroaryl groups as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring, e.g., a 5-membered heteroaromatic ring containing 1-3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic heterocycle containing 1-3 nitrogens, where the saturated or partially unsaturated ring contains 0-4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo. In heteroaryl ring systems containing two or more 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, dihydrobenzofuran, 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-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]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, 7-oxabicyclo[2.2.1]heptanyl, or benzo[c][1,2]oxaborol-1-(3H)-olyl.

[0058] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may have at one or more ring positions (e.g., a ring-forming carbon or a heteroatom such as N) a substituent as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, aryloxy ... The aryl and heteroaryl groups may be substituted with aryl, alkyl, aryl, aryl, arylcarbonyl, arylthio, arylcarbonyl, arylsulfonyl, arylthio, arylthio, arylthio, arylsulfonyl ...

[0059] As used herein, "one or more of A, B, or C," "one or more of A, B, or C," "one or more of A, B, and C," "one or more of 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 selection 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, unless otherwise indicated.

[0060] If a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When substituents are listed without indicating the atom at which such substituent is bonded to the remainder of the compound of a given formula, then such substituent may be bonded through any atom in such formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0061] When any variable (e.g., R) occurs more than once 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 to be substituted with 0-2 R moieties, that group may be optionally substituted with up to 2 R moieties, and R is independently selected from the definitions of R at each occurrence. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0062] It should be understood that the present disclosure provides methods for synthesizing any of the compounds of the formulae described herein. The present disclosure also provides detailed methods for synthesizing the various disclosed compounds of the present disclosure according to the schemes set forth below and in the Examples.

[0063] It should be understood that throughout this specification, when a composition is described as having, including, or comprising certain components, it is contemplated that the composition also consists essentially of or consists of the recited components. Similarly, when a method or process is described as having, including, or comprising certain process steps, the process also consists essentially of or consists of the recited processing steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0064] It will be understood that the synthetic processes of the present disclosure can tolerate a wide variety of functional groups, and thus variously substituted starting materials can be used. Although these processes generally provide the desired final compound at or near the end of the overall process, in certain cases it may be desirable to further convert the compound to its pharma-ceutically acceptable salt.

[0065] It will be understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, using standard synthetic methods and procedures that are known to, or will be apparent to, those skilled in the art in light of the teachings herein. 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. Without being limited to any one or more sources, 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 of organic synthesis known to those of skill in the art.

[0066] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protective groups, may be changed during the reaction procedures and synthetic schemes described herein. Those skilled in the art will recognize that it may be necessary to protect certain groups from reaction conditions by using protective groups. Protective groups may also be used to distinguish similar functional groups in a molecule. A list of protective groups and how to introduce and remove these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

[0067] It is to be understood that any description of a method of treatment or prevention includes the use of a compound to provide treatment or prevention as described herein, unless otherwise stated. It is further to be 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 condition, unless otherwise stated. Treatment or prevention includes treatment or prevention of humans or non-human animals, including rodents and other disease models.

[0068] It is to be understood that any description of a method of treatment includes the use of a compound to provide a treatment as described herein, unless otherwise stated. It is further to be understood that any description of a method of treatment includes the use of a compound to prepare a medicament for treating such a condition, unless otherwise stated. Treatment includes treatment of humans or non-human animals, such as rodents and other disease models. As used herein, the term "subject" is interchangeable with the term "subject in need thereof," both of which refer to a subject having a disease or at high risk of developing a disease. "Subject" includes mammals. A 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 thereof may be a subject that has previously been diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof may also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof may be a subject at high risk of developing such a disease or disorder compared to the population as a whole (i.e., a subject who is more susceptible to developing such a disorder compared to the population as a whole). A subject in need thereof may have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that is not responding or has not yet responded to treatment). A subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, a subject in need thereof has undergone and failed all known effective treatments for a disease or disorder disclosed herein. In some embodiments, a subject in need thereof has undergone at least one prior therapy.

[0069] As used herein, the term "treating" or "treat" refers to the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharma- ceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" may also include the treatment of an in vitro cell or animal model. It is to be understood that references to "treating" or "treatment" include the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a stage, disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the stage, disorder or condition in a human who may be affected by or is susceptible to the stage, disorder or condition, but who has not yet experienced or exhibited clinical or sub-clinical symptoms of the stage, disorder or condition; (2) inhibiting the stage, disorder or condition, i.e., arresting, alleviating or delaying (in the case of conservative treatment) the onset of the disease or its recurrence, or at least one clinical or sub-clinical symptom thereof; or (3) alleviating or attenuating the disease, i.e., regressing the stage, disorder or condition, or at least one clinical or sub-clinical symptom thereof.

[0070] It is to be understood that the compounds of the present disclosure, or pharma- ceutically acceptable salts, polymorphs, or solvates thereof, may be used to prevent the associated disease, condition, or disorder, and may also be used to identify suitable candidates for such purposes.

[0071] As used herein, the terms "preventing," "prevent," or "protecting against" refer to reducing or eliminating the onset of symptoms or complications of such a disease, condition, or disorder.

[0072] It should be understood that those skilled in the art may refer to general references for detailed descriptions of known 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 referred to when making or using certain aspects of the present disclosure.

[0073] It should be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharma- ceutically acceptable excipient or carrier.

[0074] As used herein, the term "pharmaceutical composition" refers to a formulation that contains the disclosed compound in a form 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 of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump of an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose of the composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will understand that it is sometimes necessary to make routine modifications to the dosage depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrathoracic, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of this 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 pharma- ceutically acceptable carrier, and with any preservatives or buffers or propellants which may be required.

[0075] As used herein, the term "pharmacologically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio.

[0076] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that is generally safe, non-toxic, and not biologically or otherwise harmful, useful in the preparation of a pharmaceutical composition, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "a pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0077] It is understood that the pharmaceutical composition of the present disclosure is formulated to suit its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; 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 osmolality such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0078] It should be understood that the compound or pharmaceutical composition of the present disclosure can be administered to a subject by many of the well-known methods currently used for chemotherapy treatment.For example, the compound of the present disclosure can be injected into the bloodstream or body cavity, taken orally, or applied to the skin using a patch.The dose selected should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects.The stage of the disease (e.g., disease or disorder disclosed herein) and the health condition of the patient should preferably be closely observed during and for a reasonable period after treatment.

[0079] The term "therapeutically effective amount" as used herein refers to an amount of an agent that treats, ameliorates, or prevents a confirmed disease or condition, or that exhibits a detectable therapeutic or suppressive effect. This effect can be detected by any assay method 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 condition; 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 that is within the skill and judgment of the clinician.

[0080] It should be understood that for any compound, the therapeutically effective dose can be estimated initially, for example, in cell culture assays of neoplastic cells, or in animal models, usually 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 in humans. Therapeutic / prophylactic efficacy and toxicity, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 The dose that is lethal to 50% of the population (LD) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are desirable. Dosages can vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0081] Dosage and administration are adjusted to obtain sufficient levels of active agent(s) or to maintain the desired effect. Factors that may be taken into account include the severity of the disease stage, the overall health of the subject, the subject's age, weight, and sex, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to treatment.

[0082] The pharmaceutical composition comprising the active compound of the present disclosure can be prepared in a generally known manner, for example, by conventional mixing, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, encapsulating or lyophilizing process.The pharmaceutical composition can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, which facilitate the processing of active compound into pharmaceutically usable preparations.Of course, suitable formulation depends on the selected route of administration.

[0083] 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® (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, such as sugars, polyalcohols, such as mannitol and sorbitol, and / or sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

[0084] Sterile injectable solution can be prepared by incorporating the required amount of active compound into suitable solvent with one or combination of the above-listed components as required, followed by filtration sterilization.Generally, dispersion is prepared by incorporating active compound into sterile vehicle that contains basic dispersion medium and other components required from above-listed.For the preparation of sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which obtains the powder of active ingredient plus any additional desired components from its solution that has been previously sterile-filtered.

[0085] Oral compositions generally contain an inert diluent or an edible pharma- ceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be formulated with an excipient and used in the form of tablets, lozenges, or capsules. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the fluid carrier is orally applied, swished in the mouth, and expectorated or swallowed. Pharmacologically compatible binding agents and / or adjuvant materials may be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, primogel, or corn starch; a lubricant such as magnesium stearate or Stellite; a flow agent such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0086] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0087] Systemic administration may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams, as generally known in the art.

[0088] The active compound can be prepared with a pharma- ceutically acceptable carrier that protects the body from rapid release of the compound, such as sustained release formulations, 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. Methods for preparing such formulations will be apparent to those skilled in the art. Materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions, including liposomes targeted to infected cells with monoclonal antibodies against viral antigens, can also be used as pharma- ceutically acceptable carriers. These can be prepared by methods known to those skilled in the art, for example, as taught in U.S. Pat. No. 4,522,811.

[0089] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions in dosage unit form.The term "unitary dosage form" used herein refers to a physically separate unit suitable as a unitary dosage for treating a subject, each unit containing a predetermined amount of active compound calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The specification of dosage unit form of the present disclosure is required and directly depends on the characteristics inherent to active compound and the specific therapeutic effect to be achieved.

[0090] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors that influence the selected dosage. In general, the dosage should be sufficient to slow, preferably regress, and preferably cause complete regression of the symptoms of the disease or disorder disclosed herein. Dosages may range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective amount of an agent is an amount that produces an objectively identifiable improvement as noted by a clinician or other qualified observer. Improved survival and proliferation are indicative of regression. As used herein, the term "dosage-effective method" refers to an amount of an active compound that produces a desired biological effect in a subject or cell.

[0091] It should be understood that the pharmaceutical compositions may be included in a container, pack, or dispenser together with instructions for administration.

[0092] For compounds of the present disclosure that are further capable of forming salts, it is to be understood that all of these forms are also contemplated within the scope of the claimed disclosure.

[0093] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure, where the parent compound is modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonate, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolarsanoic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, benzo ... Examples of suitable acids include salts derived from inorganic and organic acids selected from the following acids: carboxylic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic 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, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0094] In some embodiments, the pharma- ceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0095] Other examples of pharma- ceutically 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, tertiary butylacetic acid, muconic acid, etc. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., either an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that in the salt form, the ratio of compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0096] It should be understood that all references to pharma- ceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs), as defined herein, of the same salt.

[0097] The compound, or a pharma- ceutical acceptable salt thereof, is administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrathoracically, 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.

[0098] The dosage regimen utilizing the compound is selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition being treated; the route of administration; the renal and hepatic function of the patient; and the specific compound or salt thereof being used.A physician or veterinarian of ordinary skill can easily determine and prescribe the effective amount of the drug required to prevent, counter or stop the progression of the condition.A physician or veterinarian of ordinary skill can easily determine and prescribe the effective amount of the drug required to counter or stop the progression of the condition.

[0099] Techniques for formulation and administration of 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 one embodiment, the compounds described herein, and their pharmaceutically acceptable salts, are used in pharmaceutical preparations in combination with pharmaceutically acceptable carriers or diluents. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound is present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0100] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure will become apparent from the different examples. The examples provided show different components and methodologies useful for implementing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, a person skilled in the art can identify and employ other components and methodologies useful for implementing the present disclosure.

[0101] In the synthesis schemes described herein, compounds may be drawn in one specific configuration for simplicity. Such specific configurations should not be interpreted as limiting the present disclosure to one or another isomer, tautomer, positional isomer or stereoisomer, and do not exclude mixtures of isomers, tautomers, positional isomers or stereoisomers. However, it is understood that a given isomer, tautomer, positional isomer or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer or stereoisomer.

[0102] All publications and patent documents mentioned in this specification are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission of the relevant prior art, nor does it constitute any admission as to their contents or date. Although the invention has been described by way of written description, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are intended to be illustrative and not limiting of the scope of the claims that follow.

[0103] As used herein, the phrase "compounds of the present disclosure" refers generally and specifically to the compounds disclosed herein.

[0104] Compounds of the Disclosure In one aspect, the present disclosure relates to, inter alia, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein: A is a 5-8 membered monocyclic heterocycloalkyl, wherein said heterocycloalkyl contains at least one O ring atom; R 1is 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 form a 3- or 4-membered carbocyclic 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, alk-, or carbocyclic is independently substituted with 0, 1, 2, or 3 halogen atoms; and R 3 If is Cl, then [ka] teeth, [ka] isn't it.

[0105] In some embodiments, the compound of formula (I) is [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0106] In some embodiments, the compound is a compound of formula (I), where p is 1; R 1 is C1-C6 alkyl or C1-C6 alkoxy; and R 2 is C1-C6 alkyl.

[0107] In some embodiments, A is a 5-8 membered monocyclic heterocycloalkyl where the heterocycloalkyl contains at least one O ring atom. In some embodiments, A is a 5-8 membered monocyclic heterocycloalkyl where the heterocycloalkyl contains one O ring atom.

[0108] In some embodiments, A is a 5-membered monocyclic heterocycloalkyl, where the heterocycloalkyl contains at least one O ring atom. In some embodiments, A is a 5-membered monocyclic heterocycloalkyl, where the heterocycloalkyl contains one O ring atom.

[0109] In some embodiments, A is a 6-membered monocyclic heterocycloalkyl, where the heterocycloalkyl contains at least one O ring atom. In some embodiments, A is a 6-membered monocyclic heterocycloalkyl, where the heterocycloalkyl contains one O ring atom.

[0110] In some embodiments, A is a 7-membered monocyclic heterocycloalkyl, where the heterocycloalkyl contains at least one O ring atom. In some embodiments, A is a 7-membered monocyclic heterocycloalkyl, where the heterocycloalkyl contains one O ring atom.

[0111] In some embodiments, A is an 8-membered monocyclic heterocycloalkyl, where the heterocycloalkyl contains at least one O ring atom. In some embodiments, A is an 8-membered monocyclic heterocycloalkyl, where the heterocycloalkyl contains one O ring atom.

[0112] In some embodiments, p is 0 or 1.

[0113] In some embodiments, p is 0. In some embodiments, p is 1.

[0114] In some embodiments, R 1 is halogen, C1-C6 alkyl, or C1-C6 alkoxy, where the alkyl or alkoxy is independently substituted with 0, 1, 2, or 3 halogen atoms.

[0115] In some embodiments, R 1 is halogen, C1-C6 alkyl, or C1-C6 alkoxy, where the alkyl or alkoxy is substituted with 1, 2, or 3 halogen atoms.

[0116] In some embodiments, R 1 is halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0117] In some embodiments, R 1 is a halogen.

[0118] In some embodiments, R 1 is F, Cl, Br, or I.

[0119] 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 is I.

[0120] In some embodiments, R 1 is a C1-C6 alkyl substituted with 0, 1, 2, or 3 halogens.

[0121] In some embodiments, R 1 is a C1-C6 alkyl substituted with 1, 2, or 3 halogens.

[0122] In some embodiments, R 1 is C1-C6 alkyl.

[0123] In some embodiments, R 1 is methyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is ethyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is propyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is butyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, each R 1 is isopropyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is isobutyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is isopentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is isohexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is sec-butyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is sec pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is sec hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is tertbutyl substituted with 0, 1, 2, or 3 halogens.

[0124] In some embodiments, R 1is methyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is ethyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is propyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is butyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is pentyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is hexyl substituted with 1, 2, or 3 halogens. In some embodiments, each R 1 is isopropyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is isobutyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is isopentyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is isohexyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is sec-butyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is sec pentyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is sec hexyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is tert-butyl substituted with one, two, or three halogens.

[0125] In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is propyl. In some embodiments, R 1 is butyl. In some embodiments, R1 is pentyl. In some embodiments, R 1 is hexyl. In some embodiments, each R 1 is isopropyl. In some embodiments, R 1 is isobutyl. In some embodiments, R 1 is isopentyl. In some embodiments, R 1 is isohexyl. In some embodiments, R 1 is sec butyl. In some embodiments, R 1 is sec pentyl. In some embodiments, R 1 is sec hexyl. In some embodiments, R 1 is tert butyl.

[0126] In some embodiments, R 1 is a C1-C6 alkoxy substituted with 0, 1, 2, or 3 halogens.

[0127] In some embodiments, R 1 is a C1-C6 alkoxy substituted with 1, 2, or 3 halogens.

[0128] In some embodiments, R 1 is C1-C6 alkoxy.

[0129] In some embodiments, R 1 is a C alkoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is a C alkoxy substituted with 0, 1, 2, or 3 halogens. 1 is a C alkoxy substituted with 0, 1, 2, or 3 halogens. 1 is a C alkoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1is a C5 alkoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 1 is a C6 alkoxy substituted with 0, 1, 2, or 3 halogens.

[0130] In some embodiments, R 1 is a C alkoxy substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is a C alkoxy substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is a C alkoxy substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is a C alkoxy substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is a C5 alkoxy substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is a C6 alkoxy substituted with 1, 2, or 3 halogens.

[0131] In some embodiments, R 1 is C alkoxy. In some embodiments, R 1 is C alkoxy. In some embodiments, R 1 is C alkoxy. In some embodiments, R 1 is C4 alkoxy. In some embodiments, R 1 is C5 alkoxy. In some embodiments, R 1 is a C6 alkoxy.

[0132] In some embodiments, R 2 is halogen or C1-C6 alkyl substituted with 0, 1, 2, or 3 halogens.

[0133] In some embodiments, R 2is halogen or C1-C6 alkyl substituted with 1, 2, or 3 halogens.

[0134] In some embodiments, R 2 is halogen or C1-C6 alkyl.

[0135] In some embodiments, R 2 is a halogen.

[0136] In some embodiments, R 2 is F, Cl, Br, or I.

[0137] In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In embodiments, R 2 is Br. In some embodiments, R 2 is I.

[0138] In some embodiments, R 2 is a C1-C6 alkyl substituted with 0, 1, 2, or 3 halogens.

[0139] In some embodiments, R 2 is a C1-C6 alkyl substituted with 1, 2, or 3 halogens.

[0140] In some embodiments, R 2 is C1-C6 alkyl.

[0141] In some embodiments, R 2 is methyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is ethyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is propyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2is butyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is isopropyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is isobutyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is isopentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is isohexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is sec-butyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is sec pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is sec hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is tertbutyl substituted with 0, 1, 2, or 3 halogens.

[0142] In some embodiments, R 2 is methyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is ethyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is propyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is butyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is pentyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2is hexyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is isopropyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is isobutyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is isopentyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is isohexyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is sec-butyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is sec pentyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is sec hexyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is tert-butyl substituted with one, two, or three halogens.

[0143] In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is hexyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is isobutyl. In some embodiments, R 2 is isopentyl. In some embodiments, R 2 is isohexyl. In some embodiments, R 2 is sec butyl. In some embodiments, R 2is sec pentyl. In some embodiments, R 2 is sec hexyl. In some embodiments, R 2 is tert butyl.

[0144] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a 3- or 4-membered carbocyclic ring that is substituted with 0, 1, 2, or 3 halogen atoms.

[0145] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a 3- or 4-membered carbocyclic ring that is substituted with 1, 2, or 3 halogen atoms.

[0146] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a three- or four-membered carbocyclic ring.

[0147] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a 3-membered carbocyclic ring that is substituted with 0, 1, 2, or 3 halogen atoms.

[0148] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a three-membered carbocyclic ring that is substituted with one, two, or three halogen atoms.

[0149] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a three-membered carbon ring.

[0150] In some embodiments, R 1 and R 2together with the atoms to which they are attached form a 4-membered carbocyclic ring that is substituted with 0, 1, 2, or 3 halogen atoms.

[0151] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a four-membered carbocyclic ring that is substituted with one, two, or three halogen atoms.

[0152] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a four-membered carbon ring.

[0153] 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 R is independently C-C alkyl or C-C haloalkyl, 1 and R 2 are attached to the same carbon atom on ring A.

[0154] In some embodiments, p is 1 and R 1 and R 2 In some embodiments, p is 1 and R 1 and R 2 is methyl, where R 1 and R 2 are attached to the same carbon atom on ring A.

[0155] In some embodiments, R 3 is -OH, halogen, C1-C6 alkyl, or C1-C6 alkoxy, wherein the alkyl or alkoxy is independently substituted with 0, 1, 2, or 3 halogen.

[0156] In some embodiments, R3 is -OH, halogen, C1-C6 alkyl, or C1-C6 alkoxy, where the alkyl or alkoxy is substituted with 1, 2, or 3 halogens.

[0157] In some embodiments, R 3 is -OH, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0158] In some embodiments, R 3 is -OH.

[0159] In some embodiments, R 3 is a halogen.

[0160] 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 is I.

[0161] In some embodiments, R 3 is not a halogen.

[0162] In some embodiments, R 3 is C1-C6 alkyl, or C1-C6 alkoxy.

[0163] In some embodiments, R 3 is a C1-C6 alkyl substituted with 0, 1, 2, or 3 halogens.

[0164] In some embodiments, R 3 is a C1-C6 alkyl substituted with 1, 2, or 3 halogens.

[0165] In some embodiments, R 3 is C1-C6 alkyl.

[0166] In some embodiments, R 3 is methyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is ethyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is propyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is butyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is isopropyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is isobutyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 2 is independently isopentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is isohexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is sec-butyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is sec pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is sec hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is tertbutyl substituted with 0, 1, 2, or 3 halogens.

[0167] In some embodiments, R 3 is methyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3is ethyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is propyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is butyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is pentyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is hexyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is isopropyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is isobutyl substituted with 1, 2, or 3 halogens. In some embodiments, R 2 is independently isopentyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is isohexyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is sec-butyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is sec pentyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is sec hexyl substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is tert-butyl substituted with one, two, or three halogens.

[0168] In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is pentyl. In some embodiments, R 3is hexyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is isobutyl. In some embodiments, R 2 is independently isopentyl. In some embodiments, R 3 is isohexyl. In some embodiments, R 3 is sec butyl. In some embodiments, R 3 is sec pentyl. In some embodiments, R 3 is sec hexyl. In some embodiments, R 3 is tert butyl.

[0169] In some embodiments, R 3 is a C1-C6 alkoxy substituted with 0, 1, 2, or 3 halogens.

[0170] In some embodiments, R 3 is a C1-C6 alkoxy substituted with 1, 2, or 3 halogens.

[0171] In some embodiments, R 3 is C1-C6 alkoxy.

[0172] In some embodiments, R 3 is methoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is ethoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is propoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is butoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3 is pentoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, R 3is hexoxy substituted with 0, 1, 2, or 3 halogens.

[0173] In some embodiments, R 3 is methoxy substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is ethoxy substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is propoxy substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is butoxy substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is pentoxy substituted with 1, 2, or 3 halogens. In some embodiments, R 3 is hexoxy substituted with 1, 2, or 3 halogens.

[0174] In some embodiments, R 3 is methoxy. In some embodiments, R 3 is ethoxy. In some embodiments, R 3 is propoxy. In some embodiments, R 3 is butoxy. In some embodiments, R 3 is pentoxy. In some embodiments, R 3 is hexoxy.

[0175] In some embodiments, R 3 is Cl, methyl, -CF3, -CHF2, or -OCHF2.

[0176] In some embodiments, R 3 is -CF3, -CHF2, or -OCHF2.

[0177] In some embodiments, R 3 is -CF3. In some embodiments, R 3 is -CHF2. In some embodiments, R3 is -OCHF2.

[0178] In some embodiments, X is H, -OH, halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl.

[0179] In some embodiments, X is H, -OH, halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl.

[0180] In some embodiments, X is H.

[0181] In some embodiments, X is a halogen.

[0182] In some embodiments, X is Br, Cl, F, or I.

[0183] In some embodiments, X is Br. In some embodiments, X is Cl. In some embodiments, X is F. In some embodiments, X is I.

[0184] In some embodiments, X is -OH.

[0185] In some embodiments, X is -NH. In some embodiments, X is -NH(C1-C6 alkyl).

[0186] 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).

[0187] In some embodiments, X is -N(C1-C6 alkyl).

[0188] In some embodiments, X is -N(C1 alkyl). In some embodiments, X is -N(C2 alkyl). In some embodiments, X is -N(C3 alkyl). In some embodiments, X is -N(C4 alkyl). In some embodiments, X is -N(C5 alkyl). In some embodiments, X is -N(C6 alkyl).

[0189] In some embodiments, X is C1-C6 alkyl.

[0190] 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 one embodiment, X is tert-butyl.

[0191] In some embodiments, X is H or F.

[0192] In some embodiments, R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -C(O)(C1-C6 alkyl).

[0193] In some embodiments, R 4 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -C(O)(C1-C6 alkyl).

[0194] In some embodiments, R 4 is H.

[0195] In some embodiments, R 4 is C1-C6 alkyl.

[0196] In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. In some embodiments, R 4 is butyl. In some embodiments, R 4 is pentyl. In some embodiments, R 4 is hexyl. In some embodiments, each R 4 is isopropyl. In some embodiments, R 4 is isobutyl. In some embodiments, R 4 is isopentyl. In some embodiments, R 4 is isohexyl. In some embodiments, R 4 is sec butyl. In some embodiments, R 4 is sec pentyl. In some embodiments, R 4 is sec hexyl. In some embodiments, R 4 is tert butyl.

[0197] In some embodiments, R 4 is -C(O)(C1-C6 alkyl).

[0198] In some embodiments, R 4 is -C(O)(C alkyl). In some embodiments, R 4 is -C(O)(C alkyl). In some embodiments, R 4 is -C(O)(C alkyl). In some embodiments, R 4is -C(O)(C4 alkyl). In some embodiments, R 4 is -C(O)(C alkyl). In some embodiments, R 4 is -C(O)(C alkyl).

[0199] In some embodiments, each instance of alkyl, alk-, or carbocyclic is independently substituted with 0, 1, 2, or 3 halogen atoms.

[0200] In some embodiments, each instance of alkyl is substituted with 0, 1, 2, or 3 halogen atoms.

[0201] In some embodiments, each instance of alk- is substituted with 0, 1, 2, or 3 halogen atoms.

[0202] In some embodiments, each instance of the carbocyclic ring is substituted with 0, 1, 2, or 3 halogen atoms.

[0203] In certain embodiments, the phenyl ring system of formula (a): [ka] is the expression: [ka] is a phenyl ring system of wherein X is halogen or C1-C6 alkyl, e.g., -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.

[0204] In certain embodiments, an amine ring system of formula (b) is [ka] is the expression: [ka] is an amine ring system of the formula:

[0205] In certain embodiments, an amine ring system of the formula: [ka] is the expression: [ka] is an amine ring system of the formula:

[0206] In some embodiments, the compound of formula (I) is a compound of formula (Ia) or (Ib): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the phenyl ring system of formula (a) is a phenyl ring system of formula (a-1), (a-2), or (a-3), where X is hydrogen, halogen, or C1-C6 alkyl, e.g., -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, for example, -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, e.g., -CHF2, -CF3, or -CH3. In certain embodiments, the amine ring system of formula (b) is an amine ring system of formula (b-1). In certain embodiments, R 1 is -CH3 and R 2 is -CH3.

[0207] In some embodiments, the compound of Formula (I) has formula (II-a), (II-b), or (II-c): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, X is halogen or C1-C6 alkyl, e.g., -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, for example, -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, e.g., -CHF2, -CF3, or -CH3. In certain embodiments, the amine ring system of formula (b) is an amine ring system of formula (b-1). In certain embodiments, R 1 is -CH3 and R 2 is -CH3.

[0208] In some embodiments, the compound of Formula (I) has formula (II-d), (II-e), or (II-f): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, X is halogen or C1-C6 alkyl, e.g., -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, for example, -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, e.g., -CHF2, -CF3, or -CH3. In certain embodiments, the amine ring system of formula (b) is an amine ring system of formula (b-1). In certain embodiments, R 1 is -CH3 and R 2 is -CH3.

[0209] In some embodiments, the compound of Formula (I) has formula (III-a), (III-b), or (III-c): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof (wherein m is an integer of 0 to 2, and n is an integer of 1 to 2).

[0210] In some embodiments of formula (III-a), (III-b), or (III-c), m is 0, 1, or 2.

[0211] In some embodiments of formula (III-a), (III-b), or (III-c), m is 1, or 2.

[0212] 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.

[0213] In some embodiments of formula (III-a), (III-b), or (III-c), n is 0, 1, or 2.

[0214] In some embodiments of formula (III-a), (III-b), or (III-c), n is 1, or 2.

[0215] 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.

[0216] In some embodiments of Formula (III-a), (III-b), or (III-c), when one of m and n is 0, then the other of m and n is 1 or 2.

[0217] In some embodiments of Formula (III-a), (III-b), or (III-c), when one of m and n is 0, then the other of m and n is 1.

[0218] In some embodiments of Formula (III-a), (III-b), or (III-c), when one of m and n is 0, then the other of m and n is 2.

[0219] In certain embodiments of formula (III-a), (III-b), or (III-c), the phenyl ring system of formula (a) is a phenyl ring system of formula (a-1), (a-2), or (a-3), where X is hydrogen, halogen, or C1-C6 alkyl, e.g., -H, -F, -Cl, or -CH3. 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, for example, -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3is C1-C6 alkyl, e.g., -CHF2, -CF3, or -CH3. In certain embodiments, R 1 is -CH3 and R 2 is -CH3.

[0220] In some embodiments, the compound of Formula (I) has formula (III-d), (III-e), or (III-f): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein m is an integer of 0 to 2, and n is an integer of 1 to 2.

[0221] In certain embodiments of formula (III-d), (III-e), or (III-f), the phenyl ring system of formula (a) is a phenyl ring system of formula (a-1), (a-2), or (a-3), where X is hydrogen, halogen, or C1-C6 alkyl, e.g., -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, for example, -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, e.g., -CHF2, -CF3, or -CH3. In certain embodiments, R 1 is -CH3 and R 2 is -CH3 (when p=1). In certain embodiments, R 1 is -CH3 and R 2 does not exist (if p=0).

[0222] In some embodiments, the compound of Formula (I) has formula (IV-a), (IV-b), or (IV-c): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the phenyl ring system of formula (a) is a phenyl ring system of formula (a-1), (a-2), or (a-3), where X is hydrogen, halogen, or C1-C6 alkyl, e.g., -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, for example, -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, e.g., -CHF2, -CF3, or -CH3. In certain embodiments, R 1 is -CH3 and R 2 is -CH3.

[0223] In some embodiments, the compound of Formula (I) has formula (IV-a1), (IV-b1), or (IV-c1): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the phenyl ring system of formula (a) is a phenyl ring system of formula (a-1), (a-2), or (a-3), where X is hydrogen, halogen, or C1-C6 alkyl, e.g., -H, -F, -Cl, or -CH3. In certain embodiments, R 4is 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, for example, -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, for example, -CHF2, -CF3, or -CH3.

[0224] In some embodiments, the compound of Formula (I) has Formula (Va), (Vb), or (Vc): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0225] In some embodiments, the compound of Formula (I) has formula (V-a'), (V-b'), or (V-c'): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the phenyl ring system of formula (a) is a phenyl ring system of formula (a-1), (a-2), or (a-3), where X is hydrogen, halogen, or C1-C6 alkyl, e.g., -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, for example, -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3is C1-C6 alkyl, e.g., -CHF2, -CF3, or -CH3. In certain embodiments, R 1 is -CH3 and R 2 is -CH3.

[0226] 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): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the phenyl ring system of formula (a) is a phenyl ring system of formula (a-1), (a-2), or (a-3), where X is hydrogen, halogen, or C1-C6 alkyl, e.g., -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, for example, -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, e.g., -CHF2, -CF3, or -CH3. In certain embodiments, R 1 is -CH3 and R 2 is -CH3.

[0227] 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): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the phenyl ring system of formula (a) is a phenyl ring system of formula (a-1), (a-2), or (a-3), where X is hydrogen, halogen, or C1-C6 alkyl, e.g., -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, for example, -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3 is C1-C6 alkyl, for example, -CHF2, -CF3, or -CH3.

[0228] In some embodiments, the compound is selected from a compound set forth in Table 1, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0229] In some embodiments, the compound is selected from a compound selected from the compounds set forth in Table 1, or a pharma- ceutically acceptable salt thereof.

[0230] In some embodiments, the compound is selected from the compounds set forth in Table 1, or a solvate thereof.

[0231] In some embodiments, the compound is selected from the compounds set forth in Table 1, or clathrate salts thereof.

[0232] In some embodiments, the compound is selected from the compounds set forth in Table 1, or a hydrate thereof.

[0233] In some embodiments, the compound is selected from the compounds set forth in Table 1, or a stereoisomer thereof.

[0234] In some embodiments, the compound is selected from the compounds set forth in Table 1, or a tautomer thereof.

[0235] In some embodiments, the compound is selected from the compounds set forth in Table 1, or an isotopically labeled compound thereof.

[0236] In some embodiments, the compound is selected from the compounds set forth in Table 1, or a prodrug thereof.

[0237] In some embodiments, the compound is selected from the compounds set forth in Table 1. Arbitrarily assigned stereochemistry is labeled with an asterisk (*). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

[0238] In some embodiments, the compound is a pharma- ceutically acceptable salt of a compound described in Table 1.

[0239] In some embodiments, the compound is a prodrug of a compound described in Table 1.

[0240] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, or a prodrug or pharma- ceutically acceptable salt thereof.

[0241] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, or a pharma- ceutically acceptable salt thereof.

[0242] In some embodiments, the compound is an isotopic derivative of a prodrug of any one of the compounds set forth in Table 1, or a pharma- ceutically acceptable salt thereof.

[0243] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1.

[0244] In some embodiments, the compound is selected from a compound set forth in Table 2, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0245] In some embodiments, the compound is selected from the compounds set forth in Table 2, or a pharma- ceutically acceptable salt thereof.

[0246] In some embodiments, the compound is selected from the compounds set forth in Table 2, or a solvate thereof.

[0247] In some embodiments, the compound is selected from the compounds set forth in Table 2, or clathrate salts thereof.

[0248] In some embodiments, the compound is selected from the compounds set forth in Table 2, or a hydrate thereof.

[0249] In some embodiments, the compound is selected from the compounds set forth in Table 2, or a stereoisomer thereof.

[0250] In some embodiments, the compound is selected from the compounds set forth in Table 2, or a tautomer thereof.

[0251] In some embodiments, the compound is selected from the compounds set forth in Table 2, or an isotopically labeled compound thereof.

[0252] In some embodiments, the compound is selected from the compounds set forth in Table 2, or a prodrug thereof.

[0253] In some embodiments, the compound is selected from the compounds set forth in Table 2. Arbitrarily assigned stereochemistry is represented by an asterisk (*). [Table 2-1] [Table 2-2]

[0254] In some embodiments, the compound is a pharma- ceutically acceptable salt of a compound described in Table 2.

[0255] In some embodiments, the compound is a prodrug of a compound described in Table 2.

[0256] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 2, or a prodrug or pharma- ceutically acceptable salt thereof.

[0257] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 2, or a pharma- ceutically acceptable salt thereof.

[0258] In some embodiments, the compound is an isotopic derivative of a prodrug of any one of the compounds set forth in Table 2, or a pharma- ceutically acceptable salt thereof.

[0259] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 2.

[0260] In some aspects, the disclosure provides compounds that are isotopic derivatives (e.g., isotopically labeled compounds) of any one of the compounds of the formulas disclosed herein.

[0261] In another aspect, the disclosure provides, inter alia, a compound selected from: (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; and (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0262] 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.

[0263] In some embodiments, the compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0264] In some embodiments, the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydrofuran-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0265] In some embodiments, the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydrofuran-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0266] In some embodiments, the compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol.

[0267] 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.

[0268] In some embodiments, the compound is a pharma- ceutically acceptable salt of any one of the compounds described herein.

[0269] In some aspects, the present disclosure provides compounds that are isotopic derivatives (also referred to herein as isotopically labeled compounds) of any one of the compounds of the formulas disclosed herein.

[0270] In some embodiments, the compound is an isotopic derivative of any one of the compounds described herein, as well as prodrugs and pharma- ceutically acceptable salts thereof.

[0271] In some embodiments, the compound is an isotopic derivative of any one of the compounds described herein, and pharma- ceutically acceptable salts thereof.

[0272] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds described herein, as well as pharma- ceutically acceptable salts thereof.

[0273] In some embodiments, the compound is an isotopic derivative of any one of the compounds described herein.

[0274] It will be appreciated that isotopic derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotopic derivatives can generally be prepared by following the procedures disclosed in the schemes and / or examples described herein by substitution of an isotopically labeled reagent for a non-isotopically labeled reagent.

[0275] In some embodiments, the isotopic derivatives are deuterium-labeled compounds.

[0276] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulas disclosed herein.

[0277] The term "isotopic derivative" as used herein 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 with one or more isotopes or labeled with one or more isotopes compared to the corresponding disclosed compound. In some embodiments, an isotopic derivative is 2 H, 13 C. 14 C. 15 N, 18 O. 29 Si, 31 P, and 34 In some embodiments, the isotopic derivatives are deuterium-labeled compounds (i.e., enriched or labeled with one or more atoms selected from S and / or S). 2 In some embodiments, the compound is 18 F labeled compound. In some embodiments, the compound is 123 I-labeled compound, 124 I-labeled compound, 125 I-labeled compound, 129 I-labeled compound, 131 I-labeled compound, 135 I-labeled compounds, or any combination thereof. In some embodiments, the compounds are 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 S-labeled compounds, or any combination thereof.

[0278] 18 F, 123 I, 124 I, 125 I,129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 It will be appreciated that S-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, deuterium-labeled compounds are generally prepared by: 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 They can be prepared by following the procedures disclosed in the schemes and / or examples described herein by replacing the non-isotopically labeled reagent with a 3S labeled reagent.

[0279] As mentioned above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and 36 Compounds of the present invention, or pharma- ceutically acceptable salts or solvates thereof, containing one or more S atom(s) are within the scope of the present invention. In addition, isotopes (e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 Substitution with S) may confer certain therapeutic advantages (e.g., increased half-life in vivo or reduced dosage requirements) resulting from greater metabolic stability.

[0280] For the avoidance of doubt, when a group is modified herein as "as described herein," it is to be understood that the group includes the broadest definition occurring first, as well as each and every specific definition of that group.

[0281] Suitable pharma- ceutically acceptable salts of the compounds of the present disclosure are, for example, sufficiently basic acid addition salts of the compounds of the present disclosure, such as inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid methanesulfonate, or maleic acid. In addition, suitable pharma- ceutically 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 pharma- ceutically acceptable cations, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0282] It will be understood that the compounds of any one of the formulas disclosed herein, and any pharma- ceutically acceptable salts thereof, include stereoisomers of said compounds, mixtures of stereoisomers, and polymorphs of all isomeric forms of said compounds.

[0283] In some embodiments, the compound of formula (I) is not: [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0284] As used herein, the term "isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonds of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are sometimes called "enantiomers" or optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0285] As used herein, the term "chiral center" refers to a carbon atom bonded to four nonidentical substituents.

[0286] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having two or more chiral centers may exist as individual diastereomers or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Cahn, Ingold, and Prelog sequencing rules. (Cahn et al.,Angew. 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0287] As used herein, the term "geometric isomers" refers to diastereomers that result from hindered rotation around 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, to indicate that the groups are on the same or opposite sides of a double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0288] It should be understood that the compounds of the present disclosure can be depicted as different chiral isomers or geometric isomers.When a compound has chiral isomers or geometric isomers, it should also be understood that all isomeric forms are intended to be included within the scope of the present disclosure, and the name of the compound does not exclude any isomeric form.It should be understood that all isomers do not have the same activity level.

[0289] It is to be understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof. It is also to be understood that not all non-atropic forms have the same level of activity.

[0290] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer sets in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs as a result of an aldehyde group (-CHO) in a sugar molecule reacting with one of the hydroxyl groups (-OH) in the same molecule to produce a cyclic (ring-shaped) form as shown in glucose.

[0291] It should be understood that the compounds of the present disclosure can be depicted as different tautomers.When a compound has tautomeric forms, it should also be understood that all tautomeric forms are intended to be included within the scope of the present disclosure, and the name of the compound does not exclude tautomeric forms.It should be understood that certain tautomers may have a higher level of activity than other tautomers.

[0292] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their 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, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are 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 are designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds may exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0293] The compounds of the present disclosure may have one or more asymmetric centers; therefore, such compounds may 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 both individual enantiomers and their racemic or otherwise mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemic forms (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomeric centers (E- and Z-isomers). It is to be understood that the present disclosure encompasses all optical, diastereomeric, and geometric isomers, and mixtures thereof, that have inflammasome inhibitory activity.

[0294] It should be understood that the compounds of any formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable.For example, salts can be formed between anions and positively charged groups (e.g., amino) on the substituted compounds disclosed herein.Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0295] 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 a cation on the substituted compounds disclosed herein and a negatively charged group (e.g., carboxylate).Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cations such as tetramethylammonium ion or diethylamine ion.Substituted compounds disclosed herein also include salts containing quaternary nitrogen atoms.

[0296] It should be understood that the compounds of the present disclosure, for example, salts of the compounds, can exist in either hydrated or non-hydrated (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.

[0297] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate; when the solvent is 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 in which the water retains its molecular state as H2O.

[0298] As used herein, the term "analog" refers to a compound that is structurally similar to another but differs slightly in composition (e.g., when one atom is replaced by an atom of a different element, or when a particular functional group is present, or by replacing one functional group with another). Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but not similar or equivalent in structure or origin.

[0299] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0300] It should also be understood that any one of the specific compounds of the formula disclosed herein can exist in solvated form as well as non-solvated form, such as hydrated form. Suitable pharma-ceutically acceptable solvates are, for example, hydrates such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that the present disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[0301] It should also be understood that any one of the specific compounds of the formula disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms, or mixtures thereof, that have inflammasome inhibitory activity.In general, crystalline materials can be analyzed using conventional techniques, such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy.The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0302] Compounds of any one of the formulas disclosed herein may exist in several different tautomeric forms, and all such forms are intended to be encompassed.For the avoidance of doubt, even if a compound may exist in one of several tautomeric forms, and only one is specifically described or shown, all others are encompassed by formula (I).Examples of tautomeric forms include keto forms, enol forms, and enol forms, such as in the following tautomeric pairs: keto / enol (exemplified below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. [ka]

[0303] The compounds of any one of the formulas disclosed herein may be administered in the form of prodrugs that are broken down 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 a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives that contain alkyl or acyl substituents that can be cleaved in vivo in the ester or amide group in any one of the formulas disclosed herein.

[0304] Thus, the present disclosure includes compounds of any one of the formulas disclosed herein as defined hereinbefore when made available by organic synthesis and when made available in the human or animal body by cleavage of its prodrug. Thus, the present disclosure includes compounds of any one of the formulas disclosed herein produced by organic synthesis means, and also such compounds produced in the human or animal body by metabolism of a precursor compound, which is a compound of any one of the formulas disclosed herein, and may be synthetically produced compounds or metabolically produced compounds.

[0305] Suitable pharma- ceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein are those prodrugs that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, 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 p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical 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, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987.

[0306] Suitable pharma- ceutically acceptable prodrugs of the compounds of any one of the formulas disclosed herein that have a hydroxy group are, for example, their esters or ethers that can be cleaved in vivo. The in vivo cleavable esters or ethers of the compounds of any one of the formulas disclosed herein that contain a hydroxy group are, for example, pharma-ceutically acceptable esters or ethers that cleave in the human or animal body to generate the parent hydroxy compound. Suitable pharma-ceutically acceptable ester-forming groups for hydroxy groups include inorganic esters, for example, phosphate esters (including phosphoroamide cyclic esters). Further suitable pharma-ceutically acceptable ester-forming groups for hydroxy groups include C1-C 10 Alkanoyl groups, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C 10 Alkoxycarbonyl groups include, for example, ethoxycarbonyl, N,N-(C1-C6 alkyl)2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharma-ceutically acceptable ether-forming groups for the hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0307] Suitable pharma- ceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein bearing a carboxy group are, for example, in vivo cleavable amides thereof, e.g., amides formed with amines such as ammonia, C1-4 alkylamines, e.g., methylamine, (C1-C4 alkyl)2-amines, e.g., dimethylamine, N-ethyl-N-methylamine, or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines, e.g., 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amino acids such as glycine or its esters.

[0308] Suitable pharma- ceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein that has an amino group are, for example, amide derivatives thereof that can be cleaved in vivo. Suitable pharma- ceutically acceptable prodrugs from an amino group include, for example, C1-C 10 Alkanoyl groups include, for example, acetyl, benzoyl, phenylacetyl, and amides formed with substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0309] The in vivo effect of the compound of any one of the formulas disclosed herein may be exerted in part by one or more metabolic products formed in the human or animal body after administration of the compound of any one of the formulas disclosed herein.As previously described herein, the in vivo effect of the compound of any one of the formulas disclosed herein may also be exerted by metabolism of a precursor compound (prodrug).

[0310] A suitable general route for preparing the compounds of the present application uses Protocol A, which can be depicted in Scheme 1 herein. [ka]

[0311] The examples presented herein are synthesized according to the general procedures presented in Scheme 1 unless otherwise stated.

[0312] Step 1 is the reaction of an S-type amine (i) with an aryl dichloride (ii). N Ar reaction to give the target chloroaryl intermediate (iii). Step 2 involves cross-coupling between intermediate (iii) and the desired boronic acid or boronate (iv), followed by optional deprotection of the alkyl ether (e.g., methyl ether) on the phenyl ring to produce the desired compound (v). The amines (i), aryl dichlorides (ii), and boronic acids or boronates (iv) are either commercially available or known in the chemical literature unless otherwise indicated.

[0313] Another suitable general route for preparing compounds of the present disclosure is to use Protocol B in Scheme 2 herein. [ka]

[0314] Step 1 involves the opening of commercially available 3,4-pyridinedicarboxylic anhydride (vii) with a Grignard reagent to give carboxylic acid (viii). Step 2 features chlorination followed by condensation with hydrazine to give pyridazinol (ix). Step 3 then involves another chlorination to provide key intermediate (x), which may then participate in step 4 as an SNAr reaction with amine (i) to form azaphthalazine (xi). Step 5 then features methyl ether deprotection followed by providing analog (xii).

[0315] Biological assays Once generated, compounds designed, selected, and / or optimized by the methods described above and herein can be characterized using a variety of assays known to those of skill in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to the assays described below, to determine whether they have the predicted activity, binding activity, and / or binding specificity.

[0316] Furthermore, the use of high throughput screening can speed up the analysis using such assays. As a result, it may be possible to rapidly screen the molecules described herein for activity using techniques known in the art. General methodologies for carrying out high throughput screening are described, for example, in 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.

[0317] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure.These in vitro or in vivo biological assays 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 NLRP3 potency, unbound clearance, solubility, permeability, metabolic stability (e.g., in hepatocytes), and CYP inhibition and time-dependent inhibition (TDI) assays (e.g., to eliminate the risk of potential adverse drug-drug interactions in vivo).

[0318] In some embodiments, the biological assays are described in the Assay Methods section of the Examples. In some embodiments, the Assay Methods section refers to Example 12.

[0319] For example, in some embodiments, compounds of the present disclosure may be tested for their human NLRP3 inhibitory activity using known procedures, such as the methodology reported in Coll et al. Nat Med. (2015) 21(3): 248-255. See also the Examples, Assay Methods section. In some embodiments, compounds of the present disclosure may be tested for their human NLRP3 potency using known procedures. See, for example, the human whole blood NLRP3 assay described in the Examples, Assay Methods section. In some embodiments, compounds of the present disclosure may be further tested for brain penetration. See, for example, the kp and kpu,u NLRP3 assays described in the Examples, Assay Methods section.

[0320] In other embodiments, compounds of the present disclosure may be tested for unbound clearance (Clu) according to known procedures, such as those described in Miller et al., J. Med. Chem. (2020) 63:12156-12170. For example, unbound clearance (Clu) may be calculated by dividing the total clearance measured in blood or plasma ("CL" in mL / min / kg) by the unbound fraction in plasma (fu).

[0321] In yet other embodiments, the permeability of the compounds of the present disclosure may be determined according to known procedures, such as those described in Wang et al. J Mass Spectrum. (2000) 35:71-76. For example, permeability across a cell membrane may be measured using either Caco-2 or MDCK-MDR1 cell lines in transwell plates after measuring the compound in both the apical and basolateral chambers, and 10 -6 It may be reported as apparent permeability PappAB in cm / s.

[0322] In additional embodiments, the solubility of the compounds of the present disclosure may be determined according to known procedures, such as those described in Alsenz and Kansy, Advanced Drug Delivery Reviews (2007) 59:546-567, and Wang et al. J Mass Spectrum. (2000) 35:71-76. For example, kinetic solubility in physiologically relevant media, such as phosphate buffer (PBS, pH 7.4) or simulated gastric fluid (SGF), may be measured using serial dilutions and a 2-hour incubation period, followed by filtration and reported in μM by LC-MS / MS. Thermodynamic solubility in physiologically relevant media may be measured after 24 hours of incubation, followed by filtration and reported in mg / mL by LC-MS / MS. Optimized solubility may be beneficial for the manufacture and further processing of the compound. Additionally, optimizing solubility allows for more efficient in vitro analysis of the compound, including data collection regarding the compound's safety, drug-drug interactions, efficacy, selectivity, metabolism, and permeability.

[0323] Pharmaceutical Compositions 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 listed in Table 1, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and one or more pharma- ceutically acceptable carriers or excipients.In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulas listed in Table 2, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulas described herein, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the pharmaceutical composition comprises one or more carriers, fillers, vehicles, excipients, solubility enhancers, chelating agents, or combinations thereof. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound listed in Table 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound listed in Table 2. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound listed herein.

[0324] In some embodiments of the disclosure, the pharmaceutical composition comprises a compound set forth in Table 1 and a pharma- ceutically acceptable carrier.

[0325] In some embodiments of the present disclosure, the pharmaceutical composition comprises a compound set forth in Table 2 and a pharma- ceutically acceptable carrier.

[0326] In some embodiments of the present disclosure, the pharmaceutical composition comprises a compound of Formula I, as described herein, and a pharma- ceutically acceptable carrier.

[0327] In one embodiment of the disclosure, the 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 pharma- ceutically acceptable carrier.

[0328] In another embodiment of the disclosure, the 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 pharma- ceutically acceptable carrier.

[0329] In another embodiment of the disclosure, the 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 pharma- ceutically acceptable carrier.

[0330] In another aspect of the disclosure, the pharmaceutical composition comprises (S)-5-chloro-2-(4-((2,2-dimethyltetrahydrofuran-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol as described herein and a pharma- ceutically acceptable carrier.

[0331] In one embodiment of the disclosure, the 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 pharma- ceutically acceptable carrier.

[0332] In one embodiment of the disclosure, the 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 pharma- ceutically acceptable carrier.

[0333] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each of which includes sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, and the like. 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.

[0334] The formulation 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 pharma- ceutically acceptable excipient.Suitable acceptable excipients include excipients selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonicity agents, viscosity agents / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0335] Any suitable solubility enhancer may be used. Examples of solubility enhancers include cyclodextrins, such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)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 methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0336] 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.

[0337] Any suitable preservative may be used. Examples of preservatives include quaternary ammonium salts, such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, methyl methionate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0338] The aqueous vehicle may also contain an isotonicity agent to adjust the tonicity (osmotic pressure), which 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.

[0339] The aqueous vehicle may also contain a viscosity agent / suspending agent. Suitable viscosity agents / suspending agents include those selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycols (Carbopols—e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0340] The formulation may contain a pH adjuster to adjust the formulation to an acceptable pH (usually 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 pH adjuster is typically an inorganic acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters 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 either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0341] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or salts thereof including disodium tetraborate), citrate buffers (such as citric acid or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0342] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), oxyethylated octylphenols (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polymers of polyoxyethylene fatty acid esters, and mixtures thereof.

[0343] Oral compositions generally contain an inert diluent or an edible pharma- ceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be formulated with an excipient and used in the form of tablets, lozenges, or capsules. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the fluid carrier is orally applied, swished in the mouth, and expectorated or swallowed. Pharmacologically compatible binding agents and / or adjuvant materials may be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, primogel, or corn starch; a lubricant such as magnesium stearate or Stellite; a flow agent such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0344] According to a further aspect of the present disclosure there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined hereinbefore, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, in combination with a pharma- ceutically acceptable diluent or carrier.

[0345] The compositions of the present disclosure may be in a suitable form for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0346] The compositions of the present disclosure may 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, sweeteners, flavoring agents, and / or preservatives.

[0347] 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 alleviate the symptoms associated with an inflammasome-associated condition referred to herein.

[0348] An effective amount of a compound of the disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with an inflammasome-associated condition referred to herein.

[0349] The size of a dose of the compounds disclosed herein for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known pharmaceutical principles.

[0350] How to use In some aspects, the disclosure provides a method of modulating NLRP3 activity (e.g., in vitro or in vivo) comprising contacting a cell with an effective amount of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof.

[0351] In some aspects, the disclosure provides a method of modulating NLRP3 activity (e.g., in vitro or in vivo) comprising contacting a cell with a compound of the disclosure, or a pharma- ceutically acceptable salt thereof.

[0352] In some aspects, the disclosure provides a method of inhibiting NLRP3 activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof.

[0353] In some aspects, the disclosure provides a method of inhibiting NLRP3 activity (e.g., in vitro or in vivo) comprising contacting a cell with a compound of the disclosure, or a pharma- ceutically acceptable salt thereof.

[0354] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder inhibited by NLRP3 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 pharma- ceutical acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0355] In some aspects, the present disclosure provides a method of treating a disease or disorder 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 pharma- ceutical acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0356] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder inhibited by NLRP3 disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0357] In some aspects, the present disclosure provides a method for treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or its pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug, or a pharmaceutical composition of the present disclosure.In some embodiments, the disease or disorder is a disease or disorder associated with NLRP3 activity.

[0358] In some embodiments, the disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychiatric disease, graft-versus-host disease, allodynia, or an NLRP3-associated disease (in a subject identified as carrying a germline or somatic non-silent mutation in NLRP3).

[0359] In some aspects, the present disclosure provides a method of treating or preventing inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychiatric disease, a graft-versus-host disease, allodynia, or an NLRP3-associated disease (in a subject identified as carrying 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 pharma- ceutical composition of the present disclosure.

[0360] In some aspects, the present disclosure provides a method of treating inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychiatric disease, a graft-versus-host disease, allodynia, or an NLRP3-associated disease (in a subject identified as carrying a germline or somatic non-silent mutation in NLRP3) in a subject in need of such amelioration, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0361] In some aspects, the present disclosure provides a method of treating or preventing inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychiatric disease, a graft-versus-host disease, allodynia, or an NLRP3-associated disease (in a subject identified as carrying 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 pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0362] In some aspects, the present disclosure provides a method of treating inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychiatric disease, a graft-versus-host disease, allodynia, or an NLRP3-associated disease (in a subject identified as carrying a germline or somatic non-silent mutation in NLRP3) in a subject in need of amelioration thereof, comprising administering to the subject a compound of the present disclosure or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0363] In some aspects, the disclosure provides compounds of the disclosure, or pharma- ceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds, or prodrugs thereof, for use in modulating NLRP3 activity (e.g., in vitro or in vivo).

[0364] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in inhibiting NLRP3 activity (e.g., in vitro or in vivo).

[0365] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in inhibiting NLRP3 (e.g., in vitro or in vivo).

[0366] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use as an antagonist of NLRP3 (e.g., in vitro or in vivo).

[0367] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[0368] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0369] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for modulating NLRP3 activity (e.g., in vitro or in vivo).

[0370] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for modulating NLRP3 (e.g., in vitro or in vivo).

[0371] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting NLRP3 activity (e.g., in vitro or in vivo).

[0372] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting NLRP3 (e.g., in vitro or in vivo).

[0373] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0374] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0375] In some aspects, the disclosure provides uses of compounds of the disclosure, or pharma- ceutically acceptable salts thereof, for modulating NLRP3 activity (e.g., in vitro or in vivo).

[0376] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for inhibiting NLRP3 activity (e.g., in vitro or in vivo).

[0377] In some aspects, the disclosure provides uses of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for modulating NLRP3 (e.g., in vitro or in vivo).

[0378] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for inhibiting NLRP3 (e.g., in vitro or in vivo).

[0379] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for the treatment or prevention of a disease or disorder disclosed herein.

[0380] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, for the treatment of a disease or disorder disclosed herein.

[0381] The efficacy of the compounds of the present disclosure can be determined by industry-recognized assays / disease models according to standard practices described in the art and accounting for the same found in the current general knowledge.

[0382] In some embodiments, the disease or disorder is associated with involved NLRP3 activity.

[0383] In some embodiments, the disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychiatric disease, graft-versus-host disease, allodynia, or an NLRP3-associated disease (in a subject identified as carrying a germline or somatic non-silent mutation in NLRP3).

[0384] In some embodiments, the disease or disorder is inflammation.

[0385] In some embodiments, the disease or disorder is an autoimmune disease.

[0386] In some embodiments, the disease or disorder is cancer.

[0387] In some embodiments, the disease or disorder is an infection.

[0388] In some embodiments, the disease or disorder is a disease or disorder of the central nervous system.

[0389] In some embodiments, the disease or disorder is a metabolic disease.

[0390] In some embodiments, the disease or disorder is a cardiovascular disease.

[0391] In some embodiments, the disease or disorder is a respiratory disease.

[0392] In some embodiments, the disease or disorder is a renal disease.

[0393] In some embodiments, the disease or disorder is a liver disease.

[0394] In some embodiments, the disease or disorder is an ocular disease.

[0395] In some embodiments, the disease or disorder is a skin disease.

[0396] In some embodiments, the disease or disorder is a lymphatic system disease.

[0397] In some embodiments, the disease or disorder is a rheumatic disease.

[0398] In some embodiments, the disease or disorder is a psychological disease.

[0399] In some embodiments, the disease or disorder is graft-versus-host disease.

[0400] In some embodiments, the disease or disorder is allodynia.

[0401] In some embodiments, the disease or disorder is an NLRP3-associated disease.

[0402] In some embodiments, the disease or disorder of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0403] In some embodiments, the respiratory disease is steroid-resistant asthma.

[0404] In some embodiments, the respiratory disease is severe steroid-resistant asthma.

[0405] In some embodiments, the renal disease is an acute renal disease, a chronic renal disease, or a rare renal disease.

[0406] In some embodiments, the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0407] In some embodiments, the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0408] In some embodiments, the NLRP3-associated disease in a subject identified as carrying a germline or somatic non-silent mutation in NLRP3 is cryopyrin-associated autoinflammatory syndrome.

[0409] In some embodiments, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease.

[0410] In some embodiments, the compound is brain penetrant, eg, has a Kpu,u>0.3.

[0411] Compounds with a Kpu,u of 0.3 or less are not brain penetrant, hi some embodiments, the compounds are not brain penetrant.

[0412] In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 10.

[0413] In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 9. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 8. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 7. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 6. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 5. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 4. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 3. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 2. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 1.

[0414] In some embodiments, the compound has a Kpu,u of about 0.3. In some embodiments, the compound has a Kpu,u of about 0.4. In some embodiments, the compound has a Kpu,u of about 0.5.

[0415] In some embodiments, the compound has a Kpu,u of about 1. In some embodiments, the compound has a Kpu,u of about 1.5.

[0416] In some embodiments, the compound has a Kpu,u of about 2. In some embodiments, the compound has a Kpu,u of about 2.5.

[0417] In some embodiments, the compound has a Kpu,u of about 3. In some embodiments, the compound has a Kpu,u of about 3.5.

[0418] In some embodiments, the compound has a Kpu,u of about 4. In some embodiments, the compound has a Kpu,u of about 4.5.

[0419] In some embodiments, the compound has a Kpu,u of about 5. In some embodiments, the compound has a Kpu,u of about 5.5.

[0420] In some embodiments, the compound has a Kpu,u of about 6. In some embodiments, the compound has a Kpu,u of about 6.5.

[0421] In some embodiments, the compound has a Kpu,u of about 7. In some embodiments, the compound has a Kpu,u of about 7.5.

[0422] In some embodiments, the compound has a Kpu,u of about 8. In some embodiments, the compound has a Kpu,u of about 8.5.

[0423] In some embodiments, the compound has a Kpu,u of about 9. In some embodiments, the compound has a Kpu,u of about 9.5.

[0424] In some embodiments, the compound has a Kpu,u of about 10.

[0425] In certain embodiments, the compound is metabolically stable, e.g., having 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 from about 30 minutes to about 120 minutes.

[0426] Route of Administration The compounds of the present disclosure, or pharma- ceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds, or prodrugs thereof, may be administered alone as the sole therapy or in addition to one or more other substances and / or treatments. Such combination treatment may be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment.

[0427] For example, the therapeutic effect may be enhanced by administration of an adjuvant (i.e., by itself, an adjuvant may have minimal therapeutic effect, but in combination with another therapeutic agent, the overall therapeutic effect on the individual is improved). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering a compound of the present disclosure together with another therapeutic agent (including a treatment regimen) that also has a therapeutic effect.

[0428] When the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the present disclosure does not need to be administered via the same route as the other therapeutic agents, and may be administered via different routes due to different physical and chemical properties.For example, the compound of the present disclosure may be administered orally to generate and maintain good blood levels, while the other therapeutic agents may be administered intravenously.The initial administration may be performed according to established protocols known in the art, and then the dosage, mode of administration, and administration time may be modified by a skilled clinician based on the observed effects.

[0429] The particular choice of other therapeutic agents will depend on the individual's condition and the physician's diagnosis and judgment of the appropriate treatment protocol. According to this aspect of the disclosure, there is provided a combination for use in treating a disease involving inflammasome activity, comprising a compound of the disclosure as defined herein above, or a pharma- ceutically acceptable salt thereof, and another suitable agent.

[0430] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, suitably combined and in association with a pharma- ceutically acceptable diluent or carrier.

[0431] In any of the above-mentioned 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.

[0432] The compounds of the present disclosure, or pharmaceutical compositions containing those compounds, may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., at the site of desired action).

[0433] Routes of administration include, but are not limited to, oral (e.g., by ingestion), buccal; sublingual; transdermal (including, e.g., by patches, poultices, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., by inhalation or insufflation therapy used through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intraductal, subcutaneous, intraarticular, subarachnoid, and intrasternal; and depot or reservoir implants, e.g., subcutaneous or intramuscular.

[0434] Exemplary embodiments Exemplary embodiment 1. A compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein: A is a 5-8 membered monocyclic heterocycloalkyl, wherein said 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 form, together with the atoms to which they are attached, a 3- or 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 4is H, C1-C6 alkyl, or -C(O)(C1-C6 alkyl); and p is 0 or 1, wherein each instance of alkyl, alk-, or carbocyclic is independently substituted with 0, 1, 2, or 3 halogen atoms; and R 3 If is Cl, then [ka] teeth [ka] isn't it.

[0435] Exemplary embodiment 2. The compound of exemplary example 1, wherein A is a 5-membered monocyclic heterocycloalkyl containing one O ring atom, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0436] Exemplary embodiment 3. A compound of exemplary example 1 or exemplary embodiment 2, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein A is a 6-membered monocyclic heterocycloalkyl containing one O ring atom.

[0437] Exemplary embodiment 4. A compound according to any one of exemplary embodiments 1-3, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein p is 1.

[0438] Exemplary embodiment 5. A compound according to claim 1, wherein p is 1; 1 is C1-C6 alkyl or C1-C6 alkoxy; and R 2is C1-C6 alkyl, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0439] Exemplary embodiment 6. wherein R 3 is not a halogen, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0440] Exemplary embodiment 7. wherein R 3 A compound according to any one of exemplary embodiments 1-6, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein is C1-C6 alkyl, or C1-C6 alkoxy.

[0441] Exemplary embodiment 8. wherein R 3 is Cl, methyl, -CF3, -CHF2, or -OCHF2, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0442] Exemplary embodiment 9. 4 is H, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0443] Exemplary embodiment 10. A compound according to any one of exemplary embodiments 1-9, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein X is H or F.

[0444] Exemplary embodiment 11. The compound of any one of the preceding exemplary embodiments, wherein the compound has formula (Ia) or (Ib): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0445] Exemplary embodiment 12. The compound of any one of the preceding exemplary embodiments, wherein the compound has formula (II-a), (II-b), (II-c), (II-d), (II-e), or (II-f): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0446] Exemplary embodiment 13. The compound of any one of the preceding exemplary embodiments, wherein the compound has formula (III-a), (III-b), or (III-c): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein m is an integer of 0 to 2, and n is an integer of 1 to 2.

[0447] Exemplary embodiment 14. The compound of any one of the preceding exemplary embodiments, wherein the compound has formula (III-d), (III-e), or (III-f): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein m is an integer of 0 to 2, and n is an integer of 1 to 2.

[0448] Exemplary embodiment 15. The compound of any one of the preceding exemplary embodiments, wherein the compound has formula (IV-a), (IV-b), or (IV-c): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0449] 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): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0450] 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'): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0451] Exemplary embodiment 18. The compound of 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): [ka] or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0452] Exemplary embodiment 19. A compound according to exemplary embodiment 1 of the following formula: [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or an isotopically labeled compound thereof.

[0453] Exemplary embodiment 20. A compound according to exemplary embodiment 1 of the following formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or an isotopically labeled compound thereof.

[0454] Exemplary embodiment 21. A compound of the formula: [ka] or a pharma- ceutically acceptable salt or an isotopically labeled compound thereof.

[0455] Exemplary embodiment 22. A compound according to exemplary embodiment 1 of the following formula: [ka] [ka] or a pharma- ceutically acceptable salt or an isotopically labeled compound thereof.

[0456] Exemplary embodiment 23. The compound of exemplary embodiment 1, wherein the compound comprises: [ka] nor a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0457] Exemplary embodiment 24. The compound of exemplary embodiment 1, wherein the compound is not: [ka] or a pharma- ceutically acceptable salt thereof, or an isotopically labeled compound thereof.

[0458] 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.

[0459] Exemplary embodiment 26. The compound of any one of exemplary embodiments 1-21, 23, and 24, wherein the compound has a Kpu,u of greater than 0.3 to about 10.

[0460] Exemplary embodiment 27. A pharmaceutical composition comprising a compound according to any one of exemplary embodiments 1-26, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and one or more pharma- ceutically acceptable carriers.

[0461] Exemplary embodiment 28. A method of modulating NLRP3 comprising administering to the subject a compound of any one of exemplary embodiments 1-26, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of exemplary embodiment 27.

[0462] Exemplary embodiment 29. A method of treating or preventing a disease or disorder, comprising administering to said subject a compound of any one of exemplary embodiments 1-26, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of exemplary embodiment 27.

[0463] Exemplary embodiment 30. A compound according to any one of exemplary embodiments 1-26, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition according to exemplary embodiment 27, for use in treating or preventing a disease or disorder.

[0464] Exemplary embodiment 31. Use of a compound according to any one of exemplary embodiments 1-26, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder.

[0465] Exemplary embodiment 32. Use of a compound according to any one of exemplary embodiments 1-26, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, for the treatment or prevention of a disease or disorder.

[0466] Exemplary embodiment 33. The method, compound, or use of any one of exemplary embodiments 29-32, wherein said disease or disorder is an NLRP3-associated disease or disorder.

[0467] Exemplary embodiment 34. The method, compound or use of any one of exemplary embodiments 28 to 33, wherein said subject is a human.

[0468] Exemplary embodiment 35. The method, compound or use of any one of exemplary embodiments 28-34, wherein said disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychiatric disease, graft versus host disease, allodynia, or an NLRP3-related disease.

[0469] Exemplary embodiment 36. The method, compound or use of exemplary embodiment 35, wherein said disease or disorder of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0470] Exemplary embodiment 37. The method, compound, or use of exemplary embodiment 35, wherein said renal disease is an acute renal disease, a chronic renal disease, or a rare renal disease.

[0471] Exemplary embodiment 38. The method, compound, or use of exemplary embodiment 35, wherein said skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0472] Exemplary embodiment 39. The method, compound, or use of exemplary embodiment 35, wherein said rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0473] Exemplary embodiment 40. The method, compound, or use of exemplary embodiment 35, wherein the NLRP3 associated disease is in a subject identified as carrying a germline or somatic non-silent mutation in NLRP3.

[0474] Exemplary embodiment 41. The method, compound, or use of exemplary embodiment 40, wherein the NLRP3 associated disease is cryopyrin-associated autoinflammatory syndrome in a subject identified as carrying a germline or somatic non-silent mutation in NLRP3.

[0475] Exemplary embodiment 42. The method, compound, or use of exemplary embodiment 35, wherein said cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease.

[0476] Exemplary embodiment 43. A compound selected from: (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; and (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; and pharma- ceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, or prodrugs of any of the foregoing.

[0477] Exemplary embodiment 44. The compound of exemplary embodiment 43, wherein said compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0478] Exemplary embodiment 45. The compound of exemplary embodiment 43, wherein said compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0479] Exemplary embodiment 46. The compound of 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 pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0480] Exemplary embodiment 47. The compound of exemplary embodiment 43, wherein said 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 pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0481] Exemplary embodiment 48. The compound of exemplary embodiment 43, wherein said compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0482] Exemplary embodiment 49. The compound of exemplary embodiment 43, wherein said compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0483] Exemplary embodiment 50. A pharmaceutical composition comprising a compound according to exemplary embodiment 43, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0484] Exemplary embodiment 51. A pharmaceutical composition comprising a compound according to exemplary embodiment 44, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0485] Exemplary embodiment 52. A pharmaceutical composition comprising a compound according to exemplary embodiment 45, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0486] Exemplary embodiment 53. A pharmaceutical composition comprising a compound according to exemplary embodiment 46, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0487] Exemplary embodiment 54. A pharmaceutical composition comprising a compound according to exemplary embodiment 47, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0488] Exemplary embodiment 55. A pharmaceutical composition comprising a compound according to exemplary embodiment 48, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0489] Exemplary embodiment 56. A pharmaceutical composition comprising a compound according to exemplary embodiment 49, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0490] Exemplary embodiment 57. A method of treating or preventing an NLRP3-related disease or disorder, comprising administering to said subject at least one therapeutically effective amount of a compound of exemplary embodiment 43, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0491] Exemplary embodiment 58. The method according to exemplary embodiment 57, wherein said NLRP3-related disease or disorder is inflammation, autoimmune disease, cancer, infectious disease, disease or disorder of the central nervous system, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic system disease, rheumatic disease, psychiatric disease, graft-versus-host disease, allodynia, or NLRP3-related disease (in subjects identified as carrying germline or somatic non-silent mutations in NLRP3).

[0492] Exemplary embodiment 59. The method of exemplary embodiment 58, wherein said compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0493] Exemplary embodiment 60. The method of exemplary embodiment 58, wherein said compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0494] Exemplary embodiment 61. The method of 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 pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0495] Exemplary embodiment 62. The method of 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 pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0496] Exemplary embodiment 63. The method of exemplary embodiment 58, wherein said compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0497] Exemplary embodiment 64. The method of exemplary embodiment 58, wherein said compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0498] Exemplary embodiment 65. A method of treating or preventing an NLRP3-related disease or disorder selected from Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache / pain, and traumatic brain injury, comprising administering to the subject at least one therapeutically effective amount of a compound according to exemplary embodiment 43, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0499] Exemplary embodiment 66. The method of 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 pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0500] Exemplary embodiment 67. The method of exemplary embodiment 65, wherein said compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0501] Exemplary embodiment 68. The method of 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 pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0502] Exemplary embodiment 69. The method of 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 pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0503] Exemplary embodiment 70. The method of exemplary embodiment 65, wherein said compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0504] Exemplary embodiment 71. The method of exemplary embodiment 65, wherein said compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.

[0505] Exemplary embodiment 72. A method for treating or preventing an NLRP3-related disease or disorder selected from Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache / pain, and traumatic brain injury, comprising administering to the subject at least one therapeutically effective amount of the pharmaceutical composition of exemplary embodiment 50.

[0506] Exemplary embodiment A1. A compound selected from the group consisting of: (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; and (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0507] Exemplary Embodiment A2. The compound of Exemplary Embodiment A1, wherein said compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0508] Exemplary Embodiment A3. The compound of Exemplary Embodiment A1, wherein said compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0509] Exemplary Embodiment A4. The compound of 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.

[0510] Exemplary Embodiment A5. The compound of 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.

[0511] Exemplary Embodiment A6. The compound of Exemplary Embodiment A1, wherein said compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol.

[0512] Exemplary Embodiment A7. The compound of Exemplary Embodiment A1, wherein said compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0513] Exemplary Embodiment A8. A pharmaceutical composition comprising a compound according to Exemplary Embodiment A1 and a pharma- ceutically acceptable carrier.

[0514] Exemplary Embodiment A9. A pharmaceutical composition comprising a compound according to Exemplary Embodiment A2 and a pharma- ceutically acceptable carrier.

[0515] Exemplary Embodiment A10. A pharmaceutical composition comprising a compound according to Exemplary Embodiment A3 and a pharma- ceutically acceptable carrier.

[0516] Exemplary Embodiment A11. A pharmaceutical composition comprising a compound according to Exemplary Embodiment A4 and a pharma- ceutically acceptable carrier.

[0517] Exemplary Embodiment A12. A pharmaceutical composition comprising a compound according to Exemplary Embodiment A5 and a pharma- ceutically acceptable carrier.

[0518] Exemplary Embodiment A13. A pharmaceutical composition comprising a compound according to Exemplary Embodiment A6 and a pharma- ceutically acceptable carrier.

[0519] Exemplary Embodiment A14. A pharmaceutical composition comprising a compound according to Exemplary Embodiment A7 and a pharma- ceutically acceptable carrier.

[0520] Exemplary embodiment A15. A method of treating or preventing an NLRP3-associated disease or disorder, comprising administering to said subject at least one therapeutically effective amount of a compound of exemplary embodiment A1.

[0521] Exemplary embodiment A16. The method of exemplary embodiment A1, wherein the NLRP3-related disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychiatric disease, graft-versus-host disease, allodynia, or an NLRP3-related disease (in a subject identified as carrying a germline or somatic non-silent mutation in NLRP3).

[0522] 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.

[0523] Exemplary Embodiment A18. The method of Exemplary Embodiment A16, wherein said compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0524] Exemplary Embodiment A19. The method of 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.

[0525] Exemplary Embodiment A20 The method of Exemplary Embodiment A16, wherein said compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0526] Exemplary Embodiment A21. The method of Exemplary Embodiment A16, wherein said compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol.

[0527] Exemplary Embodiment A22. The method of Exemplary Embodiment A16, wherein said compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0528] Exemplary embodiment A23. A method of treating or preventing an NLRP3-related disease or disorder selected from Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache / pain, and traumatic brain injury, comprising administering to the subject at least one therapeutically effective amount of a compound according to exemplary embodiment A1.

[0529] Exemplary Embodiment A24 The method of Exemplary Embodiment A23, wherein said compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0530] Exemplary Embodiment A25. The method of Exemplary Embodiment A23, wherein said compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0531] Exemplary Embodiment A26 The method of 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.

[0532] Exemplary Embodiment A27 The method of 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.

[0533] Exemplary Embodiment A28 The method of Exemplary Embodiment A23, wherein said compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol.

[0534] Exemplary Embodiment A29. The method of Exemplary Embodiment A23, wherein said compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0535] Exemplary embodiment A30. A method of treating or preventing an NLRP3-related disease or disorder selected from Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache / pain, and traumatic brain injury, comprising administering to the subject at least one therapeutically effective amount of a pharmaceutical composition of exemplary embodiment A8. EXAMPLES

[0536] For illustrative purposes, neutral (free base) compounds described herein are synthesized and tested in the Examples. The neutral compounds disclosed herein can be converted to pharma- ceutically acceptable salts of the corresponding compounds using conventional techniques in the art (e.g., by saponification of an ester to a carboxylate salt, or by hydrolysis of an amide to form the corresponding carboxylic acid, and then converting the carboxylic acid to a carboxylate salt).

[0537] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz as indicated and at 300.3 K 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.

[0538] LC-MS chromatograms and spectra were recorded using a Shimadzu LCMS-2020. Injection volumes were 0.7-8.0 μl and flow rates were typically 0.8 or 1.2 ml / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) and electrospray ionization of positive ions. MS range was 100-1000 Da. Solvents were gradients of water and acetonitrile, both containing modifiers such as trifluoroacetic acid or ammonium carbonate (typically 0.01-0.04%).

[0539] Abbreviation: DCM Dichloromethane DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene ESI Electrospray Ionization EtOAc or EA Ethyl Acetate EtOH Ethanol FA Formic Acid h hour(s) Hex HPLC High Performance Liquid Chromatography IPA Isopropanol LCMS Liquid Chromatography-Mass Spectrometry MeCN or ACN Acetonitrile MeOH Methanol minute (fraction) mw Microwave m / z mass / charge PE Petroleum Ether Preparative-HPLC Preparative High Performance Liquid Chromatography rt room temperature RT retention time THF Tetrahydrofuran Y Yield

[0540] 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*) [ka]

[0541] Example 1 follows Protocol A.

[0542] 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. In a 5 mL microwave tube, 1,4-dichloropyrido[3,4-d]pyridazine (250 mg, 1.25 mmol, 1 equiv.), DMF (3 mL) and Na2CO3 (423.91 mg, 4 mmol, 3.2 equiv.) were added at 130 °C. The final reaction mixture was irradiated with microwave radiation at 130 °C for 40 min. After the reaction was complete, the residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile (MeCN) in water, 0% to 100% gradient (30 min); detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give 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 a yellow oil. LCMS: (ES, m / z): RT=0.735 min, m / z=279 [M+1] + .

[0543] 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 25 mL round-bottom flask was charged with 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 equiv.), 4-chloro-2-hydroxyphenylboronic acid (120.59 mmol), and 1,2-dichloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-1-amine (150 mg, 0.53 mmol, 1 equiv.). g, 0.69 mmol), 1.3 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (78.75 mg, 0.10 mmol, 0.2 equiv.), Na2CO3 (171.11 mg, 1.61 mmol), 3 equiv.), dioxane (6 mL) and H2O (1.2 mL) were added at 80 °C. The final reaction mixture took 2 h at 80 °C. After the reaction was complete, the reaction mixture was concentrated and the residue was purified by reverse flash chromatography using the following conditions (column, C18 silica gel; mobile phase, acetonitrile (MeCN) in water, 0% to 100% gradient (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*250mm, 5μm; mobile phase, water (10mmol / L NH4HCO3) and acetonitrile (MeCN) (25% MeCN, up to 45% in 12 min); detector, UV254).This gave 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 crude light yellow 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 crude light yellow solid. 20 mg of 5-chloro-2-(4-{[-4,4-dimethyloxolan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (compound 1A) was then purified using the following conditions (column, Chiral ART Chiral separation was performed using Cellulose-SA, 4.6* x 50 mm, 3 um; mobile phase, methyl tert-butyl ether (MtBE) (0.2% formic acid (FA)) and isopropyl:dichloromethane (IPA:DCM) = 1:1 (50% IPA:DCM = 1:1 held for 4 minutes); detector, UV254) to obtain 5-chloro-2-(4-{[(3R)-4,4-dimethyloxolan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (referred to herein as (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3, (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 1*) (RT = 1.12 min, 5.4 mg, 2.69% yield) was obtained as a pale yellow solid, 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) was obtained as a pale yellow solid. Stereochemistry was arbitrarily assigned.

[0544] (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,2 H),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).

[0545] (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).

[0546] 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*) [ka]

[0547] Example 2 follows protocol B.

[0548] 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 furo[3,4-c]pyridine-1,3-dione (30.0 g, 201.20 mmol, 1 equiv.) and tetrahydrofuran (300 mL), bromo(4-chloro-2-methoxyphenyl)magnesium (0.5 M in tetrahydrofuran (THF)) (241 mL, 120 mmol, 0.6 equiv.) was added dropwise at −78° C. under nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 2 h under nitrogen atmosphere. The reaction progress was monitored by LCMS. The reaction was quenched by addition of water (150 mL) at 0° C. The precipitated solid was collected by filtration and washed with water (3×50 mL). This gave 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] + .

[0549] Step 2: Synthesis of 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol. In a 250 mL round bottom flask, 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (5 g, 17.1 mmol, 1 equiv.) and SOCl2 (50 mL) were added. The mixture was stirred at 70 °C for 2 h. The reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the 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 equiv.), methanol (MeOH) (50 mL) at 0 °C. The mixture was stirred in an oil bath at 70 °C 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)) using the following conditions: column, XBridge Shield RP18 OBD column, 19×250 mm, 10 μm; mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (MeCN) (39% MeCN held for 17 min); detector, UV254 / 220 nm. This gave 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] + . 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).

[0550] Step 3: Synthesis of 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine. To a 250 mL round bottom flask was added 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2.5 g, 8.69 mmol, 1 equiv.), POCl3 (40 mL) and pyridine (4 mL). 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 (3×500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 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).

[0551] Step 4: Synthesis of 1-(4-chloro-2-methoxyphenyl)-N-(3,3-dimethyltetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine. In a 40 mL vial, 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (200 mg, 0.65 mmol, 1 eq.) and 3,3-dimethyloxan-4-amine (101.28 mg, 7.84 mmol, 1.2 eq.), triethylamine (TEA) (198.32 mg, 1.96 mmol, 3 eq.), and dimethylsulfoxide (DMSO) (5 mL) were added at room temperature. The resulting mixture was stirred overnight at 80° C. under nitrogen atmosphere. 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] + .

[0552] 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, (ethylsulfanyl)sodium (1054.30 mg, 12.53 mmol, 25 equiv), and DMSO (8 mL) at room temperature. The resulting mixture was stirred at 120° C. for 2 h under nitrogen atmosphere. The progress of the reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with MeCN (3×5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions (column, C18 gel; mobile phase, aqueous MeCN (10 mmol / L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV 254 nm) to give the product as an off-white solid.The product (90 mg, 98.2% purity) was purified by preparative HPLC using the following conditions (Prep HPLC-064: column, CHIRALPAK IG, 2*25 cm, 5 um; mobile phase, Hex and MeOH:DCM=1:1 (hold 50% MeOH:DCM=1:1- at 23 min); detector, UV 254 nm) to give 5-chloro-2-(4-{[(4R)-3,3-dimethyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (herein (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol) (chemical product). Compound 3B*) (RT = 1.50 min, 27.8 mg, 14.3% yield) was obtained as an off-white solid, and 5-chloro-2-(4-{[(4S)-3,3-dimethyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (herein (S)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol) (compound 3*) (RT = 3.28 min, 24.4 mg, 12.5% ​​yield) was obtained as an off-white solid. Stereochemistry was arbitrarily assigned.

[0553] 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).

[0554] 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).

[0555] 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) [ka]

[0556] Example 3 follows Protocol A.

[0557] In an 8 mL sealed tube was added 1-chloro-N-(5,5-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine (120 mg, 0.430 mmol, 1 equiv), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (201 mg, 0.860 mmol, 2 equiv), Pd(dppf)Cl2 (94.5 mg, 0.130 mmol, 0.300 equiv), dioxane (2 mL) and HO (0.4 mL) 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 and eluted 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 / LNH4HCO3; Mobile phase B: MeCN; Flow rate: 60mL / min; Gradient: 34%B to 34%B (in 11 min), 34%B; 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 Further purification by ART Amylose-SA, 2*25 cm, 5 m; mobile phase A: hexane (Hex) HPLC, mobile phase B: MeOH:DCM=1:1, HPLC; flow rate: 20 mL / min; gradient: 20% B to 20% B in 15 min; wavelength: 220 / 254 nm) gave (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol (compound 5) (28.4 mg, yield 18.8%) (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, yield 15.7%) (RT(min): 13.52). The absolute stereochemistry was determined by X-ray crystallography.

[0558] (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] + . 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),5.05-4.97(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).

[0559] (S)-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] + . 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,1 H),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).

[0560] Table A shows protocols for preparing compounds of the present disclosure, and Table B provides the NMR data thereof. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 4-1] [Table 4-2]

[0561] 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*) [ka]

[0562] Example 4 follows Protocol A.

[0563] Step 1. Synthesis of 1-bromo-4-(difluoromethoxy)-2-methoxybenzene. In a 100 mL round bottom flask, 4-bromo-3-methoxyphenol (5 g, 24.62 mmol, 1 equiv.), acetonitrile (MeCN) (10 mL), diethyl bromodifluoromethylphosphonate (13.15 g, 49.25 mmol, 2 equiv.), and KOH (2.76 g, 49.25 mmol, 2 equiv.), H2O (10 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by gas chromatography / mass spectrometry (GCMS). The reaction was quenched with water (10 mL) at 0 °C. The resulting mixture was extracted with 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 silica gel column chromatography, eluted 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] + .

[0564] 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 equiv.) in dioxane (25 mL), triethylamine (2639.37 mg, 26.08 mmol, 3 equiv.) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5563.40 mg, 43.47 mmol, 5 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for 0.5 h under nitrogen atmosphere. The above mixture was treated with Pd(OAc) 2(195.19 mg, 0.86 mmol, 0.1 equiv) and 2-(dicyclohexylphosphino)biphenyl, (2-biphenyl)dicyclohexylphosphine (Cy-JohnPhos) (609.44 mg, 1.73 mmol, 0.2 equiv) in dioxane (2 mL) were added at room temperature. The resulting mixture was stirred at 80° C. for another 2 h 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 (2×20 mL). The combined organic layers were washed with brine (1×20 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] + .

[0565] Step 3. Synthesis of 1-chloro-N-(5,5-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine. In a 20 mL sealed tube, 1,4-dichloropyrido[3,4-d]pyridazine (800 mg, 3.99 mmol, 1 eq.), 5,5-dimethyloxolan-3-amine (552.79 mg, 4.79 mmol, 1.2 eq.), Na2CO3 (1270.94 mg, 11.99 mmol, 3 eq.) and dimethylformamide (10 mL) were added. The final reaction mixture was irradiated with microwave radiation at 130° C. for 30 min. The reaction was monitored by LCMS. The reaction was repeated five times. The combined mixture was filtered and the filter cake was washed with EtOAc (3×20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (2#SHIMADZU (HPLC-01): column, XBridge Prep Phenyl OBD Column, 19*250mm, 5μm; mobile phase, water (50mmol / L NH4HCO3) and acetonitrile (MeCN) (12% MeCN up to 22% in 10min, hold 22% in 2min); detector, UV 254nm) to give 1-chloro-N-(5,5-dimethyloxolan-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).

[0566] 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 equiv.) and 4-(difluoromethoxy)-2-methoxyphenylboronic acid (3284.18 mg, 15.06 mmol, 3 equiv.) in dioxane (12 mL) and water (2.4 mL) was added Na2CO3 (1596.36 mg, 15.06 mmol, 3 equiv.) and Pd(dppf)Cl2 (735.02 mg, 1 mmol, 0.2 equiv.) at room temperature. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (MeCN), gradient 40% to 50% 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] + .

[0567] 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 equiv) in dimethylformamide (10 mL) was added (ethylsulfanyl)sodium (666.53 mg, 7.92 mmol, 3 equiv) 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 (3×5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm,n; Mobile phase A: Water (0.05% trifluoroacetic acid (TFA)), Mobile phase B: MeCN, Flow rate: 60mL / min; Gradient: 18%B to 28%B in 10min, 28%B, Wavelength: 254nm; RT(min): 8.4) to give the title compound (Compound 9A) (751.6mg, Yield 55.1%). LCMS, ESI: RT=0.67min, m / z=403.1[M+H] + ; 1 H 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* and Compound 9B* were then isolated by chiral HPLC and their stereochemistry was assigned based on extrapolation from the stereochemical assignments of Compound 5 and Compound 5B.

[0568] Isolation 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 .75(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] + .

[0569] Isolation 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] + .

[0570] 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*) [ka]

[0571] Example 5 follows Protocol B.

[0572] Step 1. Synthesis of 4-(2-methoxy-4-methylbenzoyl)pyridine-3-carboxylic acid. To a 250 mL three-neck round bottom flask, furo[3,4-c]pyridine-1,3-dione (10 g, 67.06 mmol, 1 equiv), THF (100 mL), and bromo(2-methoxy-4-methylphenyl)magnesium (9 g, 40.24 mmol, 0.6 equiv) were added dropwise at -78 °C. The resulting mixture was stirred at room temperature for 1 h under 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] + .

[0573] Step 2. Synthesis of 1-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazin-4-ol. To a 250 mL round bottom flask was added 4-(2-methoxy-4-methylbenzoyl)pyridine-3-carboxylic acid (2 g, 7.37 mmol, 1 eq) and SOCl2 (20 mL). The resulting mixture was stirred at 70 °C for 2 h 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 (50 mL) and added to a solution of hydrazine hydrate (1.70 g, 33.99 mmol, 4.61 eq) and EtOH (10 mL) at 0 °C. The resulting mixture was stirred in an oil bath at 70 °C for 3 h. 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 ((Prep-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 (60% MeOH:DCM=1:1 held for 10 min); detector, UV254) to give 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).

[0574] Step 3. Synthesis of 4-(2-methoxy-4-methylbenzoyl)pyridine-3-carboxylic acid. In a 250 mL round bottom flask, 1-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazin-4-ol (800 mg, 2.99 mmol, 1 equiv), POCl3 (10 mL) and pyridine (1 mL) were added at room temperature. The resulting mixture was stirred at 110 °C under nitrogen atmosphere for 2 h. The reaction progress was monitored by LCMS. The reaction was quenched by adding aqueous NaHCO3 (500 mL) and ethyl acetate (EtOAc) (500 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with H2O (1 x 500 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford 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).

[0575] Step 4. Synthesis of N-(6,6-dimethyloxan-3-yl)-1-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazin-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 equiv) in DMSO (4.5 mL) was added 6,6-dimethyloxan-3-amine (81.39 mg, 0.630 mmol, 1.2 equiv) and triethylamine (TEA) (159.4 mg, 1.58 mmol, 3 equiv). 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 flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10%-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] + .

[0576] 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-dimethyloxan-3-yl)-1-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazin-4-amine (50 mg, 0.026 mmol, 1 equiv) in DMF (1.5 mL) was added (ethylsulfanyl)sodium (166.3 mg, 1.98 mmol, 15 equiv). 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 (2×10 mL) and concentrated in vacuo. 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 (in 10 min), 43% B; wavelength: 254 nm; RT1 (min): 9.5) to give the title compound (compound 10A). Compound 10* and compound 10B* were then isolated by chiral HPLC. Stereochemistry was arbitrarily assigned.

[0577] Isolation 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, 2.12×25 cm, 5 μm, Mobile phase A: Hexane (0.2% formic acid (FA)), Mobile phase B: MeOH:EtOH=1:1, Flow rate: 20 mL / min, Gradient: 15% B to 15% B in 12.5 min, Wavelength: 220 / 254 nm; RT (min): 2.81; (13.3 mg, yield 27.6%). LCMS: (ES, m / z): RT=1.372 min, m / z=365 [M+H] + ; 1 H 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).

[0578] (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, Yield 11.2). LCMS: (ES,m / z): RT=1.36min,m / z=365[M+H] + ; 1H 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).

[0579] 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*) [ka]

[0580] Example 6 follows Protocol A.

[0581] Step 1. Synthesis of 1-chloro-N-(2,2-dimethyloxan-4-yl)pyrido[3,4-d]pyridazin-4-amine. To a 100 mL sealed tube, 2,2-dimethyloxan-4-amine (2 g, 15.5 mmol, 1 equiv.), Na2CO3 (4921 mg, 46.44 mmol, 3 equiv.), and DMF (20 mL) were added. 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 (3 × 10 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% 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=0.93 min, m / z=293.0[M+H]+.

[0582] 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*). To a 20 mL vial was added 1-chloro-N-(2,2-dimethyloxan-4-yl)pyrido[3,4-d]pyridazin-4-amine (250 mg, 0.85 mmol, 1 equiv), Na2CO3 (271.51 mg, 2.56 mmol, 3 equiv), Pd(dppf)Cl2 (187.44 mg, 0.25 mmol, 0.3 equiv), dioxane (2.5 mL), and H2O (0.5 mL). The resulting mixture was stirred at 80 °C under 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 flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, 30% to 60% gradient (in 10 min); detector, UV 254 nm) to give 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 (from 35% MeCN up 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, CHIRALPAK Purification by ID, 2*25 cm, 5 um; mobile phase, hexane (0.2% formic acid) and ethanol (EtOH) (10% EtOH held at 20 min); detector, UV 254 nm) afforded (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (26.5 mg, 7.25% yield) (compound 11*) at RT of 1.66 min, and (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (24.3 mg, 5.33% yield) (compound 11B*) at RT of 2.37 min. Stereochemistry was arbitrarily assigned.

[0583] (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] + ; 1H 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=1.7H) z,1H),4.86-4.75(m,1H),3.99-3.88(m,1H),3.91-3.82(m,1H),2.24-2.1 0(m,2H),1.75-1.64(m,1H),1.67-1.58(m,1H),1.41(s,3H),1.32(s,3H).

[0584] (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (compound 11*B): 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,1 H),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).

[0585] 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*) [ka]

[0586] Example 7 follows Protocol A.

[0587] Step 1. Synthesis of 1-bromo-4-(difluoromethoxy)-2-methoxybenzene. To a stirred solution of 4-bromo-3-methoxybenzaldehyde (1 g, 4.65 mmol, 1 equiv.) in DCM (10 mL), diethylaminosulfur trifluoride (DAST) (3.75 g, 23.25 mmol, 5 equiv.) was added. The resulting mixture was stirred at room temperature for 2 h under air atmosphere. The reaction was quenched at 0° C. with ice water (20 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane / petroleum ether (DCM / PE) (1:1) to give the title compound (1.03 g, 93% yield).

[0588] 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 equiv.) in dioxane (10 mL) was treated with triethylamine (512.27 mg, 5.04 mmol, 3 equiv.) for 30 min at room temperature under nitrogen atmosphere, followed by the addition of Pd(OAc)2 (37.88 mg, 0.17 mmol, 0.1 equiv.) and 2-(dicyclohexylphosphino)biphenyl, (2-biphenyl)dicyclohexylphosphine (Cy-JohnPhos) (118.29 mg, 0.33 mmol, 0.2 equiv.). The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. 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 (crude 1 g), which was used directly in the next step without further purification. GCMS: m / z = 202.06.

[0589] 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 equiv.) in 1,4-dioxane (9 mL) and HO (1.8 mL) was added NaCO (152.05 mg, 1.43 mmol, 3 equiv.) and Pd(dppf)Cl (104.97 mg, 0.14 mmol, 0.3 equiv.). The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction was diluted with water (20 mL) at 0° C. The aqueous layer was extracted with EtOAc (3×50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous MeCN, 10% to 50% gradient (in 10 min); detector, UV 254 nm) to give 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).

[0590] Step 4. 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]pyridazin-4-amine (150 mg, 0.36 mmol, 1 equiv.) in DMF (1.5 mL) was added sodium ethanethiolate (EtSNa) (457 mg, 5.43 mmol, 15 equiv.). 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 (3×5 mL). The filtrate was concentrated under reduced pressure.The residue was purified by reverse flash chromatography (column, C18 silica gel; mobile phase, aqueous MeCN (10 mmol / L NH4HCO3), 25%-45% gradient (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: hexane (0.2% Further purification by HPLC using 1:1 elution time, mobile phase B: IPA:DCM = 1:1, flow rate: 20 mL / min, gradient: 30% B to 30% B in 15 min; wavelength: 254 / 220 nm; RT1 (min): 10.29) gave (R)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (compound 16B*) at RT of 14.32 min (16.5 mg, 11.4% yield) and (S)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (compound 16*) at RT of 10.29 min (18.5 mg, 12.3% yield). The stereochemistry was arbitrarily assigned.

[0591] (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 H NMR(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).

[0592] (S)-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 H NMR(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).

[0593] 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 (Compound 18A *), 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-(((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (compound 18D*) [ka]

[0594] Example 8 follows Protocol B.

[0595] Step 1: Synthesis of 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid. To a stirred solution of furo[3,4-c]pyridine-1,3-dione (30.0 g, 201.20 mmol, 1 equiv.) and tetrahydrofuran (300 mL), bromo(4-chloro-2-methoxyphenyl)magnesium (0.5 M in THF) (241 mL, 120 mmol, 0.60 equiv.) was added dropwise at −78° C. under nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 2 h under nitrogen atmosphere. The reaction progress was monitored by LCMS. The reaction was quenched by the addition of water (150 mL) at 0° C. The precipitated solid was collected by filtration and washed with water (3×50 mL). This afforded the title compound (20 g, 34.1% yield). LCMS(ES,m / z):RT=0.662min,m / z=292.0[M+1] + .

[0596] Step 2: Synthesis of 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol. To a 250 mL round bottom flask was added 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (5 g, 17.1 mmol, 1 equiv) and SOCl2 (50 mL). The mixture was stirred at 70 °C for 2 h. The reaction was monitored by TLC. After the reaction was completed, the 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 equiv), MeOH (50 mL) at 0 °C. The mixture was stirred in an oil bath at 70 °C 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 (39% MeCN held for 17 min); detector, UV254 / 220 nm) to give 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).

[0597] Step 3: Synthesis of 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine. To a 250 mL round bottom flask was added 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2.5 g, 8.69 mmol, 1 eq.), POCl3 (40 mL) and pyridine (4 mL). 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 (3×500 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] + . 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).

[0598] Step 4: Synthesis of 1-(4-chloro-2-methoxyphenyl)-N-(3-methyltetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazin-4-amine. To a 20 mL vial was added 3-methyloxan-4-amine hydrochloride (200 mg, 1.31 mmol, 3 equiv), DMSO (3 mL), 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (134.60 mg, 0.44 mmol, 1 equiv) and DIEA (170.48 mg, 1.31 mmol, 3 equiv) at room temperature. The resulting mixture was stirred overnight at 80° C. under nitrogen atmosphere. The reaction progress was monitored by LCMS. The residue was purified by reverse flash chromatography (column, C18 gel; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm) to give the title compound as a mixture of cis and trans stereoisomers (150 mg, 88.7% yield). LCMS: (ES, m / z): RT=0.688 min, m / z=385[M+1]+.

[0599] 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 equiv.), DMSO (3 mL) and a cis / trans mixture of (ethylsulfanyl)sodium (204.14 mg, 2.43 mmol, 10 equiv.) at room temperature. The resulting mixture was stirred at 120° C. for 1 h under nitrogen atmosphere. The reaction progress was monitored by LCMS. The residue was purified by reversed-phase flash chromatography (column, C18 gel; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm) to give a crude mixture of stereoisomers (70 mg, 90% pure).

[0600] Step 6: Isolation of the 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 with the following conditions: column, Chiral ART Cellulose-SA, 2*25cm, 5um; mobile phase, Hex(0.2% FA)- and EtOH:DCM=1:1 (30% EtOH:DCM=1:1 held at 15.5min); detector, UV254nm.This resulted in the synthesis of 5-chloro-2-(4-{[(3R,4R)-3-methyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also called 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 a 4.6×50 mm column) as a pale yellow solid, and 5-chloro-2-(4-{3-methyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also called 5-chloro-2-(4-{3-methyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol) (compound 18'*) as a putative mixture of trans isomers (30 mg, 34.6% yield, RT=2.39 on a 4.6*50 mm column) as a pale yellow solid, and 5-chloro-2-(4-{[(3S ,4S)-3-Methyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also called 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 4.6*50 mm column) was obtained as a pale yellow solid (cis and trans isomers and stereochemistry arbitrarily assigned).

[0601] 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]+; 1H 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).

[0602] 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:

[0603] Isolation 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 expected trans mixture (30 mg, 98% purity) was separated by chiral-preparative HPLC using the following conditions: column, Chiral ART Cellulose-SA, 2*25 cm, 5 um; mobile phase, Hex(0.2% FA)- and EtOH:DCM=1:1- (30% EtOH:DCM=1:1- held at 18.2 min); detector, UV254 nm. This gave 5-chloro-2-(4-{[(3R,4S)-3-methyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (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 was arbitrarily assigned.

[0604] 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, 1H),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).

[0605] 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).

[0606] Additional compounds shown in Table C below are amenable to the protocols and examples described herein. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12] [Table 5-13] [Table 5-14] [Table 5-15] [Table 5-16]

[0607] 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*) [ka]

[0608] Example 9 follows Protocol A.

[0609] Step 1: To a 20 ml sealed tube was added 1,4-dichloropyrido[3,4-d]pyridazine (500 mg, 2.50 mmol, 1 equiv), 5,5-dimethyloxolan-3-amine (201.53 mg, 1.75 mmol, 0.7 equiv), Na2CO3 (802.39 mg, 7.50 mmol, 3 equiv), and DMF (5 mL). The final reaction mixture was irradiated with microwave radiation at 130° C. for 30 min. The reaction was repeated once. 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 flash chromatography using 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 a crude product, which was purified by preparative HPLC using 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, UV 254 nm to give 1-chloro-N-(5,5-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine as a mixture of R and S stereoisomers (1.2 g, 28% yield). LCMS: (ES, m / z): RT=0.62 min, m / z=279.0 [M+H] + 。

[0610] Step 2: The stereoisomeric mixture from step 1 was purified under the following conditions: Column: CHIRALPAK IG, 2*25cm, 5μm; Mobile phase A: Hexane (0.5% 2M NH3 in methanol), Mobile phase B: Isopropanol / dichloromethane (1:1), Flow rate: 20mL / min; Gradient: 70%B to 70%B in 14.5min; 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): 4.81; RT3 (min): 11.33 Purification by Chiral-HPLC with sample solvent: methanol / dichloromethane (1:1), injection volume: 1 mL, gave (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] + ) was obtained (stereochemistry arbitrarily assigned).

[0611] Step 3: To a 20 mL vial, 2-bromo-3,5-dimethylphenol (600 mg, 2.98 mmol, 1 equiv.) and dioxane (6 mL), triethylamine (905.92 mg, 8.95 mmol, 3 equiv.), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1909.55 mg, 14.92 mmol, 5 equiv.) were added. The resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. To the above mixture, palladium(II) acetate (Pd(OAc)2) (67 mg, 0.29 mmol, 0.1 equiv.), 2-(dicyclohexylphosphino)biphenyl (Cy-JohnPhos) (209.18 mg, 0.59 mmol, 0.2 equiv.) were added. The resulting mixture was stirred at 80° C. for 1 h under nitrogen atmosphere. The reaction progress was monitored by GCMS. The reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (EtOAc) (3×10 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.

[0612] Step 4. In an 8 mL vial, add 2-hydroxy-4,6-dimethylphenylboronic acid (214.37 mg, 1.29 mmol, 3 equiv.) and intermediate A* (120 mg, 0.43 mmol, 1 equiv.), water (0.2 mL), Na2CO3 (138.19 mg, 1.29 mmol, 3 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (Pd(dppf)Cl2CH2Cl2) (94.50 mg, 0.12 mmol, 0. 3 equiv.), and dioxane (1 mL) were added. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10% to 50% gradient (in 10 min); detector, UV 254 nm to give the crude product (70 mg), which was purified using the following conditions: column: XBridge Purification by preparative HPLC on a Shield RP18 OBD column, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60mL / min; gradient: 25%B to 35%B (in 10min), 35%B; wavelength: 254nm; 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*) (41.90mg, 27% yield). Stereochemistry was arbitrarily assigned. LCMS: (ES,m / z):RT 1= 1.43 minutes, m / z=365.2[M+H] + . 1H 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)。

[0613] Step 5. To an 8 mL vial was added 2-hydroxy-4,6-dimethylphenylboronic acid (214.37 mg, 1.29 mmol, 3 equiv), intermediate B* (120 mg, 0.43 mmol, 1 equiv), water (0.2 mL), Na2CO3 (138.19 mg, 1.29 mmol, 3 equiv), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with dichloromethane (Pd(dppf)Cl2CH2Cl2) (94.50 mg, 0.12 mmol, 0.3 equiv)), 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 reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10%-50% gradient (in 10 min); detector, UV 254 nm, to give a crude product (70 mg), which was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 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-35% B (in 10 min), 35% B; 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 was arbitrarily assigned. LCMS: (ES, m / z): RT 1= 1.43 minutes, m / z=365.2[M+H] + . 1H 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).

[0614] 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*) Synthesis of 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*) [ka]

[0615] Example 10 follows Protocol B.

[0616] Step 1: To a 250 mL three-neck round bottom flask was added furo[3,4-c]pyridine-1,3-dione (3 g, 20.12 mmol, 1 equiv), tetrahydrofuran (THF) (30 mL), and bromo(4-chloro-2-methoxyphenyl)magnesium (0.5 mol / L) (24.16 mL, 12.07 mmol, 0.6 equiv) at -78 °C. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction progress was monitored by LCMS. The reaction was quenched by the addition of ice water (300 mL) at 0 °C. The resulting mixture was concentrated under vacuum. The precipitated solid was collected by filtration, washed with water (3 x 20 mL), and dried under vacuum to give 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (2.5 g, 43% yield). LCMS:(ES,m / z):RT=0.633min,m / z=292.0[M+1] + 。

[0617] Step 2: To a 250 mL round bottom flask was added 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (2.5 g, 8.56 mmol, 1 equiv) and SOCl2 (25 mL). 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 equiv) in methanol (MeOH) (50 mL) at 0 °C. The resulting mixture was stirred in an oil bath at 80 °C for 1 h. The reaction progress was monitored by LCMS. The precipitated solid was collected by filtration. The crude product (2g, 73% purity) was purified by the following conditions: (2#SHIMADZU(HPLC-01)): Column, XBridge Shield RP18 OBD column, 19*250mm, 10μm, Mobile phase, water (10mmol / L NH4HCO3) and acetonitrile (41% retention at 19min); Detector, UV254 / 220nm to give 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (1.2g, 49% yield). LCMS: (ES,m / z):RT=0.678min,m / z=288.0[M+1] + .

[0618] Step 3: In a 250 mL round bottom flask was added 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (1.2 g, 4.16 mmol, 1 equiv.), POCl3 (25 mL), and pyridine (2.5 mL). The mixture was stirred at 110 °C for 2 h. The reaction progress was monitored by LCMS. The mixture was diluted with ethyl acetate (EtOAc) (20 mL). The mixture was slowly poured into EtOAc (1 L) and saturated sodium bicarbonate (aq) (1 L) at 0 °C. The aqueous layer was extracted with EtOAc (2 × 1 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] + .

[0619] Step 4. In a 20 mL sealed tube, 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 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] + .

[0620] Step 5. Sodium ethanethiolate (EtSNa) (654.78 mg, 7.80 mmol, 15 equiv.) was added directly to the reaction solution of Step 4. The resulting mixture was stirred at 120° C. for 1 h under air atmosphere. The reaction was monitored by LCMS. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel, mobile phase; acetonitrile in water, 15% to 18% gradient (in 15 min); detector, UV 254 nm and 220 nm 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 as a mixture of cis and trans isomers (120 mg, 99% purity). LCMS: RT=0.62 min, m / z=371 [M+H] + .

[0621] Step 6. The mixture of isomers of 5-chloro-2-{4-[(2-methyloxan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (120 mg) was subjected to HPLC under the following conditions: (Column: CHIRALPAK IG, 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% B in 20 min; wavelength: 220 / 254 nm; 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: 0.7 mL) was used to purify by chiral preparative HPLC to give a mixture of compounds 25A* and 25B* (55 mg, 98% purity), compound 25C* (11.2 mg, 99.8% purity) and compound 25D* (10.6 mg, 99.9% purity); stereochemistry has been arbitrarily assigned.

[0622] Compound 25C*:LCMS:R=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).

[0623] 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).

[0624] Step 7: The mixture of compounds 25A* and 25B* (55 mg) was purified by chiral preparative HPLC using 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); Stereochemistry has been arbitrarily assigned.

[0625] 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,1 H),1.72(qd,J=12.3,4.7Hz,1H),1.44(q,J=11.6Hz,1H),1.27(d,J=6.2Hz,3H).

[0626] Compound 25B*:LCMS:RT=0.91 min, m / z=371[M+H] + . 1 H NMR (400MHz, methanol-d4) δ9.72(d,J=1.0Hz,1H),8.68(d,J=5.7Hz,1H),7.54(d d,J=5.7,1.0Hz,1H),7.38(d,J=7.9Hz,1H),7.09-7.02(m,2H),4.63-4.53(m,1 H),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).

[0627] 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*) [ka]

[0628] Example 11 follows Protocol A.

[0629] Step 1. To a 40 mL vial, chloro-M-cresol (3 g, 21.04 mmol, 1 equiv), acetonitrile (20 mL), K2CO3 (8.72 g, 63.12 mmol, 3 equiv) and methyl iodide (MeI) (8.96 g, 63.12 mmol, 3 equiv) were added at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The reaction was monitored by LCMS. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 50 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. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (18:1) to give 1-chloro-3-methoxy-5-methylbenzene (3.1 g, 94% yield). LCMS: RT=1.04 min, m / z=157.0[M+H] + .

[0630] Step 2. In a 100 mL round bottom flask, to a solution of 1-chloro-3-methoxy-5-methylbenzene (3 g, 19.16 mmol, 1 equiv.) in tetrahydrofuran (THF) (5 mL) was added t-butyllithium solution (1.6 M in hexanes, 20 mL, 1.7 equiv.) dropwise at -78 °C under N2 atmosphere. The reaction mixture was stirred at -78 °C for 1 h. Then, a solution of triisopropyl borate (5.40 g, 28.73 mmol, 1.50 equiv.) in THF solution (10 mL) was added dropwise and the mixture was stirred at -20 °C for another 2 h. The reaction was monitored by LCMS. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and then the mixture was extracted with ethyl acetate (EtOAc) (2x30 mL). The combined organic extracts were washed with brine (30 mL), 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] + .

[0631] 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) (3×10 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile, 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] + . 1 H 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 was arbitrarily assigned.

[0632] 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 equiv), DMSO (1 mL) and (ethylsulfanyl)sodium (168.69 mg, 2.01 mmol, 10 equiv) 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 reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10% to 40% gradient (in 10 min); detector, UV254 / 220 nm to give crude product (70 mg, 90% purity), which was purified by preparative HPLC using 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).

[0633] Step 5. To an 8 mL vial was added intermediate B* from Example 9 (80.0 mg, 0.29 mmol, 1 equiv), dioxane (0.5 mL), HO (0.1 mL), 2-chloro-6-methoxy-4-methylphenylboronic acid (173 mg, 9.86 mmol, 3 equiv), NaCO (91.3 mg, 0.86 mmol, 3 equiv) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (Pd(dppf)ClCHCl) (63 mg, 0.09 mmol, 0.3 equiv) 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 using the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile, 15% to 40% gradient (in 20 min); detector, UV220 / 254 nm. This afforded 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 was arbitrarily assigned.

[0634] Step 6. 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 equiv.), dimethylformamide (DMF) (1 mL) and (ethylsulfanyl)sodium (168.69 mg, 2.01 mmol, 10 equiv.) 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 using the following conditions: (2#SHIMADZU(HPLC-01)): column, XBridge Prep Phenyl OBD Column, 19*250mm, 5μm; mobile phase, water (10mmol / L NH4HCO3) and acetonitrile (from 30% up to 40% in 10min); detector, UV220 / 254nm to give compound 26B* (20mg, 20% yield). LCMS, ESI: RT=0.85min, m / z=385.0[M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ 9.82 (s, 1H), 8.93 (s, 1H), 7.38 (d, J = 5.4 Hz, 1H), 6.97 (s, 1H), 6.81 (s, 1H), 4.97 (d, J = 6.2 Hz, 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 = 2.4 Hz, 3H), 1.36 (s, 3H).

[0635] Example 12. Biological activity of compounds of the present disclosure The biological activity of the compounds of the present disclosure was determined utilizing the assays described herein.

[0636] Human whole blood-NLRP3 Blood was collected from volunteers using lithium heparin coated tubes. Blood samples were distributed into 96-well plates using 90 μl per well. Priming was performed by adding 5 μl of LPS (O26:B6, Sigma L-2654) at a final concentration of 1 μg / ml for 4.5 hours in a humidified incubator at 37°C and 5% CO2. 30 minutes prior to NLRP3 activation, 5 μl of 20× compound solution or vehicle (2% DMSO) was added to each well and the plate was incubated on a shaker (450 rpm) at 37°C in a humidified incubator with 5% CO2. Activation was then performed by adding 3.3 μl of 31× ATP solution per well. At the end of the 30 minutes of stimulation, the plate was centrifuged (800 g, 10 minutes, room temperature) and the plasma from each well was frozen at -80°C. IL-1β levels in the supernatants were analyzed using a Mesoscale Discovery Assay (MSD K151TUK) according to the manufacturer's instructions. Human whole blood was collected from healthy volunteers after written informed consent was obtained.

[0637] Brain level (kp and kpu,u)-NLRP3 In vivo total brain-to-plasma ratios were assessed in CD1 mice following oral administration of compounds. Blood was collected at several time points up to 24 h and transferred to plastic microcentrifuge tubes containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 4000g for 5 min at 4°C to obtain plasma, which was then immediately frozen and stored at -75±15°C prior to analysis. Animals were terminally anesthetized with increasing concentrations of CO2 gas for approximately 1 min. At selected time points, whole brains were removed from the skull, rinsed with cold PBS to remove blood, dried with clean gauze, then frozen in liquid nitrogen and kept at -75±15°C prior to analysis. At the time of analysis, brain samples were homogenized with PBS at a ratio of 1:3 tissue weight (g) to PBS volume (mL). Drug levels in plasma and brain were quantified by LC / MS / MS on an AB Sciextriple Quad 5500+ instrument after separation on a HALO 160A ES-C18, 2.7 μm 2.1 × 50 mm column. Quantification was performed using calibration curves generated with blank plasma or blank brain homogenate. AUC inf and AUC last The software WinNonlin (Phoenix™) was used for pharmacokinetic analysis from concentration versus time data, including the Kp ratio (total brain concentration versus total plasma concentration) (AUC tot,br ) / (AUC tot,pl ) was calculated as

[0638] The unbound brain exposure is expressed as Kp uu This was evaluated as the free brain / free plasma concentration ratio (C u,br / C u,pl ) is. C u,br / C u,pl The ratio is the F determined in vitro. u,br and F u,pl Using the method, the in vivo total brain-to-plasma ratio (C tot,br / C tot,pl ) was obtained.

[0639] Plasma protein binding and brain homogenate protein binding were measured by equilibrium dialysis on HTD dialysis plates. The dialysis membrane was soaked in ultrapure water for 60 min to separate the strips, then soaked in 20% ethanol for 20 min, and finally soaked in dialysis buffer for 20 min. The dialysis apparatus was assembled according to the manufacturer's instructions. Each cell received 150 μL of plasma or brain homogenate spiked with 1 mM compound and dialyzed against an equal volume of dialysis buffer (PBS). The dialysis plate was sealed and incubated for 6 hours in an incubator at 37°C, 5% CO2, 100 rpm. At the end of the incubation, compound concentrations were measured in both chambers by LC-MS / MS on a Triple Quad™ 5500 from AB Inc after separation on an XSelect Hss T3 2.5μ (2.1×30 mm) column. The free fraction (Fu) was calculated as (peak area ratio buffer chamber / peak area ratio plasma chamber).

[0640] Kp uu is (AUC tot,br ×F u,br ) / (AUC tot,pl ×F u,pl ) was calculated.

[0641] Activity Data Table D assigns each compound a code for potency in the human whole blood (hWB) NLRP3 assay: A or B. According to this code, A is IC 50 A represents an IC value ≤ 1.0 µM; B represents an IC 50 Values ​​>1.0 μM represent the corresponding raw activity data.

[0642] The table below also assigns each compound a code of kp and kpu,u values: A or B, where A represents a value greater than 0.3 and B represents a value less than 0.3. The kp values ​​were calculated by measuring the total brain drug level (AUC) over 24 hours in mice dosed at 20 mpkPO and dividing by the plasma AUC. The kpu,u was then calculated by 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 ​​0.3 or less are not brain penetrant. ND=not determined. The corresponding raw kp and kpu,u data are also included. [Table 6-1] [Table 6-2]

[0643] Comparative Example The compounds described in the present disclosure are useful for treating NLRP3 protein-mediated diseases and / or disorders, and are structurally related to the compounds previously disclosed in US Patent Application No. 17 / 528,928 as inhibitors of the same NLRP3 protein.However, the brain levels of these active pharmaceutical ingredients are unexpected and therefore not contemplated in US Patent Application No. 17 / 528,928.Therefore, the unexpected ability of the present compounds 1*, 2*, 3*, 4*, 5 and 6 to penetrate the blood-brain barrier constitutes a novel invention.

[0644] Moreover, as shown in Table D above, it is not clear that the inhibitors of NLPR3 protein described in USSN 17 / 528,928 exhibit this unexpected activity. Selected NLPR3 inhibitors of the present disclosure have been found to exhibit stronger brain-penetrating properties in direct comparison with compounds of the USSN 17 / 528,928 application that have similar NLPR3 inhibitory activity in blood, as shown in Table D. As illustrated more clearly in the above table, compounds 1*, 2, 3*, 4*, 5, and 6 of the present disclosure exhibit 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), each of which exhibits "B" brain levels and is not brain-penetrating, thereby making the compounds of the present application more useful for treating NLPR3-mediated CNS diseases.

[0645] The solubility of the compound of formula (I) is also improved by the incorporation of R groups such as chloro groups while maintaining a Kpu,u of more than 0.3. 3 It has further been discovered that the compounds can be improved by replacing the halogen moiety of with a C1-C6 alkyl or C1-C6 alkoxy group, where alkyl or alk- are independently substituted with 0, 1, 2, or 3 halogen atoms. See, for example, Table E below. For example, chloro R 3 The solubility of Comparative Example 3 (compound 105 of USSN 17 / 528,928) having the moiety in phosphate buffer solution (PBS, pH 7.4) is compared to compounds 9*, 9B*, and 5. Both compound 9* and compound 9B* have chloro R 3 Part from -OCHF2R 3 Compound 5 results in a seven-fold increase in solubility in the chloro R 3 Part -CH3R 3 Each of these maintains good brain penetration. 3Incorporation of meta non-hydrogen groups into the moiety results in further increases in solubility: Compound 21* (37-fold increase), Compound 26* (42-fold increase), and Compound 24* (43-fold increase) compared to Comparative Example 3. Compounds with improved properties such as solubility, but not brain penetrability, may be useful for treating systemic (non-CNS) NLPR3-mediated diseases. [Table 7-1] [Table 7-2]

[0646] Equivalent The details of one or more embodiments of the present disclosure are set forth in the attached detailed description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are described herein. Other features, objects, and advantages disclosed herein will be apparent from this detailed description and from the claims. In this specification and the appended claims, the singular form includes the plural referent unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety.

[0647] The foregoing description has been presented for purposes of illustration only and is not intended to limit the disclosure to the precise form disclosed, but rather is intended to be limited by the claims appended hereto.

Claims

1. The following: 【Chemistry 1】 【Chemistry 2】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt or isotope-labeled compound of any of the above compounds.

2. Formula: 【Transformation 3】 The compound according to claim 1, which is a compound of or a pharmaceutically acceptable salt thereof.

3. Formula: 【Chemistry 4】 The compound according to claim 1, which is a compound of or a pharmaceutically acceptable salt thereof.

4. Formula: 【Transformation 5】 The compound according to claim 1, which is a compound of or a pharmaceutically acceptable salt thereof.

5. Formula: 【Transformation 6】 The compound according to claim 1, which is a compound of or a pharmaceutically acceptable salt thereof.

6. Formula: 【Transformation 7】 The compound according to claim 1, which is a compound of or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt or isotope-labeled compound thereof, or the compound described in any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

8. The pharmaceutical composition according to claim 7, for use in the treatment or prevention of a disease or disorder.

9. The pharmaceutical composition according to claim 8, wherein the disease or disorder is inflammation, autoimmune disease, cancer, infectious disease, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic system disease, rheumatic disease, mental disorder, graft-versus-host disease, allodynia, or NLRP3-related disease in a subject confirmed to possess germline or somatic nonsilent mutations in NLRP3.

10. The pharmaceutical composition according to claim 8, wherein the disease or disorder is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, acute kidney disease, chronic kidney disease, rare kidney disease, psoriasis, hidradenitis suppurativa, atopic dermatitis, dermatomyositis, Still's disease, juvenile idiopathic arthritis, cryopyrin-associated autoinflammatory syndrome, refractory epilepsy, stroke, or headache / pain, and optionally, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Macklewells syndrome, or neonatal onset multisystem inflammatory disease.

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