TW202345836A - Pyrido-[3,4-d]pyridazine amine derivatives useful as nlrp3 derivatives - Google Patents

Abstract

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

Description

Pyrido-[3,4-d]pyridazinamine derivatives that can be used as NLRP3 derivatives

The present disclosure relates to inhibitors of NLR family pyrin domain 3 (NLRP3)-containing proteins. The inhibitors described herein can be used to treat diseases and conditions associated with modulation of the NLRP3 protein. In particular, the present invention is directed to compounds and pharmaceutical compositions that inhibit NLRP3, methods of using these compounds and pharmaceutical compositions to treat NLRP3-related diseases and conditions, and methods of synthesizing such compounds and compositions.

Innate immune responses are mediated by different types of receptors called pattern recognition receptors (PRRs). PRR recognizes the presence of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Once engaged, these receptors trigger activation of downstream inflammatory pathways, which help resolve the damage. However, in many cases, this activation may be uncontrolled and lead to disease.

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

NLRP3 is the best-characterized inflammasome and has been shown to be critical in innate immunity and inflammatory responses. While several other NLR complexes such as NLRC4 are activated under very specific circumstances, NLRP3 can be activated by a wide variety of stimuli and should be considered a sensor of imbalances in cellular homeostasis. Therefore, its exact function is necessary. In addition to its role in host immune defense, dysregulation of NLRP3 has been implicated in the pathogenesis of many inflammatory conditions. These include genetic disorders such as cryptopyrin-associated periodic syndrome (CAPS) caused by gain-of-function mutations in the NLRP3 gene, as well as many common neurological and systemic diseases. Importantly, NLRP3 overactivation has been preclinically shown to play a key role in a number of inflammatory and degenerative diseases, including NASH, atherosclerosis and other cardiovascular diseases, and Alzheimer's disease. , Parkinson's disease, diabetes, gout and many other autoinflammatory diseases. Accordingly, there is an unmet need in the art for the development of small molecules for modulating NLRP3 activity to treat various diseases and conditions.

In one aspect, the present disclosure provides , inter alia, compounds of formula (I): (I), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, wherein: A is 5 to 8 membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom; R ¹ is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; R ² is halogen or C ₁ -C ₆ alkyl; or R ¹ and R ² together with the atoms to which they are connected form a 3- or 4-membered carbocyclic ring; R ³ is -OH, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy ; X is H, -OH, halogen, -NH2 _, -NH( _C1 - _C6alkyl ), -N( _C1 - _C6alkyl ) ₂ or _C1 - _C6alkyl ; and ^R4 is H, C ₁ -C ₆ alkyl, or -C(O)(C ₁ -C ₆ alkyl); and p is 0 or 1, where each instance of alkyl, alkyl-, or carbocyclic ring is independently 0, 1, 2 or 3 halogen atoms are substituted, and when R ³ is Cl, then Not for .

In some embodiments, compounds of formula (I) are other than .

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

In another aspect, the disclosure particularly provides suitable compounds selected from Table 1 or Table 2, and pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers or interactions thereof. Allomers.

In another aspect, the present disclosure provides, inter alia, suitable compounds 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]pyridazine-1- base) phenol; (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)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-(tri Fluoromethyl)phenol and its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers or tautomers.

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

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

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

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

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

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

In some aspects, the present disclosure provides compounds obtainable by or by methods for preparing compounds as described herein (e.g., methods comprising one or more steps described in Schemes 1 and 2) .

In some aspects, the disclosure provides pharmaceutical compositions that include a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

In some aspects, the disclosure provides intermediates as described herein that are useful in methods of preparing compounds as described herein ( e.g. , the intermediates are selected from the group consisting of intermediates described in Examples 1-11 ).

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

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

In some aspects, the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition disclosed herein.

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

In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing the diseases or conditions disclosed herein.

In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating the diseases or conditions disclosed herein.

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

In some embodiments, the disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, renal disease, liver disease, eye disease, skin disease, Lymphoid diseases, rheumatic diseases, psychiatric disorders, graft-versus-host disease, allodynia, or NLRP3-related diseases in individuals identified to carry germline or somatic non-silent mutations in NLRP3.

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

In some embodiments, the kidney disease is acute kidney disease, chronic kidney disease, or rare kidney disease.

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

In some embodiments, the rheumatic disease is dermatomyositis, Still’s disease, or juvenile idiopathic arthritis.

In some embodiments, the NLRP3-related disease in individuals identified as carrying germline or somatic non-silent mutations in NLRP3 is cryptopyrin-related autoinflammatory syndrome.

In some embodiments, the cryptopyrin-associated autoinflammatory syndrome is familial cryogenic autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease.

In some aspects, the disclosure provides a method of preparing a compound of the disclosure.

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

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 the specification, the singular also includes the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. There is no admission that the references cited herein constitute prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between the chemical structure and name of a compound disclosed herein, the chemical structure shall control.

Other features and advantages of the present disclosure will become apparent from the following embodiments and patent claims.

Related applications

This application refers to U.S. Non-Provisional Application 17/704,983 filed on March 25, 2022, U.S. Provisional Application 63/420,930 filed on October 31, 2022, and U.S. Provisional Application No. 63/420,930 filed on February 7, 2023. No. 63/443,874, the entire contents of each of these applications are incorporated herein by reference.

The present disclosure relates to phthalazine derivatives, pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers ( e.g., single stereoisomers, mixtures or stereoisomers). racemic mixtures of isomers), tautomers, prodrugs and isotopically labeled compounds that inhibit NLRP3 activity and are therefore useful in methods of treating the human or animal body. Certain compounds of the present invention exhibit surprising and unexpected superiority in brain penetration. The present disclosure also relates to processes for preparing such compounds, pharmaceutical compositions containing them, and their use in the treatment of conditions involving NLRP3, such as inflammation, autoimmune diseases, cancer, infection, central nervous system Systemic disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, renal disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or To identify NLRP3-related diseases in individuals carrying germline or somatic non-silent mutations in NLRP3. definition

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

As used herein, "alkyl", "C ₁ , C ₂ , C ₃ , C ₄ , C ₅ or C ₆ alkyl" or "C ₁ -C ₆ alkyl" is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ or C ₆ straight chain (linear) saturated aliphatic hydrocarbon group and C ₃ , C ₄ , C ₅ or C ₆ branched saturated aliphatic hydrocarbon group. For example, C ₁ -C ₆ alkyl is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkyl. Examples of alkyl groups include moieties having one to six carbon atoms such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, Isopentyl or n-hexyl. In some embodiments, a linear or branched alkyl group has six or fewer carbon atoms ( e.g. , C ₁ -C ₆ for linear, C ₃ -C ₆ for branched), and in another embodiment In examples, straight or branched chain alkyl groups have four or fewer carbon atoms.

Alkyl may be "optionally substituted alkyl," which refers to an unsubstituted alkyl group or an alkyl group having the specified substituent 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, alkoxy, phosphate, phosphonato, sulfonate Phosphonate group (phosphinato), amine group (including alkylamino group, dialkylamino group, arylamine group, diarylamine group and alkylarylamine group), acylamino group (including alkylcarbonyl group Amino group, arylcarbonylamino group, carbamate group and urea group), formamidino group, imine group, sulfhydryl group, alkylthio group, arylthio group, thiocarboxylate, sulfate ester, alkyl sulfenyl group acyl, sulfonate, sulfonamide, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkaryl, or aromatic or heteroaromatic moiety.

Other optionally substituted moieties, such as optionally substituted carbocyclic or heterocycloalkyl groups, include both unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl -1,2,3,6-tetrahydropyridyl.

As used herein, the term "alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyl groups described above, but containing at least one double bond. For example, the term "alkenyl" includes linear alkenyl groups (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and Branched alkenyl. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C ₂ -C ₆ for straight chain, C ₃ -C ₆ for branched chain) . The term "C ₂ -C ₆ " includes alkenyl groups containing from two to six carbon atoms. The term "C ₃ -C ₆ " includes alkenyl groups containing three to six carbon atoms.

As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl group or an alkenyl group having the specified substituent replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, Alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphonite , Amino group (including alkylamino group, dialkylamino group, arylamine group, diarylamine group and alkylarylamine group), acylamino group (including alkylcarbonylamino group, arylcarbonyl group Amine group, carbamide group and urea group), formamidinyl group, imine group, sulfhydryl group, alkylthio group, arylthio group, sulfur carboxylate, sulfate ester, alkylsulfinyl group, sulfonate group , sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkaryl, or aromatic or heteroaromatic moiety.

As used herein, the term "alkynyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyl groups described above, but containing at least one bond. For example, "alkynyl" includes straight chain alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and Branched alkynyl. In certain embodiments, a straight or branched chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C ₂ -C ₆ for straight chain, C ₃ -C ₆ for branched chain) . The term "C ₂ -C ₆ " includes alkynyl groups containing two to six carbon atoms. The term "C ₃ -C ₆ " includes alkynyl groups containing three to six carbon atoms. As used herein, a "C ₂ -C ₆ alkenyl linker" or "C ₂ -C ₆ alkenyl linker" is intended to include a C ₂ , C ₃ , C ₄ , C ₅ or C ₆ chain (linear or branched chain) divalent unsaturated aliphatic hydrocarbon group. For example, a C ₂ -C ₆ alkenyl linker is intended to include C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkenyl linker groups.

As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl group or an alkynyl group having the specified substituent replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, Alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphonite , Amino group (including alkylamino group, dialkylamino group, arylamine group, diarylamine group and alkylarylamine group), acylamino group (including alkylcarbonylamino group, arylcarbonyl group Amine group, carbamide group and urea group), formamidinyl group, imine group, sulfhydryl group, alkylthio group, arylthio group, sulfur carboxylate, sulfate ester, alkylsulfinyl group, sulfonate group , sulfonamide group, sulfonamide group, nitro group, trifluoromethyl group, cyano group, azide group, heterocyclyl group, alkaryl group, or aromatic or heteroaromatic moiety.

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

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

As used herein, the term "cycloalkyl" or "carbocycle" or "carbocyclyl" means having 3 to 30 carbon atoms (e.g., C ₃ -C ₁₂ , C ₃ -C ₁₀ or C ₃ -C ₈ ) saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (for example, fused, bridged or spirocyclic) systems. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2 ,3,4-tetrahydronaphthyl and adamantyl.

As used herein, the term "heterocycloalkyl" refers to a ring having one or more ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur (such as O, N, S, P, or Se), such as 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 ring heteroatoms, or a saturated or, for example, 1, 2, 3, 4, 5 or 6 ring heteroatoms Partially unsaturated 3-8 membered monocyclic ring, 7-12 membered bicyclic ring (fused ring, bridged ring or spiro ring) or 11-14 membered tricyclic ring system (fused ring, bridged ring or spiro ring). Examples of heterocycloalkyl include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuryl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, Oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydro Pyridyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazacycloheptyl, 1,4-oxazacycloheptyl , 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3] Heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl base, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H -Spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c] Pyridin]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3 ,4-c]pyridyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-nitrogen Azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl Base-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]oct-6-yl, 5,6-dihydro -4H-cyclopenta[b]thienyl and the like. In the case of polycyclic heterocycloalkyl groups, only one ring in the heterocycloalkyl group must be non-aromatic ( eg , 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

As used herein, the term "optionally substituted heterocycloalkyl" refers to a heterocycloalkyl group having the specified substituent replacing one or more hydrogen atoms on one or more carbons 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, alkoxy, phosphate, phosphonate, phosphonite , Amino group (including alkylamino group, dialkylamino group, arylamine group, diarylamine group and alkylarylamine group), acylamino group (including alkylcarbonylamino group, arylcarbonyl group Amine group, carbamide group and urea group), formamidinyl group, imine group, sulfhydryl group, alkylthio group, arylthio group, sulfur carboxylate, sulfate ester, alkylsulfinyl group, sulfonate group , sulfonamide group, sulfonamide group, nitro group, trifluoromethyl group, cyano group, azide group, heterocyclyl group, alkaryl group, or aromatic or heteroaromatic moiety.

As used herein, the term "hydroxy" or "hydroxyl" includes groups having -OH or ^-O- .

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

The term "haloalkyl" or "haloalkoxy" refers to the alkyl portion of an alkyl or alkoxy group substituted with one or more halogen atoms.

As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl groups covalently attached to an oxygen atom. Examples of alkoxy or alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy may be substituted by groups such as: alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid Esters, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphine Acid group, amine group (including alkylamino group, dialkylamino group, arylamine group, diarylamine group and alkylarylamine group), acylamine group (including alkylcarbonylamino group, arylamine group (carbonylamino group, carbamate group and urea group), formamidino group, imine group, sulfhydryl group, alkylthio group, arylthio group, thiocarboxylate, sulfate ester, alkylsulfinyl group, sulfonyl group Acid group, sulfonamide group, sulfonamide group, nitro group, trifluoromethyl group, cyano group, azide group, heterocyclyl group, alkaryl group, or aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

Unless otherwise explicitly defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. In the case of two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be linked at a single point ( eg , biphenyl), or fused ( eg , naphthyl). Aryl groups may optionally be substituted at any point of attachment with one or more substituents, for example 1 to 5 substituents. Exemplary substituents include, but are not limited to -H, -halogen, -O-(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl, -O-(C ₂ -C ₆ )alkenyl, -O-(C ₂ -C ₆ )alkynyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, -OH, -OP(O)(OH) ₂ , -OC(O )(C ₁ -C ₆ )alkyl, -C(O)(C ₁ -C ₆ )alkyl, -OC(O)O(C ₁ -C ₆ )alkyl, -NH ₂ , NH((C ₁ -C ₆ )alkyl), N((C ₁ -C ₆ )alkyl) ₂ , -S(O) ₂ -(C ₁ -C ₆ )alkyl, -S(O)NH(C ₁ - C ₆ )alkyl and -S(O)N((C ₁ -C ₆ )alkyl) ₂ . The substituents themselves may optionally be substituted. Furthermore, when containing two or more fused rings, an aryl group as defined herein may have a saturated or partially unsaturated ring fused to a fully unsaturated aromatic ring. Exemplary ring systems for such aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzonacene base, 10,11-dihydro-5H-dibenzo[a,d][7]annyl and the like.

Unless otherwise explicitly defined, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, containing one or more elements selected from the group consisting of N, O, S, P, Se Or the ring heteroatom of B, and the remaining ring atoms are C. Heteroaryl as defined herein also means bicyclic heteroaryl in which the heteroatom is selected from N, O, S, P, Se or B. Heteroaryl as defined herein also means a tricyclic heteroaryl containing one or more heterocyclic atoms selected from N, O, S, P, Se or B. Aromatic groups are optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophene -2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazolyl, indazolyl, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl , triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridyl, imidazo[1,2-a]pyridyl, indazolyl, pyrrolo[2 ,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thieno[2, 3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indolyl, indolinyl, indolinonyl (indolinonyl), dihydrobenzothienyl, dihydrobenzothienyl Hydrobenzofuranyl, benzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolyl, dihydrobenzothiazinyl, quinolyl, iso Quinolyl, 1,6-naphthyridinyl, benzo[de]isoquinolyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyridinyl Azinyl, quinazolinyl, tetrazolo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, isoindolyl, pyrrolo[2 ,3-b]pyridyl, pyrro[3,4-b]pyridyl, pyrro[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrro[1,2 -a]pyrimidinyl, tetrahydropyrro[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]pyridyl, furo[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiophene Azinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridyl, benzothienyl, 1,5-naphthyridinyl, furo[3,2-b] Pyridine, [1,2,4]triazolo[1,5-a]pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1, 2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole , 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4 ,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4] Thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl and their derivatives. Furthermore, when containing two or more fused rings, a heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring, for example, containing 1 to 3 A 5-membered heteroaromatic ring with heteroatoms selected from N, O, S, P, Se or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 A heteroatom selected from N, O, S, P, Se or B, optionally substituted with one or more pendant oxygen groups. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused with a saturated or partially unsaturated ring as described herein. Exemplary ring systems for such heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothienyl, dihydrobenzofuryl, chromanyl, thiobenzo Dihydropyranyl, tetrahydroquinolyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolyl, 2,3-dihydrobenzofuranyl, benzofuranyl, indo Dolinyl, indolinyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 7,8-dihydro-6H-pyrido [3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolazinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3- e]pyridyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolazinyl, pyrazolo[1,5-a]pyrimidine-7(4H)-one, 3,4 -Dihydropyrazino[1,2-a]indole-1(2H)-one, 7-oxabicyclo[2.2.1]heptyl or benzo[ c ][1,2]oxy Heteraborole-1( 3H )-alcohol group.

Cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be substituted at one or more ring positions (e.g., ring-forming carbons or heteroatoms such as N) with such substituents as described above, e.g., alkyl , alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkyl Aminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphoric acid Ester, phosphonate group, phosphonite group, amine group (including alkylamino group, dialkylamino group, arylamine group, diarylamine group and alkylarylamino group), acylamine group ( Including alkylcarbonylamino, arylcarbonylamino, carboxyl and ureido), formamidino, imine, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, Alkylsulfinyl, sulfonate, sulfonamide, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkaryl, or aromatic or heteroaromatic family part. Aryl and heteroaryl groups can also be fused or bridged with nonaromatic alicyclic or heterocyclic rings to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl, such as benzo[d][ 1,3]dioxol-5-yl).

As used herein, unless otherwise stated, the expressions "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 the group consisting of A, B and C" and the like are used interchangeably and all refer to a selection from the group consisting of A, B and C /or a group of C, that is, one or more A, one or more B, one or more C, or any combination thereof.

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

When any variable (eg, R) occurs more than once in any component or formula of a compound, its definition on each occurrence is independent of its definition on every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group is optionally substituted with up to two R moieties, and R is selected independently of the definition of R at each occurrence. Furthermore, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

It will be appreciated that the present disclosure provides methods for the synthesis of compounds of any formula described herein. This disclosure also provides detailed methods for synthesizing various disclosed compounds of this disclosure according to those shown in the following schemes and examples.

It should be understood that throughout this specification, when a composition is described as having, including, or containing a particular component, it is contemplated that the composition also consists essentially of or consists of the recited components. Similarly, where a method or process is described as having, including, or including a particular process step, the process also consists essentially of or consists of the enumerated process steps. Furthermore, it should be understood that the order of steps or the order in which certain actions are performed is not critical so long as the invention remains operable. In addition, two or more steps or actions can be performed simultaneously.

It will be appreciated that the synthetic methods of the present disclosure are tolerant of a wide variety of functional groups and thus a variety of substituted starting materials may be used. Such processes typically provide the desired final compound at or near the end of the entire process, although in some cases further conversion of the compound to its pharmaceutically acceptable salt may be required.

It will be understood that compounds of the present disclosure may be prepared using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, in a variety of ways known to those skilled in the art, or in view of the teachings herein. Standard synthetic methods and procedures will be apparent to those skilled in the art. 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 technical field. Although not limited to any one or a few sources, classic texts such as Smith, M. B., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., John Wiley & Sons: New York, 2001; Greene , T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd ed., 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, eds. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated herein by reference, are known to those skilled in the art to be useful and Recognized reference textbook on organic synthesis

One of ordinary skill in the art will note that during the reaction sequences and synthetic schemes described herein, the order of certain steps, such as the introduction and removal of protecting groups, may be changed. One of ordinary skill in the art will recognize that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups can also be used to distinguish similar functional groups in molecules. A list of protecting groups and how to introduce and remove such groups can be found in Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999.

It is to be understood that, unless otherwise indicated, any description of a method of treatment or prevention includes the use of a compound to provide such treatment or prevention as described herein. It will be further understood that, unless otherwise indicated, any description of a method of treatment or prevention includes the use of the compounds in the preparation of a medicament for the treatment or prevention of such disorders. Treatment or prevention includes treatment or prevention in humans or non-human animals, including rodents and other disease models.

It is to be understood that, unless otherwise indicated, any description of a method of treatment includes the use of the compounds as described herein to provide such treatment. It will be further understood that, unless otherwise indicated, any description of a method of treatment includes the use of the compounds in the preparation of a medicament for treating such disorders. Treatment includes treatment of humans or non-human animals, including rodents and other disease models. As used herein, the term "individual" is interchangeable with the term "individual in need," both of which refer to an individual who has a disease or is at increased risk of developing the disease. "Individual" includes mammals. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or pig. In one embodiment, the mammal is human. An individual in need thereof may be one who has been previously diagnosed or identified as having a disease or condition disclosed herein. The individual in need may also be an individual suffering from a disease or condition disclosed herein. Alternatively, an individual in need thereof may be an individual who is at increased risk of developing such disease or disorder relative to the general population (ie, an individual who is susceptible to developing such disorder relative to the general population). An individual in need thereof may have a disease or condition disclosed herein that is refractory or resistant (ie, a disease or condition disclosed herein that is unresponsive or has not yet responded to treatment). Individuals may be resistant at the beginning of treatment or may become resistant during treatment. In some embodiments, an individual in need thereof receives and fails all known effective therapies for a disease or condition disclosed herein. In some embodiments, the individual in need thereof received at least one prior therapy.

As used herein, the terms "treating" or "treat" describe the management and care of a patient for the purpose of combating a disease, disorder, or condition, and include administration of a compound of the present disclosure or its pharmaceutical Above acceptable salts, polymorphs or solvates to reduce symptoms or complications of a disease, disorder or condition, or to eliminate a disease, disorder or condition. The term "treatment" may also include treatment of in vitro cell or animal models. It will be understood that references to "treating" or "treatment" include alleviation of established symptoms of a disorder. Therefore, "treating" or "treatment" a condition, condition or disorder includes: (1) preventing or delaying the occurrence of the condition, condition or disorder in a person who may be suffering from or susceptible to the condition, condition or disorder but has not yet experienced or exhibited the condition, condition or disorder; clinical or subclinical symptoms of a condition, condition, or disorder in a human being who develops clinical symptoms of that condition, condition, or disorder, (2) inhibiting that condition, condition, or disorder, that is, preventing, reducing, or delaying the progression of the disease or its recurrence (in in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof, or (3) alleviation or alleviation of the disease, that is, causing resolution of the state, condition or disorder, or at least one clinical or subclinical symptom thereof.

It should be understood that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs, or solvates thereof, may or may also be used to prevent related diseases, disorders, or conditions, or to identify compounds for such purposes. Suitable candidates.

As used herein, the terms "preventing," "preventing" or "protecting from" describe reducing or eliminating the onset of symptoms or complications of such disease, disorder or condition.

It will be understood that those skilled in the art can consult general reference texts for detailed descriptions of known or equivalent technologies discussed herein. Such 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 ed.), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975) , Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th ed. (1990). You may also refer to these texts when making or using any aspect of this disclosure.

It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to an individual. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. A unit dosage form can be any of a variety of forms, including, for example, a capsule, IV bag, tablet, single pump on an aerosol inhaler, or vial. The amount of active ingredient (eg, a formulation of a disclosed compound or a salt, hydrate, solvate or isomer thereof) in a unit dosage composition is an effective amount and will vary depending on the particular treatment involved. Those skilled in the art will understand that routine changes in dosage may sometimes be necessary depending on the age and condition of the patient. Dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

As used herein, the term "pharmaceutically acceptable" means within the context of reasonable medical diagnosis; suitable for contact with human and animal tissue without undue toxicity, irritation, allergic reactions or other problems or complications; and reasonably Those compounds, anions, cations, materials, compositions, carriers and/or dosage forms that are commensurate with their benefit/risk ratio.

As used herein, the term "pharmaceutically acceptable excipient" means an excipient useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable , and includes excipients acceptable for veterinary use and human pharmaceutical use. As used in the specification and patent application, "pharmaceutically acceptable excipients" include one and more than one such excipients.

It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral administration, such as intravenous, intradermal, subcutaneous, oral (eg, ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous application may include the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents , such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate or phosphate, and Tonicity-adjusting agents such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be enclosed in ampoules, disposable syringes or multi-dose vials made of glass or plastic.

It will be appreciated that a compound or pharmaceutical composition of the present disclosure can be administered to an individual by many of the well-known methods currently used in chemotherapy treatments. For example, compounds of the present disclosure can be injected into the bloodstream or body cavity or administered orally or through the skin using a patch. The dose selected should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The status of a disease condition (such as a disease or disorder disclosed herein) and the patient's health should preferably be closely monitored during treatment and for a reasonable period thereafter.

As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents an identified disease or disorder, or that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any testing method known in the art. The precise effective amount for an individual will depend on the individual's weight, size and health condition; 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 condition can be determined by routine experimentation within the skill and judgment of the clinician.

It will be appreciated that for any compound, the therapeutically effective amount can be estimated initially in cell culture assays, such as with tumor cells, or in animal models, typically rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration to humans. Therapeutic/preventive efficacy and toxicity can be determined by standard medical procedures in cell cultures or experimental animals, such as ED ₅₀ (the dose that is therapeutically effective in 50% of the population) and LD ₅₀ (the dose that is lethal in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio _LD50 / _ED50 . There is a need for pharmaceutical compositions that exhibit a large therapeutic index. The dosage may vary within this range depending on the dosage form employed, the patient's sensitivity and the route of administration.

Adjust dosage and administration to provide adequate levels of active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the individual's general health, the individual's age, weight and gender, diet, timing and frequency of administration, drug combinations, reaction sensitivities and tolerance/response to therapy.

Pharmaceutical compositions containing the active compounds of the present disclosure can be produced in a generally known manner, such as by conventional mixing, dissolving, granulating, dragee manufacturing, grinding, emulsifying, encapsulating, embedding or freeze-drying processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients that facilitate processing of the active compounds into pharmaceutically acceptable preparations. agents and/or auxiliaries. Of course, the appropriate formulation will depend on the route of administration chosen.

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, N.J.), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that it is easy to inject. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating effects of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (eg, glycerin, propylene glycol and liquid polyethylene glycol and the like), and suitable mixtures thereof. Proper flowability can be maintained, for example, by using coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. Prevention of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. In many cases, it is preferred to include isotonic agents such as sugars, polyols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition agents delaying absorption, such as aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with one or a combination of ingredients enumerated above, as required, in the appropriate solvent, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional required ingredients from its previous sterile-filtered solution.

Oral compositions usually include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compounds may be mixed with excipients and used in the form of tablets, dragees, or capsules. Oral compositions can also be prepared using a fluid carrier that acts as a mouthwash, wherein the compound in the fluid carrier is administered orally and swished around the mouth and spitted out or swallowed. Pharmaceutically compatible binders and/or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges and the like may contain any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients, such as starch or lactose; disintegrants, Such as alginic acid, Primogel or cornstarch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silica; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, salicylate ester or orange flavoring.

For inhalation administration, the compounds are delivered as an aerosol spray from a pressurized container or dispenser containing a suitable propellant, for example a gas such as carbon dioxide, or a spray.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels or creams well known in the art.

The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art. These materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the individuals to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. Effect. The specifications for dosage unit forms of this disclosure are determined by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect sought to be achieved.

In therapeutic applications, the dosage of the pharmaceutical composition used in accordance with this disclosure depends on the agent; the age, weight and clinical condition of the receiving patient; and the experience and judgment of the clinician or practitioner administering the therapy; and factors affecting the selected dosage. vary depending on other factors. Generally, the dosage will be sufficient to cause slowing and preferably regression of symptoms of the diseases or conditions disclosed herein, and preferably also to cause complete resolution of the disease or condition. Doses may range from about 0.01 mg/kg per day to about 5000 mg/kg per day. An effective amount of a pharmaceutical agent is one that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term "dose effective manner" refers to the amount of active compound that produces the desired biological effect in an individual or cell.

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

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

As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of a compound of the present disclosure in which the parent compound is modified by preparing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali metal or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional nontoxic salts or quaternary ammonium salts of the parent compound, for example formed from nontoxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from: 2-acetyloxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, Benzoic acid, bicarbonate, carbonic acid, citric acid, ethylenediamine tetraacetate, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, gluconic acid, gluconic acid, glutamic acid, ethanol Acid, ethanolic acid, hexylresorcin, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxythiosulfonic acid, lactic acid, lactobionic acid , Lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, paraptopic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, Salicylic acid, stearic acid, ethylenic acid, succinic acid, sulfamic acid, p-sulfonamide, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid; and common amino acids such as glycine, alanine, amphetamine Acid, arginine, etc.

In some embodiments, pharmaceutically acceptable salts are sodium salts, potassium salts, calcium salts, magnesium salts, diethylamine salts, choline salts, meglumine salts, benzathine salts, tromethamine salts, Amine salt, arginate or lysate.

Other examples of pharmaceutically acceptable salts include caproic 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, trimethyl Acetic acid, tertiary butylacetic acid, muconic acid and the like. The disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or with an organic base such as ethanolamine, diethanolamine, triethanolamine, ambutylamine Triols, N-methylglucamine and the like. In the salt form, it is understood that the ratio of the cation or anion of the compound to the salt may be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2 or 1:3.

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

The compound or a pharmaceutically acceptable salt thereof is administered orally, nasally, transdermally, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal and parenteral. Invest. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain investment approaches.

Dosage regimens for use of compounds are selected based on a variety of factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compounds used or their salts. A generally skilled physician or veterinarian can readily determine and prescribe the effective amount of drug required to prevent, combat, or arrest the progression of the disease. A generally skilled physician or veterinarian can readily determine and prescribe the effective amount of drug required to combat or arrest the progression of the disease.

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

Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of the disclosure will be apparent from various examples. The examples provided illustrate different components and methods that can be used to practice the present disclosure. Examples do not limit the claimed disclosures. Based on the present disclosure, skilled artisans can identify and employ other components and methods useful in practicing the present disclosure.

In the synthetic scheme described here, the compounds are drawn in a specific configuration for simplicity. Such specific configurations should not be construed to limit this disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor to exclude isomers, tautomers, Mixtures of regioisomers or stereoisomers; however, it is understood that a given isomer, tautomer, regioisomer or stereoisomer may have greater than or equal to that of another isomer, tautomer , regioisomers or stereoisomers with higher levels of activity.

All publications and patent documents mentioned herein are hereby incorporated by reference in their entirety, as if each such publication or document was specifically and individually indicated to be incorporated by reference. Reference to publications and patent documents does not constitute an admission of any relevant prior art, nor does it constitute any admission of their content or date. Having now described the invention by way of written description, those skilled in the art will recognize that the invention may be practiced in various embodiments, and that the foregoing description and the following examples are for purposes of illustration and are not limiting of what follows. The scope of the patent application.

As used herein, the phrase "compounds of the present disclosure" refers to those compounds disclosed herein, both generally and specifically. Compounds disclosed in this disclosure

In one aspect, the disclosure particularly provides compounds of formula ( I ): ( I ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, wherein: A is 5 to 8 membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom; R ¹ is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; R ² is halogen or C ₁ -C ₆ alkyl; or R ¹ and R ² together with the atoms to which they are connected form a 3- or 4-membered carbocyclic ring; R ³ is -OH, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy ; X is H, -OH, halogen, -NH2 _, -NH( _C1 - _C6alkyl ), -N( _C1 - _C6alkyl ) ₂ or _C1 - _C6alkyl ; and ^R4 is H, C ₁ -C ₆ alkyl, or -C(O)(C ₁ -C ₆ alkyl); and p is 0 or 1, where each instance of alkyl, alkyl-, or carbocyclic ring is independently 0, 1, 2 or 3 halogen atoms are substituted; and when R ³ is Cl, then Not for .

In some embodiments, compounds of formula (I) are other than , or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs.

In some embodiments, the compound has formula (I), wherein p is 1; R ¹ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; and R ² is C ₁ -C ₆ alkyl .

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

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

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

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

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

In some embodiments, p is 0 or 1.

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, R ¹ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, wherein alkyl or alkoxy is independently substituted with 0, 1, 2, or 3 halogen atoms.

In some embodiments, R ¹ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, wherein the alkyl or alkoxy is substituted with 1, 2, or 3 halogen atoms.

In some embodiments, R ¹ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy.

In some embodiments, ^R1 is halogen.

In some embodiments, ^R1 is F, Cl, Br, or I.

In some embodiments, ^R1 is F. In some embodiments, ^R1 is Cl. In some embodiments, ^R1 is Br. In some embodiments, ^R1 is I.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 halogens.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl substituted with 1, 2, or 3 halogens.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl.

In some embodiments, ^R1 is methyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is ethyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is propyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is butyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, each ^R1 is isopropyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is isobutyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 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, ^R1 is secondary butyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is secondary pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is secondary hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is tertiary butyl substituted with 0, 1, 2, or 3 halogens.

In some embodiments, ^R1 is methyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is ethyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is propyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is butyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is pentyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is hexyl substituted with 1, 2, or 3 halogens. In some embodiments, each ^R1 is isopropyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is isobutyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 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, ^R1 is secondary butyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is secondary pentyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is secondary hexyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is tertiary butyl substituted with 1, 2, or 3 halogens.

In some embodiments, ^R1 is methyl. In some embodiments, ^R1 is ethyl. In some embodiments, ^R1 is propyl. In some embodiments, ^R1 is butyl. In some embodiments, ^R1 is pentyl. In some embodiments, ^R1 is hexyl. In some embodiments, each ^R1 is isopropyl. In some embodiments, ^R1 is isobutyl. In some embodiments, ^R1 is isopentyl. In some embodiments, ^R1 is isohexyl. In some embodiments, ^R1 is secondary butyl. In some embodiments, ^R1 is secondary pentyl. In some embodiments, ^R1 is secondary hexyl. In some embodiments, ^R1 is tertiary butyl.

In some embodiments, R ¹ is C ₁ -C ₆ alkoxy substituted with 0, 1, 2, or 3 halogens.

In some embodiments, R ¹ is C ₁ -C ₆ alkoxy substituted with 1, 2, or 3 halogens.

In some embodiments, R ¹ is C ₁ -C ₆ alkoxy.

In some embodiments, ^R1 is _C1 alkoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is _C2 alkoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is _C3 alkoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is _C4 alkoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is _C5 alkoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R1 is _C6 alkoxy substituted with 0, 1, 2, or 3 halogens.

In some embodiments, ^R1 is _C1 alkoxy substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is _C2 alkoxy substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is _C3 alkoxy substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is _C4 alkoxy substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is _C5 alkoxy substituted with 1, 2, or 3 halogens. In some embodiments, ^R1 is _C6 alkoxy substituted with 1, 2, or 3 halogens.

In some embodiments, R ¹ is C ₁ alkoxy. In some embodiments, ^R1 is _C2 alkoxy. In some embodiments, R ¹ is C ₃ alkoxy. In some embodiments, R ¹ is C ₄ alkoxy. In some embodiments, R ¹ is C ₅ alkoxy. In some embodiments, R ¹ is C ₆ alkoxy.

In some embodiments, R ² is halogen or C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 halogens.

In some embodiments, R ² is halogen or C ₁ -C ₆ alkyl substituted with 1, 2, or 3 halogens.

In some embodiments, R ² is halogen or C ₁ -C ₆ alkyl.

In some embodiments, ^R2 is halogen.

In some embodiments, ^R2 is F, Cl, Br, or I.

In some embodiments, ^R2 is F. In some embodiments, ^R2 is Cl. In some embodiments, ^R2 is Br. In some embodiments, ^R2 is I.

In some embodiments, R ² is C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 halogens.

In some embodiments, R ² is C ₁ -C ₆ alkyl substituted with 1, 2, or 3 halogens.

In some embodiments, R ² is C ₁ -C ₆ alkyl.

In some embodiments, ^R2 is methyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is ethyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is propyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is butyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is isopropyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is isobutyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is isopentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is isohexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is secondary butyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is secondary pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is secondary hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R2 is tertiary butyl substituted with 0, 1, 2, or 3 halogens.

In some embodiments, ^R2 is methyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is ethyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is propyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is butyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is pentyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is hexyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is isopropyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is isobutyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is isopentyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is isohexyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is secondary butyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is secondary pentyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is secondary hexyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R2 is tertiary butyl substituted with 1, 2, or 3 halogens.

In some embodiments, ^R2 is methyl. In some embodiments, ^R2 is ethyl. In some embodiments, ^R2 is propyl. In some embodiments, ^R2 is butyl. In some embodiments, ^R2 is pentyl. In some embodiments, ^R2 is hexyl. In some embodiments, ^R2 is isopropyl. In some embodiments, ^R2 is isobutyl. In some embodiments, ^R2 is isopentyl. In some embodiments, ^R2 is isohexyl. In some embodiments, ^R2 is secondary butyl. In some embodiments, ^R2 is secondary pentyl. In some embodiments, ^R2 is secondary hexyl. In some embodiments, ^R2 is tertiary butyl.

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 substituted with 0, 1, 2, or 3 halogen atoms.

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 substituted with 1, 2, or 3 halogen atoms.

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.

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

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

In some embodiments, R ¹ and R ² together with the atoms to which they are attached form a 3-membered carbocyclic ring.

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

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

In some embodiments, R ¹ and R ² together with the atoms to which they are attached form a 4-membered carbocyclic ring.

In some embodiments, p is 1, and each of R ¹ and R ² is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In some embodiments, p is 1, and each of R ¹ and R ² is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, wherein R ¹ and R ² are connected to Ring A the same carbon atom above.

In some embodiments, p is 1 and each of R ¹ and R ² is methyl. In some embodiments, p is 1 and each of R ¹ and R ² is methyl, wherein R ¹ and R ² are connected to the same carbon atom on Ring A.

In some embodiments, R ³ is -OH, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, wherein alkyl or alkoxy is independently modified by 0, 1, 2, or 3 halogens replace.

In some embodiments, R ³ is -OH, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, wherein alkyl or alkoxy is substituted with 1, 2, or 3 halogens.

In some embodiments, R ³ is -OH, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy.

In some embodiments, ^R3 is -OH.

In some embodiments, ^R3 is halogen.

In some embodiments, ^R3 is Br. In some embodiments, ^R3 is Cl. In some embodiments, ^R3 is F. In some embodiments, ^R3 is I.

In some embodiments, ^R3 is other than halogen.

In some embodiments, R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy.

In some embodiments, R ³ is C ₁ -C ₆ alkyl substituted with 0, 1, 2 or 3 halogens.

In some embodiments, R ³ is C ₁ -C ₆ alkyl substituted with 1, 2, or 3 halogens.

In some embodiments, R ³ is C ₁ -C ₆ alkyl.

In some embodiments, ^R3 is methyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R3 is ethyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R3 is propyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R3 is butyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R3 is pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R3 is hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R3 is isopropyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R3 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, ^R3 is secondary butyl substituted with 0, 1, 2 or 3 halogens. In some embodiments, ^R3 is secondary pentyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R3 is secondary hexyl substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R3 is tertiary butyl substituted with 0, 1, 2, or 3 halogens.

In some embodiments, ^R3 is methyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is ethyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is propyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is butyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is pentyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is hexyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is isopropyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 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, ^R3 is isohexyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is secondary butyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is secondary pentyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is secondary hexyl substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is tertiary butyl substituted with 1, 2, or 3 halogens.

In some embodiments, ^R3 is methyl. In some embodiments, ^R3 is ethyl. In some embodiments, ^R3 is propyl. In some embodiments, ^R3 is butyl. In some embodiments, ^R3 is pentyl. In some embodiments, ^R3 is hexyl. In some embodiments, ^R3 is isopropyl. In some embodiments, ^R3 is isobutyl. In some embodiments, ^R2 is independently isopentyl. In some embodiments, ^R3 is isohexyl. In some embodiments, ^R3 is secondary butyl. In some embodiments, ^R3 is secondary pentyl. In some embodiments, ^R3 is secondary hexyl. In some embodiments, ^R3 is tertiary butyl.

In some embodiments, R ³ is C ₁ -C ₆ alkoxy substituted with 0, 1, 2 or 3 halogens.

In some embodiments, R ³ is C ₁ -C ₆ alkoxy substituted with 1, 2 or 3 halogens.

In some embodiments, R ³ is C ₁ -C ₆ alkoxy.

In some embodiments, ^R3 is methoxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, ^R3 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, ^R3 is butoxy substituted with 0, 1, 2 or 3 halogens. In some embodiments, R ³ is pentyloxy substituted with 0, 1, 2, or 3 halogens. In some embodiments, R ³ is hexyloxy substituted with 0, 1, 2 or 3 halogens.

In some embodiments, ^R3 is methoxy substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is ethoxy substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is propoxy substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is butoxy substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is pentyloxy substituted with 1, 2, or 3 halogens. In some embodiments, ^R3 is hexyloxy substituted with 1, 2, or 3 halogens.

In some embodiments, ^R3 is methoxy. In some embodiments, ^R3 is ethoxy. In some embodiments, ^R3 is propoxy. In some embodiments, ^R3 is butoxy. In some embodiments, ^R3 is pentyloxy. In some embodiments, ^R3 is hexyloxy.

In some embodiments, ^R3 is Cl, methyl, _-CF3 , _-CHF2, or _-OCHF2 .

In some embodiments, ^R3 is _-CF3 , _-CHF2 , or _-OCHF2 .

In some embodiments, ^R3 is _-CF3 . In some embodiments, ^R3 is _-CHF2 . In some embodiments, ^R3 is _-OCHF2 .

In some embodiments, X is H, -OH, halogen, _-NH2 , -NH( _C1 - _C6alkyl ), -N( _C1 - _C6alkyl ) ₂ , or C1 _{- C6alkyl} base.

In some embodiments, X is -OH, halogen, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ or C ₁ -C ₆ alkyl.

In some embodiments, X is H.

In some embodiments, X is halogen.

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

In some embodiments, X is Br. In some embodiments, X is Cl. In some embodiments, X is F. In some embodiments, X is I.

In some embodiments, X is -OH.

In some embodiments, X is _-NH2 . In some embodiments, X is -NH(C ₁ -C ₆ alkyl).

In some embodiments, X is -NH(C ₁ alkyl). In some embodiments, X is -NH(C ₂ alkyl). In some embodiments, X is -NH(C ₃ alkyl). In some embodiments, X is -NH(C ₄ alkyl). In some embodiments, X is -NH(C ₅ alkyl). In some embodiments, X is -NH(C ₆ alkyl).

In some embodiments, X is -N(C ₁ -C ₆ alkyl) ₂ .

In some embodiments, X is -N(C ₁ alkyl) ₂ . In some embodiments, X is -N(C ₂ alkyl) ₂ . In some embodiments, X is -N(C ₃ alkyl) ₂ . In some embodiments, X is -N(C ₄ alkyl) ₂ . In some embodiments, X is -N(C ₅ alkyl) ₂ . In some embodiments, X is -N(C ₆ alkyl) ₂ .

In some embodiments, X is C ₁ -C ₆ alkyl.

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 secondary butyl. In some embodiments, X is secondary pentyl. In some embodiments, X is secondary hexyl. In some embodiments, X is tertiary butyl.

In some embodiments, X is H or F.

In some embodiments, R ⁴ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or -C(O)(C ₁ -C ₆ alkyl).

In some embodiments, R ⁴ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or -C(O)(C ₁ -C ₆ alkyl).

In some embodiments, R ⁴ is H.

In some embodiments, R ⁴ is C ₁ -C ₆ alkyl.

In some embodiments, R ⁴ is methyl. In some embodiments, R ⁴ is ethyl. In some embodiments, R ⁴ is propyl. In some embodiments, ^R4 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 secondary butyl. In some embodiments, R ⁴ is secondary pentyl. In some embodiments, R ⁴ is secondary hexyl. In some embodiments, R ⁴ is tertiary butyl.

In some embodiments, R ⁴ is -C(O)(C ₁ -C ₆ alkyl).

In some embodiments, R ⁴ is -C(O)(C ₁ alkyl). In some embodiments, R ⁴ is -C(O)(C ₂ alkyl). In some embodiments, R ⁴ is -C(O)(C ₃ alkyl). In some embodiments, R ⁴ is -C(O)(C ₄ alkyl). In some embodiments, R ⁴ is -C(O)(C ₅ alkyl). In some embodiments, R ⁴ is -C(O)(C ₆ alkyl).

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

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

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

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

In certain embodiments, the benzene ring system of formula ( a ): ( a ) has the formula: ( a-1 ), ( a-2 ) or ( a-3 ), wherein X is halogen or C ₁ -C ₆ alkyl, such as -F, -Cl or -CH ₃ . In certain embodiments, ^R4 is hydrogen. In certain embodiments, R ³ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, such as -Cl, -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ .

In certain embodiments, the amine ring system of formula ( b ): ( b ) has the formula: ( b-1 ), ( b-2 ), ( b-3 ) or ( b-4 ).

In certain embodiments, an amine ring system of the formula: ( b ) has the formula: ( b-5 ), ( b-6 ), ( b-7 ), ( b-8 ) or ( b-9 ).

In some embodiments, a compound of Formula ( I ) has Formula ( Ia ) or ( Ib ): ( Ia ) or ( Ib ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. In certain embodiments, the benzene ring system of formula ( a ) has formula ( a-1 ), ( a-2 ) or ( a- 3 ), wherein X is hydrogen, halogen or C ₁ -C ₆ alkyl, For example -H, -F, -Cl or _-CH3 . In certain embodiments, ^R4 is hydrogen. In certain embodiments, R ³ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, such as -Cl, -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, such as -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl, such as -CHF ₂ , -CF ₃ or -CH ₃ . In certain embodiments, the amine ring system of formula ( b ) has formula ( b-1 ). In certain embodiments, R ¹ is -CH ₃ and R ² is -CH ₃ .

In some embodiments, the compound of formula ( I ) has formula ( II-a ), ( II-b ) or ( II-c ): ( II-a ), ( II-b ) or ( II-c ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. In certain embodiments, X is halogen or C ₁ -C ₆ alkyl, such as -F, -Cl or -CH ₃ . In certain embodiments, ^R4 is hydrogen. In certain embodiments, R ³ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, such as -Cl, -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, such as -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl, such as -CHF ₂ , -CF ₃ or -CH ₃ . In certain embodiments, the amine ring system of formula ( b ) has formula ( b-1 ). In certain embodiments, R ¹ is -CH ₃ and R ² is -CH ₃ .

In some embodiments, the compound of formula ( I ) has formula ( II-d ), ( II-e ) or ( II-f ): ( II-d ), ( II-e ) or ( II-f ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. In certain embodiments, X is halogen or C ₁ -C ₆ alkyl, such as -F, -Cl or -CH ₃ . In certain embodiments, ^R4 is hydrogen. In certain embodiments, R ³ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, such as -Cl, -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, such as -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl, such as -CHF ₂ , -CF ₃ or -CH ₃ . In certain embodiments, the amine ring system of formula ( b ) has formula ( b-1 ). In certain embodiments, R ¹ is -CH ₃ and R ² is -CH ₃ .

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

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

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

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.

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

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

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.

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

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

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

In certain embodiments of formula ( III-a ), ( III-b ) or ( III-c ), the benzene ring system of formula ( a ) has formula ( a-1 ), ( a-2 ) or ( a -3 ), wherein X is hydrogen, halogen or C ₁ -C ₆ alkyl, such as -H, -F, -Cl or -CH ₃ . In certain embodiments, ^R4 is hydrogen. In certain embodiments, R ³ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, such as -Cl, -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, such as -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl, such as -CHF ₂ , -CF ₃ or -CH ₃ . In certain embodiments, R ¹ is -CH ₃ and R ² is -CH ₃ .

In some embodiments, the compound of formula ( I ) has formula ( III-d ), ( III-e ) or ( III-f ): ( III-d ), ( III-e ) or ( III-f ), or its pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug, where m is 0 to is an integer of 2, and n is an integer of 1 to 2.

In certain embodiments of formula ( III-d ), ( III-e ) or ( III-f ), the benzene ring system of formula ( a ) has formula ( a-1 ), ( a-2 ) or ( a -3 ), wherein X is hydrogen, halogen or C ₁ -C ₆ alkyl, such as -H, -F, -Cl or -CH ₃ . In certain embodiments, ^R4 is hydrogen. In certain embodiments, R ³ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, such as -Cl, -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, such as -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl, such as -CHF ₂ , -CF ₃ or -CH ₃ . In certain embodiments, R ¹ is -CH ₃ and R ² is -CH ₃ (where p = 1). In certain embodiments, R ¹ is -CH ₃ and R ² is absent (where p = 0).

In some embodiments, the compound of formula ( I ) has formula ( IV-a ), ( IV-b ) or ( IV-c ): ( IV-a ), ( IV-b ) or ( IV-c ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. In certain embodiments, the benzene ring system of formula ( a ) has formula ( a-1 ), ( a-2 ), or ( a-3 ), wherein X is hydrogen, halogen, or C ₁ -C ₆ alkyl, For example -H, -F, -Cl or _-CH3 . In certain embodiments, ^R4 is hydrogen. In certain embodiments, R ³ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, such as -Cl, -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, such as -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl, such as -CHF ₂ , -CF ₃ or -CH ₃ . In certain embodiments, R ¹ is -CH ₃ and R ² is -CH ₃ .

In some embodiments, the compound of formula ( I ) has formula ( IV-a1 ), ( IV-b1 ) or ( IV-c1 ): ( IV-a1 ), ( IV-b1 ) or ( IV-c1 ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. In certain embodiments, the benzene ring system of formula ( a ) has formula ( a-1 ), ( a-2 ), or ( a-3 ), wherein X is hydrogen, halogen, or C ₁ -C ₆ alkyl, For example -H, -F, -Cl or _-CH3 . In certain embodiments, ^R4 is hydrogen. In certain embodiments, R ³ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, such as -Cl, -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, such as -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl, such as -CHF ₂ , -CF ₃ or -CH ₃ .

In some embodiments, a compound of formula ( I ) has formula ( Va ), ( Vb ) or ( Vc ): ( Va ), ( Vb ) or ( Vc ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs.

In some embodiments, the compound of formula ( I ) has formula ( V-a' ), ( V-b' ) or ( V-c' ): ( V-a' ), ( V-b' ) or ( V-c' ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. In certain embodiments, the benzene ring system of formula ( a ) has formula ( a-1 ), ( a-2 ), or ( a-3 ), wherein X is hydrogen, halogen, or C ₁ -C ₆ alkyl, For example -H, -F, -Cl or _-CH3 . In certain embodiments, R ³ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, such as -Cl, -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, such as -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl, such as -CHF ₂ , -CF ₃ or -CH ₃ . In certain embodiments, R ¹ is -CH ₃ and R ² is -CH ₃ .

In some embodiments, compounds of formula ( I ) have formulas ( VI-a ), ( VI-b ), ( VI-c ), ( VI-d ), ( VI-e ), ( VI-f ), ( VI-g ) or ( VI-h ): ( VI-a ), ( VI-b ), ( VI-c ), ( VI-d ), ( VI-e ), ( VI-f ), ( VI-g ) or ( VI-h ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. In certain embodiments, the benzene ring system of formula ( a ) has formula ( a-1 ), ( a-2 ), or ( a-3 ), wherein X is hydrogen, halogen, or C ₁ -C ₆ alkyl, For example -H, -F, -Cl or _-CH3 . In certain embodiments, ^R4 is hydrogen. In certain embodiments, R ³ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, such as -Cl, -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, such as -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl, such as -CHF ₂ , -CF ₃ or -CH ₃ . In certain embodiments, R ¹ is -CH ₃ and R ² is -CH ₃ .

In some embodiments, compounds of formula ( I ) have formulas ( VI-a1 ), ( VI-b1 ), ( VI-c1), (VI-d1 ), (VI - e1 ), ( VI-f1 ), ( VI-g1 ) or ( VI-h1 ): ( VI-a1 ), ( VI-b1 ), ( VI-c1 ), ( VI-d1 ), ( VI-e1 ), ( VI-f1 ), ( VI-g1 ) or ( VI-h1 ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. In certain embodiments, the benzene ring system of formula ( a ) has formula ( a-1 ), ( a-2 ), or ( a-3 ), wherein X is hydrogen, halogen, or C ₁ -C ₆ alkyl, For example -H, -F, -Cl or _-CH3 . In certain embodiments, ^R4 is hydrogen. In certain embodiments, R ³ is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, such as -Cl, -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, such as -CHF ₂ , -CF ₃ , -CH ₃ or -OCHF ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl, such as -CHF ₂ , -CF ₃ or -CH ₃ .

In some embodiments, the compound is selected from the compounds described in Table 1, or pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, Isotopically labeled compounds or prodrugs.

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

In some embodiments, the compound is selected from the compounds described in Table 1, or solvates thereof.

In some embodiments, the compound is selected from the compounds described in Table 1, or clathrates thereof.

In some embodiments, the compound is selected from the compounds described in Table 1, or hydrates thereof.

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

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

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

In some embodiments, the compound is selected from the compounds described in Table 1, or prodrugs thereof.

In some embodiments, the compound is selected from the compounds described in Table 1. Arbitrarily designated stereoisomers are indicated by an asterisk (*). Table 1. Compound number Compound name / structure 1* (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 1A 5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 1B* (S)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 2 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 3B* (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol 3A 5-Chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 3* (S)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol 4* (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol 4A 5-Chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 4B* (R)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol 5A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol 5 (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol 5B (S)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol 6A 2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl) phenol 6* (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol 6B* (R)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol 9A 5-(Difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 9B* (R)-5-(difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol 9* (S)-5-(difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol 10A 2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methyl phenol 10* (S)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol 10B* (R)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol 11A 2-(4-((2,2-dimethyltetrahydro-2H-piran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol 11* (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol 11B* (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol 12A 6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3-methylphenol 12* (R)-6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3- Methylphenol 12B* (S)-6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3- Methylphenol 13A 2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methyl phenol 13B* (R)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol 13* (S)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol 14A 2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methyl phenol 14B* (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol 14* (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol 15A 2-(4-((3,3-dimethyltetrahydro-2H-piran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol 15* (S)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol 15B* (R)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol 16A 5-(Difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine- 1-yl)phenol 16B* (R)-5-(difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol 16* (S)-5-(difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol 17A 5-(Difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine- 1-yl)phenol 17* (S)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol 17B* (R)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol 18B 5-Chloro-2-(4-((3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 18A* 5-Chloro-2-(4-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 18* 5-Chloro-2-(4-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 18C* 5-Chloro-2-(4-(((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 18D* 5-Chloro-2-(4-(((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 19A 2-(4-((4-oxaspiro[2.4]heptan-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl) phenol 19B* (S)-2-(4-((4-oxaspiro[2.4]heptan-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol 19* (R)-2-(4-((4-oxaspiro[2.4]heptan-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol 20A 5-(Difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazine- 1-yl)phenol 20B* (R)-5-(difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol 20* (S)-5-(difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol 21A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5-methylphenol twenty one* 2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5- Methylphenol 21B* 2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5- Methylphenol 22A 2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol 22B* (S)-2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl base) phenol twenty two* (R)-2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl base) phenol 23A 5-(Difluoromethyl)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol twenty three* (R)-5-(difluoromethyl)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 23B* (S)-5-(Difluoromethyl)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol

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

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

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

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

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

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

In some embodiments, the compound is selected from the compounds described in Table 2, or pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, Isotopically labeled compounds or prodrugs.

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

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

In some embodiments, the compound is selected from the compounds described in Table 2, or clathrates thereof.

In some embodiments, the compound is selected from the compounds described in Table 2, or hydrates thereof.

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

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

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

In some embodiments, the compound is selected from the compounds described in Table 2, or prodrugs thereof.

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

Arbitrarily designated stereoisomers are indicated by an asterisk (*). Table 2. Compound number Compound name / structure twenty four* 2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethyl base phenol 24B* 2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethyl base phenol 25A* 5-Chloro-2-(4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 25B* 5-Chloro-2-(4-(((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 25C* 5-Chloro-2-(4-(((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 25D* 5-Chloro-2-(4-(((2R,4S)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 26* 3-Chloro-2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5- Methylphenol 26B* 3-Chloro-2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5- Methylphenol

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

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

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

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

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

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

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

In another aspect, the disclosure particularly provides compounds selected from: (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyridine And[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-piran) -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-methylmorpholine) -2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

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

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

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

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

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

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

In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds disclosed herein.

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

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

In some embodiments, the compound is an isotopic derivative of any of the compounds described herein, and a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is an isotopic derivative of any of the precursors to the compounds described herein, and a pharmaceutically acceptable salt thereof.

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

It will be appreciated that isotopic derivatives may be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by substituting isotopically labeled reagents for non-isotopically labeled reagents by performing the procedures disclosed in the Schemes and/or Examples described herein.

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

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

As used herein, the term "isotopic derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, isotopic derivatives of compounds disclosed herein are enriched for or labeled with one or more isotopes compared to the corresponding disclosed compounds. In some embodiments, the isotopic derivative is enriched with or treated with one or more isotopes selected from ^2H , ^13C , ^14C , ^15N , ^18O , ^29Si , ^31P , and ^34S mark. In some embodiments, the isotopic derivative is a deuterium-labeled compound (ie, rich in ² H with respect to one or more of its atoms). In some embodiments, the compound is ^an18F -labeled compound. In some embodiments, the compound is a ¹²³ I-labeled compound, a ¹²⁴ I-labeled compound, a ¹²⁵ I-labeled compound, ^{a 129} I-labeled compound, ^{a 131} I-labeled compound, a ¹³⁵ I-labeled compound or any combination thereof. In some embodiments, the compound is a ^33S -labeled compound, a ^34S -labeled compound, a ^35S -labeled compound, a ^36S -labeled compound, or any combination thereof.

It will be ^{appreciated that 18F, 123I, 124I, 125I, 129I, 131I, 135I, 32S, 34S , 35S and / or 36S labeled compounds may be} prepared using a variety of art-recognized techniques . For example, deuterium-labeled compounds can generally be prepared by using ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, ¹³¹ I, ¹³⁵ by carrying out the procedures disclosed in the schemes and/or examples described herein. I, ^32S , ^34S , ^35S and/or ^36S labeled reagents are prepared instead of non-isotopically labeled reagents.

The compound of the present invention or its pharmaceutical containing one or more of the aforementioned ^18F , ^123I , ^124I , ^125I , ^129I , ^131I , ^135I , ^32S , ^34S , ^35S and ^36S atoms Acceptable salts or solvates of the above are within the scope of this invention. ^Additionally , substitution with isotopes (e.g., ^18F , ^123I , ^124I , 125I, ^129I , ^131I , ^135I , ^32S , ^34S , ^35S , and/or ^36S ) may provide certain therapeutic advantages, These advantages are due to greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements.

For the avoidance of doubt, it is understood that in this specification, if a group is qualified by "as described herein," that group encompasses the first and broadest definition that appears and each and all specific definitions of the group.

Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, sufficiently basic acid addition salts of the compounds of the present disclosure, for example, with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, Acid addition salts of phosphoric acid, trifluoroacetic acid, formic acid, citric acid methanesulfonate or maleate. In addition, suitable pharmaceutically acceptable salts of the compounds of the present disclosure that are acidic enough 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. Salts which provide pharmaceutically acceptable cations. For example, salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

It should be understood that the compounds of any of the formulas disclosed herein and any pharmaceutically acceptable salts thereof include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of such compounds. .

In some embodiments, the compound of formula ( I ) is: 1A ; 5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3A 5-Chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ; 4A 5-Chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ;or 5A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs.

As used herein, the term "isomerism" means compounds that have the same molecular formula but differ in the order of atomic bonding or arrangement of atoms in space. Isomers with different arrangements of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. Mixtures containing equal amounts of individual enantiomeric forms of opposite chiral properties are called "racemic mixtures".

As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds with more than one chiral center may exist as individual diastereomers or as mixtures of diastereomers, termed "diastereomer mixtures". When a chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of the chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Substituents attached to the chiral center considered are ordered according to the ordering rules of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London) , 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

As used herein, the term "geometric isomer" means a diastereomer that exists due to hindered rotation about a double bond or a cycloalkyl linker (eg, 1,3-cyclobutyl). According to the Cahn-Ingold-Prelog rules, these configurations are distinguished in name by the prefixes cis and trans or Z and E, which indicate that the groups are located on the same or opposite sides of the double bond in the molecule.

It will be appreciated that the compounds of the present disclosure may be described as different chiral or geometric isomers. It should also be understood that when a compound has chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included within the scope of this disclosure, and the naming of these compounds does not exclude any isomeric forms. It should be understood that not all isomeric forms are included. The structures can all have the same level of activity.

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

As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This transformation results in the migration of hydrogen atoms, accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as mixtures of tautomeric sets in solution. In a solution where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that transform into each other through tautomerization is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, electrons and hydrogen atoms are displaced simultaneously. Ring-chain tautomerism occurs when the aldehyde group (-CHO) in the sugar chain molecule reacts with one of the hydroxyl groups (-OH) of the same molecule to form a ring (ring shape) like that of glucose. results appear.

It should be understood that the compounds of the present disclosure may be described as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of this disclosure, and the naming of such compounds does not exclude any tautomeric form. It is understood that certain tautomers may have higher levels of activity than other tautomers.

Compounds with the same molecular formula but different bonding properties or order of atoms or arrangement of atoms in space are called "isomers". Isomers with different arrangements of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, such as when it is bonded to four different groups, there may be a pair of mirror image isomers. Mirror isomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the rotation of the molecule in the plane of polarized light and being designated as dextrorotatory or levorotatory manner (i.e., the (+) or (-) isomer, respectively). Chiral compounds may exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

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

It is to be understood that reference to a compound of any formula described herein includes the compound itself as well as its salts and solvates thereof, where applicable. For example, a salt can be formed between an anion and a positively charged group (eg, an amine group) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, hydrogen sulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, and glucuronide. Acid, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetic acid root).

As used herein, the term "pharmaceutically acceptable anion" refers to anions suitable for forming pharmaceutically acceptable salts. Likewise, salts can be formed between cations and negatively charged groups (eg, carboxylate groups) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium and ammonium cations such as tetramethylammonium or diethylamine. Substituted compounds disclosed herein also include salts containing quaternary nitrogen atoms.

It will be appreciated that compounds of the present disclosure, such as salts of the compounds, may exist in hydrated or unhydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrate, dihydrate, and the like. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.

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

As used herein, the term "analog" refers to a compound that is structurally similar to another but has a slightly different composition (e.g., one atom is replaced by an atom of a different element, or in the case of a specific functional group, or one functional group is replaced by another). functional group replacement). Therefore, analogues are compounds that are similar or comparable in function and appearance, but differ from the reference compound in structure or origin.

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

It is also understood that certain compounds of any of the formulas disclosed herein can exist in solvated as well as unsolvated forms (eg, hydrated forms). Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrate, monohydrate, dihydrate or trihydrate. It should be understood that the present disclosure encompasses all solvated forms possessing inflammasome inhibitory activity.

It is also understood that certain compounds of any of the formulas disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms, or mixtures thereof, having inflammasome inhibitory activity. It is well known that crystalline materials can be analyzed using well-known techniques such as: Solution and/or solid-state NMR spectroscopy. The moisture content of such crystalline materials is determined by Karl Fisher analysis.

Compounds of any of the formulas disclosed herein may exist in a variety of different tautomeric forms, and references to such forms include all such forms. For the avoidance of doubt, when a compound can exist in one of several tautomeric forms and only one is specifically described or shown, all other forms are included in formula (I). Examples of tautomeric forms include ketone, enol, and enolate forms, such as the following tautomeric pairs: ketone/enol (shown below), imine/enamine, amide/iminoalcohol, amidine/ Amidine, nitroso/oxime, thione/enethiol and nitro/acid nitro.

Compounds of any of the formulas disclosed herein may be administered in the form of prodrugs that break down in the human or animal body to release the compounds disclosed herein. Prodrugs can be used to modify the physical properties and/or pharmacokinetic properties of the compounds disclosed herein. Prodrugs can be formed when the compounds of the present disclosure contain suitable groups or substituents to which property-modifying groups can be attached. Examples of prodrugs include derivatives containing an in vivo cleavable alkyl or acyl substituent at the ester or amide group in any of the formulas disclosed herein.

Accordingly, the present disclosure includes any of the formulas disclosed herein as defined above when obtainable by organic synthesis and when obtainable in the human or animal body by cleaving its prodrugs. compound. Therefore, the present disclosure includes compounds of any of the formulas disclosed herein produced by organic synthesis means, as well as such compounds produced in the human or animal body by metabolism of precursor compounds, that is, Compounds of any of the formulas disclosed herein may be synthetically produced compounds or metabolically produced compounds.

Suitable pharmaceutically acceptable prodrugs for compounds of any of the formulas disclosed herein are prodrugs based on sound medical diagnosis that are suitable for administration to the human or animal body without adverse pharmacological activity and without adverse effects. Appropriate toxicity. Various forms of prodrugs have been described, for example, in: a) Methods in Enzymology, Volume 42, pages 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Pro- drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs,” by H. Bundgaard pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutical 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,” A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987.

Suitable pharmaceutically acceptable precursors to compounds of any of the formulas disclosed herein having a hydroxyl group are, for example, in vivo cleavable esters or ethers thereof. In vivo cleavable esters or ethers of compounds of any of the formulas disclosed herein containing a hydroxyl group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in humans or animals to yield the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for hydroxyl groups include inorganic esters such as phosphate esters (including phosphatide cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for hydroxyl include C ₁ -C ₁₀ alkyl groups such as acetyl, benzyl, phenylethyl and substituted benzoyl and phenethyl groups. C1- _C10 alkoxycarbonyl, such as ethoxycarbonyl, N, _N- ( _C1 - _C6 alkyl) _2- aminoformyl, 2-dialkylaminoacetyl and 2-carboxylic acid -Carbonyl acetyl. Examples of phenylacetyl and ring substituents on the benzyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinylmethyl, piperazine -1-ylmethyl and 4-(C ₁ -C ₄ alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ester-forming groups for hydroxyl include alpha-acyloxyalkyl groups such as acetyloxymethyl and neopentyloxymethyl.

Suitable pharmaceutically acceptable precursors of compounds of any of the formulas disclosed herein having a carboxyl group are, for example, their in vivo cleavable amides, for example with ammonia, C _{1 -4} alkyl amines such as Methylamine), (C ₁ -C ₄ alkyl) ₂ -amine (such as dimethylamine, N-ethyl-N-methylamine or diethylamine), C ₁ -C ₄ alkoxy-C ₂ -C Amides formed from amines of _4- alkyl amines (such as 2-methoxyethylamine), phenyl-C ₁ -C ₄ alkyl amines (such as benzylamine) and amino acids (such as glycine or its esters) .

Suitable pharmaceutically acceptable precursors to compounds of any of the formulas disclosed herein having an amine group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amide groups derived from amine groups include, for example, C ₁ -C ₁₀ alkyl groups such as acetyl, benzyl, phenylacetyl and substituted benzyl and phenyl groups. Amide formed from acetyl group. Examples of phenylacetyl and ring substituents on the benzyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinylmethyl, piperazine -1-ylmethyl and 4-(C ₁ -C ₄ alkyl)piperazin-1-ylmethyl.

The in vivo effects of the compounds of any one of the formulas disclosed herein may be exerted in part by one or more metabolites that, upon administration of the compounds of any one of the formulas disclosed herein, affect the human body or formed in animals. As mentioned above, the in vivo effects of the compounds of any of the formulas disclosed herein can also be exerted through the metabolism of precursor compounds (prodrugs).

A suitable general route for preparing the compounds of this application is using Scheme A and can be described in Scheme 1 herein. Process 1

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

Step one involves the _SN Ar reaction between amine ( i ) and aryl dichloride ( ii ) to obtain the target chloroaryl intermediate ( iii ). Step two involves cross-coupling between intermediate ( iii ) and the desired boronic acid or borate ( iv ), optionally followed by deprotection of the alkyl ether ( e.g., methyl ether) on the benzene ring to produce the desired Compound ( v ). Unless otherwise stated, amines ( i ), aryl dichlorides ( ii ) and boronic acids or borates ( iv ) are commercially available or known in the chemical literature.

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

Step one involves opening the commercial 3,4-pyridinedicarboxylic anhydride ( vii ) with Grignard reagent to obtain the carboxylic acid ( viii) . The second step is characterized by chlorination and then condensation with hydrazine to obtain pyridazinol ( ix ). Step three then involves another chlorination to give the key intermediate ( x) , which can in turn react with amine ( i ) in step four to form azaphthalazine ( xi) . Step five then features deprotection of the methyl ether, providing analog ( xii) . Creature check

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

Additionally, high-throughput screening can be used to accelerate analyzes using such assays. As a result, the molecules described herein can be rapidly screened for activity using techniques known in the art. General methodologies for performing high throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and US Patent No. 5,763,263. High-throughput assays may use one or more different assay techniques, including but not limited to those described below.

Various in vitro or in vivo biological assays may be suitable for detecting the effects of compounds of the present disclosure. Such in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility change assays, reporter gene assays, in vitro cell viability assays, binding assays, and cell assays (cell lines, primary cells, and whole cells) , in vitro cell viability assays, and assays to determine NLRP3 potency, unbound clearance, solubility, permeability, metabolic stability ( e.g., in hepatocytes) and CYP inhibition, as well as time-dependent inhibition (TDI) assays ( e.g. , , to reduce the risk of potential adverse in vivo drug-drug interactions).

In some embodiments, bioassays are described in the Examples, Assay Methods section. In some embodiments, the Assay Methods section refers to Example 12.

For example, in some embodiments, compounds of the present disclosure can 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 Examples, Calibration Methods section. In some embodiments, compounds of the present disclosure can be tested for their human NLRP3 potency using known procedures. See , for example, the human whole blood NLRP3 assay described in the Assay Methods section of the Example. In some embodiments, compounds of the present disclosure can be further tested for brain penetration. See , for example, the kp and kpu,u NLRP3 tests described in the Test Methods section of the example.

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

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

In additional embodiments, the solubility of compounds of the present disclosure can be determined following known procedures, such as described in Alsenz and Kansy, Advanced Drug Delivery Reviews (2007) 59:546-567, and Wang et al. J Mass Spectrom. ( 2000) 35:71-76. For example, kinetic solubility in physiologically relevant media such as phosphate buffered saline (PBS, pH 7.4) or analog gastric fluid (SGF) can be measured using serial dilutions and a two-hour incubation period, followed by filtration, and by LC -MS/MS reported in μM. Thermodynamic solubility in physiologically relevant media can be measured by LC-MS/MS after twenty-four hours of incubation, followed by filtration, and reported in mg/mL. Optimizing solubility may facilitate the manufacture and further processing of compounds. Additionally, optimized solubility allows for more efficient in vivo analysis of compounds, including the collection of data surrounding the compound's safety, drug-drug interactions, potency, selectivity, metabolism, and permeability. pharmaceutical composition

In some aspects, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulas described in Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, Hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, and one or more pharmaceutically acceptable carriers or diluents. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulas described in Table 2, or a pharmaceutically acceptable salt, solvate, clathrate, Hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, and one or more pharmaceutically acceptable carriers or diluents. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate thereof compounds, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, and one or more pharmaceutically acceptable carriers or diluents. In some embodiments, pharmaceutical compositions include one or more carriers, fillers, vehicles, excipients, solubilizers, chelating agents, or combinations thereof. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound described in Table 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound described in Table 2. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound described herein.

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

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

In some embodiments of the present disclosure, a pharmaceutical composition includes a compound of Formula I described herein and a pharmaceutically acceptable carrier.

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

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

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

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

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

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

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

Formulations of the present disclosure may be in the form of aqueous solutions containing an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include excipients selected from the group consisting of solubilizers, chelating agents, preservatives, tonicity agents, viscosity/suspension agents, buffers, and pH adjusters, and mixtures thereof.

Any suitable solubilizing agent may be used. Examples of solubilizers include cyclodextrins, such as cyclodextrins selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated-β-cyclodextrin Essence, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin Cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD) , maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, random methylated-γ-cyclodextrin , and trimethyl-γ-cyclodextrin, and mixtures thereof.

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.

Any suitable preservative can be used. Examples of the preservative include a preservative selected from the group consisting of quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzonine chloride ( benzethonium chloride), cetylpyridinium chloride, toluene bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, Potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropylbiguanide, and butylparaben, and sorbic acid, and mixtures thereof.

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

Aqueous vehicles may also contain viscosity/suspension agents. Suitable viscosity/suspension agents include those selected from the group consisting of cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycols (such as polyethylene glycol). alcohol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and cross-linked acrylic polymers (carbomers), such as acrylic acid with polyalkenyl ethers or di- Vinyl glycol crosslinked polymers (carbopol, such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and mixtures thereof.

In order to adjust the formulation to an acceptable pH (generally in the range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, especially about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9 or about 7.5 to about 8.0), the formulation may contain a pH adjusting agent. The pH adjuster is usually a mineral acid or metal hydroxide base, selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and is 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 acid and base, depending on the formulation, the addition of either acid or base may be sufficient to bring the mixture to the desired pH range.

Aqueous vehicles may also contain buffering agents to stabilize the pH. When used, the buffering agent is selected from the group consisting of: phosphate buffers (such as sodium phosphate dibasic and disodium hydrogen phosphate), borate buffers (such as boric acid, or salts thereof, including disodium tetraborate), lemon Acid buffers (such as citric acid, or salts thereof, including sodium citrate), and epsilon-aminocaproic acid, and mixtures thereof.

The formulation may further comprise a humectant. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylene Polysorbate (polysorbate), polymer of oxyethylated octylphenol (Tyloxapol), polyoxyethylene 40 stearate, fatty acid glycol ester, fatty acid glyceryl ester, sucrose fatty acid ester, and polyoxyethylene fatty acid esters, and mixtures thereof.

Oral compositions usually include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compounds may be mixed with excipients and used in the form of tablets, dragees, or capsules. Oral compositions can also be prepared using a fluid carrier that acts as a mouthwash, wherein the compound in the fluid carrier is administered orally and swished around the mouth and spitted out or swallowed. Pharmaceutically compatible binders and/or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges and the like may contain any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients, such as starch or lactose; disintegrants, Such as alginic acid, Primogel or cornstarch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silica; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, salicylate ester or orange flavoring.

According to a further aspect of the disclosure, a pharmaceutical composition is provided, which includes a compound of the disclosure as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable combination of diluents or carriers.

The compositions of the present disclosure may be in a form suitable for oral use (for example, as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), suitable Forms for topical use (e.g., as a cream, ointment, gel, or aqueous or oily solution or suspension), forms suitable for administration by inhalation (e.g., as a fine powder or liquid aerosol), suitable for administration by insufflation In a form for administration (e.g., as a fine powder) or in a form suitable for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as a rectally suppositories for administration).

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, sweetening agents, flavoring agents and/or preservatives.

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

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

In accordance with well-known medical principles, the dosage of a compound 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. Instructions

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

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

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

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

In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder as inhibited by NLRP3 as disclosed herein in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the present disclosure or its Pharmaceutically acceptable salts or pharmaceutical compositions disclosed in this disclosure.

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

In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder as inhibited by NLRP3 as disclosed herein in an individual in need thereof, comprising administering to the individual a compound of the present disclosure or a pharmaceutically acceptable compound thereof. Acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, or pharmaceutical compositions of the present disclosure.

In some aspects, the present disclosure provides a method of treating a disease or condition disclosed herein in an individual in need thereof, comprising administering to the individual a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof , clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, or pharmaceutical compositions disclosed in this disclosure. In some embodiments, the disease or condition is one involving NLRP3.

In some embodiments, the disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, renal disease, liver disease, eye disease, skin disease, Lymphoid diseases, rheumatic diseases, psychiatric disorders, graft-versus-host disease, allodynia, or NLRP3-related diseases in individuals identified to carry germline or somatic non-silent mutations in NLRP3.

In some aspects, the present disclosure provides a method for treating or preventing inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease in an individual in need thereof , eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or NLRP3 association in individuals identified to carry germline or somatic non-silent mutations in NLRP3 A method for treating diseases, which includes administering to an individual a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

In some aspects, the present disclosure provides a method of treating inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, renal disease, liver disease, eye disease in an individual in need thereof. genital disease, dermatological disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or NLRP3-related disease in individuals identified to carry germline or somatic non-silent mutations in NLRP3 A method comprising administering to an individual a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

In some aspects, the present disclosure provides a method for treating or preventing inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease in an individual in need thereof , eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or NLRP3 association in individuals identified to carry germline or somatic non-silent mutations in NLRP3 Methods for treating diseases, which comprise administering to an individual a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopically labeled compound thereof or prodrugs, or pharmaceutical compositions disclosed in this disclosure.

In some aspects, the present disclosure provides a method of treating inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, renal disease, liver disease, eye disease in an individual in need thereof. genital disease, dermatological disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or NLRP3-related disease in individuals identified to carry germline or somatic non-silent mutations in NLRP3 Methods comprising administering to an individual a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or precursor thereof Medicines, or pharmaceutical compositions described in this disclosure.

In some aspects, the disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, tautomer, or isotopically labeled compound thereof. Compounds or prodrugs for modulating NLRP3 activity (eg, in vitro or in vivo ).

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

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

In some aspects, the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, that acts as an antagonist of NLRP3 (eg, in vitro or in vivo ).

In some aspects, the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition disclosed herein.

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

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

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

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

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

In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing the diseases or conditions disclosed herein.

In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating the diseases or conditions disclosed herein.

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

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

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

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

In some aspects, the disclosure provides for the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease or condition disclosed herein.

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

The effectiveness of the compounds of the present disclosure can be determined by industry-accepted assays/disease models, which are based on standard practices elucidating their origin as described in this art and are found within the current general knowledge.

In some embodiments, the disease or disorder is associated with implicated NLRP3 activity.

In some embodiments, the disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, renal disease, liver disease, eye disease, skin disease, Lymphoid diseases, rheumatic diseases, psychiatric disorders, graft-versus-host disease, allodynia, or NLRP3-related diseases in individuals identified to carry germline or somatic non-silent mutations in NLRP3.

In some embodiments, the disease or condition is inflammation.

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

In some embodiments, the disease or condition is cancer.

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

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

In some embodiments, the disease or condition is a metabolic disease.

In some embodiments, the disease or condition is cardiovascular disease.

In some embodiments, the disease or condition is a respiratory disease.

In some embodiments, the disease or condition is renal disease.

In some embodiments, the disease or condition is liver disease.

In some embodiments, the disease or condition is an eye disease.

In some embodiments, the disease or condition is a skin disease.

In some embodiments, the disease or disorder is a lymphoid disease.

In some embodiments, the disease or condition is a rheumatic disease.

In some embodiments, the disease or condition is a psychological disorder.

In some embodiments, the disease or condition is graft versus host disease.

In some embodiments, the disease or condition is allodynia.

In some embodiments, the disease or disorder is an NLRP3-related disease.

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

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

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

In some embodiments, the kidney disease is acute kidney disease, chronic kidney disease, or rare kidney disease.

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

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

In some embodiments, the NLRP3-related disease in individuals identified as carrying germline or somatic non-silent mutations in NLRP3 is cryptopyrin-related autoinflammatory syndrome.

In some embodiments, the cryptopyrin-associated autoinflammatory syndrome is familial cryogenic autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease.

In some embodiments, the compound is , for example, a brain penetrating agent with a Kpu,u >0.3.

Compounds with Kpu,u less than or equal to 0.3 are not brain penetrants. In some embodiments, the compound is not a brain penetrating agent.

In some embodiments, the compound has a Kpu,u from greater than 0.3 to about 10.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

The compounds of this disclosure, or their pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, can be used alone as monotherapy administered, or may be administered together with one or more other substances and/or treatments. Such combination therapy may be achieved by administering the individual components of the therapy simultaneously, sequentially, or separately.

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

Where a compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the present disclosure need not be administered via the same route as the other therapeutic agent, and may (because of different physical and chemical characteristics) be administered via a different route Invest. For example, a compound of the present disclosure can be administered orally to produce and maintain good blood levels, while another therapeutic agent can be administered intravenously. Initial administration can be made according to established protocols known in the art, and the dosage, mode of administration, and timing of administration can then be modified by the skilled clinician based on the observed effects.

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

According to a further aspect of the disclosure, a pharmaceutical composition is provided, which includes a compound of the disclosure or a pharmaceutically acceptable salt thereof, in combination with a suitable pharmaceutically acceptable diluent or carrier, United.

Any of the above-described pharmaceutical compositions, processes, methods, uses, medicaments, and manufacturing features of the disclosure also apply to any of the alternative embodiments of the compounds of the disclosure described herein.

The compounds of the present disclosure, or pharmaceutical compositions containing such compounds, may be administered to an individual by any convenient route of administration, whether systemically/peripherally or locally (i.e., at the desired site of action).

Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.) etc.); intranasally (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, use e.g. via aerosol, e.g. through the mouth or nose) ; Rectal (e.g., by suppository or enema); Vaginal (e.g., by pessary); Parenterally, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal Endo, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid and intrasternal; by implanting the depot or depot, for example, subcutaneously or intramuscularly. Exemplary embodiments

Exemplary embodiment 1. A compound of formula ( I ): ( I ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, wherein: A is 5 to 8 membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom; R ¹ is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; R ² is halogen or C ₁ -C ₆ alkyl; or R ¹ and R ² together with the atoms to which they are connected form a 3 to 4-membered carbocyclic ring; R ³ is -OH, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy ; X is H, -OH, halogen, -NH2 _, -NH( _C1 - _C6alkyl ), -N( _C1 - _C6alkyl ) ₂ or _C1 - _C6alkyl ; and ^R4 is H, C ₁ -C ₆ alkyl, or -C(O)(C ₁ -C ₆ alkyl); and p is 0 or 1, where each instance of alkyl, alkyl-, or carbocyclic ring is independently 0, 1, 2 or 3 halogen atoms are substituted, and when R ³ is Cl, then Not for .

Exemplary Embodiment 2. A compound as in Exemplary Embodiment 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopically labeled compound thereof Or a prodrug, wherein A is a 5-membered monocyclic heterocycloalkyl group containing an O ring atom.

Exemplary Embodiment 3. Compounds as in Exemplary Embodiment 1 or Exemplary Embodiment 2, or pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, and tautomers thereof substance, isotope-labeled compound or prodrug, wherein A is a 6-membered monocyclic heterocycloalkyl group containing an O ring atom.

Exemplary Embodiment 4. The compound of any one of Exemplary Embodiments 1-3, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof substances, isotopically labeled compounds or prodrugs, where p is 1.

Exemplary Embodiment 5. The compound of any one of Exemplary Embodiments 1-4, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof substance, isotopically labeled compound or prodrug, wherein p is 1; R ¹ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; and R ² is C ₁ -C ₆ alkyl.

Exemplary Embodiment 6. The compound of any one of Exemplary Embodiments 1-5, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof substances, isotopically labeled compounds or prodrugs, wherein R ³ is not halogen.

Exemplary Embodiment 7. The compound of any one of Exemplary Embodiments 1-6, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof substance, isotopically labeled compound or prodrug, wherein R ³ is a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group.

Exemplary Embodiment 8. The compound of any one of Exemplary Embodiments 1-5, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof substance, isotope-labeled compound or prodrug, wherein R ³ is Cl, methyl, -CF ₃ , -CHF ₂ or -OCHF ₂ .

Exemplary Embodiment 9. The compound of any one of Exemplary Embodiments 1-8, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof substances, isotopically labeled compounds or prodrugs, wherein R ⁴ is H.

Exemplary Embodiment 10. The compound of any one of Exemplary Embodiments 1-9, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof substances, isotopically labeled compounds or prodrugs, where X is H or F.

Exemplary embodiment 11. The compound according to any one of the preceding exemplary embodiments, wherein the compound has formula ( Ia ) or ( Ib ): ( Ia ) or ( Ib ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs.

Exemplary embodiment 12. The compound as in 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) : ( II-a ), ( II-b ), ( II-c ), ( II-d ), ( II-e ) or ( II-f ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs.

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) : ( III-a ), ( III-b ) or ( III-c ), or its pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug, wherein m is 0 to is an integer of 2, and n is an integer of 1 to 2.

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) : ( III-d ), ( III-e ) or ( III-f ), or its pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug, where m is 0 to is an integer of 2, and n is an integer of 1 to 2.

Exemplary Embodiment 15. The compound according to any one of the preceding exemplary embodiments, wherein the compound has formula ( IV-a ), ( IV-b ) or ( IV-c ): ( IV-a ), ( IV-b ) or ( IV-c ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 16. The compound according to any one of the preceding exemplary embodiments, wherein the compound has formula ( IV-a1 ), ( IV-b1 ) or ( IV-c1 ): ( IV-a1 ), ( IV-b1 ) or ( IV-c1 ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs.

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') : ( Va ), ( Vb ), ( Vc ), ( V-a' ), ( V-b' ) or ( V-c' ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs.

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) : ( VI-a ), ( VI-b ), ( VI-c ), ( VI-d ), ( VI-e ), ( VI-f ), ( VI-g ) or ( VI-h ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 19. The compound of Exemplary Embodiment 1, which has the formula: 1A 5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3A 5-Chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ; 4A 5-Chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ; 5A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 9A 5-(Difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ; 10A 2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methyl phenol; 11A 2-(4-((2,2-dimethyltetrahydro-2H-piran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol; 12A 6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3-methylphenol; 13A 2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methyl phenol; 14A 2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methyl phenol; 15A 2-(4-((3,3-dimethyltetrahydro-2H-piran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol; 16A 5-(Difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine- 1-yl)phenol; 17A 5-(Difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine- 1-yl)phenol; 18B 5-Chloro-2-(4-((3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 19A 2-(4-((4-oxaspiro[2.4]heptan-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl) phenol; 20A 5-(Difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazine- 1-yl)phenol; 21A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5-methylphenol; 22A 2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; or its pharmaceutically acceptable salts or isotope-labeled compounds.

Exemplary Embodiment 20. The compound of Exemplary Embodiment 1, which has the formula: 1* (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 1B* (S)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3B* (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 3* (S)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 4* (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 4B* (R)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 5 (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 5B (S)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 9B* (R)-5-(difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 9* (S)-5-(difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 10* (S)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 10B* (R)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 11* (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol; 11B* (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol; 12* (R)-6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3- methylphenol; 12B* (S)-6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3- methylphenol; 13B* (R)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 13* (S)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 14B* (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 14* (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 15* (S)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol; 15B* (R)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol; 16B* (R)-5-(difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; 16* (S)-5-(difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; 17* (S)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; 17B* (R)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; 18A* 5-Chloro-2-(4-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 18* 5-Chloro-2-(4-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 18C* 5-Chloro-2-(4-(((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 18D* 5-Chloro-2-(4-(((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 19B* (S)-2-(4-((4-oxaspiro[2.4]heptan-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol; 19* (R)-2-(4-((4-oxaspiro[2.4]heptan-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol; 20B* (R)-5-(difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; 20* (S)-5-(difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; twenty one* 2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5- methylphenol; 21B* 2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5- methylphenol; 22B* (S)-2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl base) phenol; twenty two* (R)-2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl base) phenol; 23A 5-(Difluoromethyl)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol twenty three* (R)-5-(difluoromethyl)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 23B* (S)-5-(Difluoromethyl)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol or its pharmaceutically acceptable salts or isotope-labeled compounds.

Exemplary Embodiment 21. A compound having the formula: 2 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 6A 2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl) phenol; or its pharmaceutically acceptable salts or isotope-labeled compounds.

Exemplary Embodiment 22. The compound of Exemplary Embodiment 1, which has the formula: twenty four* 2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethyl base phenol; 24B* 2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethyl base phenol; 25A* 5-Chloro-2-(4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 25B* 5-Chloro-2-(4-(((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 25C* 5-Chloro-2-(4-(((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 25D* 5-Chloro-2-(4-(((2R,4S)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 26* 3-Chloro-2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5- methylphenol; 26B* 3-Chloro-2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5- methylphenol; or its pharmaceutically acceptable salts or isotope-labeled compounds.

Exemplary Embodiment 23. The compound of Exemplary Embodiment 1, wherein the compound is not , or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 24. The compound of Exemplary Embodiment 1, wherein the compound is not: 1A ; 5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3A 5-Chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ; 4A 5-Chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ;or 5A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol, or its pharmaceutically acceptable salts or isotope-labeled compounds.

Exemplary Embodiment 25. The compound of any one of Exemplary Embodiments 1-21, 23, and 24, wherein the Kpu,u of the compound is greater than 0.3.

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

Exemplary Embodiment 27. A pharmaceutical composition, which includes a compound as in any one of Exemplary Embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereo compound thereof. isomers, tautomers, isotopically labeled compounds or prodrugs, and one or more pharmaceutically acceptable carriers.

Exemplary Embodiment 28. A method of modulating NLRP3, the method comprising administering to an individual a compound as in any one of Exemplary Embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathrate thereof compounds, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, or pharmaceutical compositions as in Exemplary Embodiment 27.

Exemplary Embodiment 29. A method of treating or preventing a disease or disorder, the method comprising administering to an individual a compound such as any one of Exemplary Embodiments 1-26, or a pharmaceutically acceptable salt or solvate thereof. substance, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug, or a pharmaceutical composition as in Exemplary Embodiment 27.

Exemplary Embodiment 30. The compound of any one of Exemplary Embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof substances, isotopically labeled compounds or prodrugs, or pharmaceutical compositions as in Exemplary Embodiment 27, which are used to treat or prevent diseases or conditions.

Exemplary Embodiment 31. The compound of any one of Exemplary Embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof The use of substances, isotopically labeled compounds or prodrugs in the manufacture of medicaments for the treatment or prevention of diseases or conditions.

Exemplary Embodiment 32. The compound of any one of Exemplary Embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof substances, isotopically labeled compounds or prodrugs for the treatment or prevention of diseases or conditions.

Exemplary Embodiment 33. The method, compound, or use of any of Exemplary Embodiments 29-32, wherein the disease or disorder is an NLRP3-related disease or disorder.

Exemplary Embodiment 34. The method, compound, or use of any of Exemplary Embodiments 28-33, wherein the system is human.

Exemplary Embodiment 35. The method, compound, or use of any one of Exemplary Embodiments 28-34, wherein the disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolism disease, cardiovascular disease, respiratory disease, renal disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or NLRP3-related disease.

Exemplary Embodiment 36. The method, compound or use of Exemplary Embodiment 35, wherein the central nervous system disease or disorder is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, muscle atrophy Lateral sclerosis or multiple sclerosis.

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

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

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

Exemplary Embodiment 40. The method, compound, or use of Exemplary Embodiment 35, wherein the NLRP3-related disease is in an individual determined to carry a germline or somatic non-silent mutation in NLRP3.

Exemplary Embodiment 41. The method, compound, or use of Exemplary Embodiment 40, wherein the NLRP3-related disease in an individual determined to carry a germline or somatic non-silent mutation in NLRP3 is cryptopyrin-related autoinflammation sexual syndrome.

Exemplary Embodiment 42. The method, compound, or use of Exemplary Embodiment 35, wherein the cryptopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal onset of multiple systemic inflammatory diseases.

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-piran-4-yl) Amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-piran) -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 pharmaceutically acceptable salts and solvates of any of the foregoing. substance, clathrate, hydrate, stereoisomer, tautomer or prodrug.

Exemplary Embodiment 44. The compound of Exemplary Embodiment 43, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amine) Pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, and isotopes Labeled compound or prodrug.

Exemplary Embodiment 45. The compound of Exemplary Embodiment 43, wherein the compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3))-2-methylpropane base)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, and Allomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 46. The compound of Exemplary Embodiment 43, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-piran-4 -(yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, Tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 47. The compound of Exemplary Embodiment 43, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-piran-4 -(yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, Tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 48. The compound of Exemplary Embodiment 43, wherein the compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3 ,4-d]pyridazin-1-yl)-5-methylphenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, Isotopically labeled compounds or prodrugs.

Exemplary Embodiment 49. The compound of Exemplary Embodiment 43, wherein the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido [3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, and stereoisomers , tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 50. A pharmaceutical composition comprising the compound of Exemplary Embodiment 43, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof. constructs, isotopically labeled compounds or prodrugs, and pharmaceutically acceptable carriers.

Exemplary Embodiment 51. A pharmaceutical composition comprising the compound of Exemplary Embodiment 44, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof. constructs, isotopically labeled compounds or prodrugs, and pharmaceutically acceptable carriers.

Exemplary Embodiment 52. A pharmaceutical composition comprising the compound of Exemplary Embodiment 45, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof. constructs, isotopically labeled compounds or prodrugs, and pharmaceutically acceptable carriers.

Exemplary Embodiment 53. A pharmaceutical composition comprising the compound of Exemplary Embodiment 46, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof. constructs, isotopically labeled compounds or prodrugs, and pharmaceutically acceptable carriers.

Exemplary Embodiment 54. A pharmaceutical composition comprising the compound of Exemplary Embodiment 47, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof. constructs, isotopically labeled compounds or prodrugs, and pharmaceutically acceptable carriers.

Exemplary Embodiment 55. A pharmaceutical composition comprising the compound of Exemplary Embodiment 48, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof. constructs, isotopically labeled compounds or prodrugs, and pharmaceutically acceptable carriers.

Exemplary Embodiment 56. A pharmaceutical composition comprising the compound of Exemplary Embodiment 49, or a pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, or tautomer thereof. constructs, isotopically labeled compounds or prodrugs, and pharmaceutically acceptable carriers.

Exemplary Embodiment 57. A method of treating or preventing NLRP3-related diseases or disorders, comprising administering to an individual at least one therapeutically effective amount of a compound such as Exemplary Embodiment 43, or a pharmaceutically acceptable salt or solvent thereof compounds, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 58. The method of Exemplary Embodiment 57, wherein the NLRP3-related disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease , kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or individuals who carry germline or somatic non-silent mutations in identified NLRP3 Among NLRP3-related diseases.

Exemplary Embodiment 59. The method of Exemplary Embodiment 58, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amine) Pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, and isotopes Labeled compound or prodrug.

Exemplary Embodiment 60. The method of Exemplary Embodiment 58, wherein the compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropanol) base)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, and Allomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 61. The method of Exemplary Embodiment 58, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-piran-4 -(yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, Tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 62. The method of Exemplary Embodiment 58, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-piran-4 -(yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, Tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 63. The method of Exemplary Embodiment 58, wherein the compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3 ,4-d]pyridazin-1-yl)-5-methylphenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, Isotopically labeled compounds or prodrugs.

Exemplary Embodiment 64. The method of Exemplary Embodiment 58, wherein the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido [3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, and stereoisomers , tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 65. A method of treating or preventing an NLRP3-related disease or condition selected from: Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache/pain and traumatic brain injury, the method comprising administering to the individual at least one therapeutically effective amount of a compound such as Exemplary Embodiment 43, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereo Isomers, tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 66. The method of Exemplary Embodiment 65, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amine) Pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, and isotopes Labeled compound or prodrug.

Exemplary Embodiment 67. The method of Exemplary Embodiment 65, wherein the compound is 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropanol) base)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, and Allomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 68. The method of Exemplary Embodiment 65, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-piran-4 -(yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, Tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 69. The method of Exemplary Embodiment 65, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-piran-4 -(yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, Tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 70. The method of Exemplary Embodiment 65, wherein the compound is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3 ,4-d]pyridazin-1-yl)-5-methylphenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, Isotopically labeled compounds or prodrugs.

Exemplary Embodiment 71. The method of Exemplary Embodiment 65, wherein the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido [3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, and stereoisomers , tautomers, isotopically labeled compounds or prodrugs.

Exemplary Embodiment 72. A method of treating or preventing an NLRP3-related disease or condition selected from: Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache/pain and traumatic brain injury, the method comprising administering to the subject at least one therapeutically effective amount of a pharmaceutical composition such as Exemplary Embodiment 50.

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)amine yl)pyrido[3,4-d]pyridazin-1-yl)phenol; (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-piran-) 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-methylmorpholine- 2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

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

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

Exemplary Embodiment A4. The compound of Exemplary Embodiment A1, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-piran-4 -yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

Exemplary Embodiment A5. The compound of Exemplary Embodiment A1, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-piran-4 -yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

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

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

Exemplary Embodiment A8. A pharmaceutical composition comprising the compound of Exemplary Embodiment A1, and a pharmaceutically acceptable carrier.

Exemplary Embodiment A9. A pharmaceutical composition comprising a compound as in Exemplary Embodiment A2, and a pharmaceutically acceptable carrier.

Exemplary Embodiment A10. A pharmaceutical composition comprising the compound of Exemplary Embodiment A3, and a pharmaceutically acceptable carrier.

Exemplary Embodiment A11. A pharmaceutical composition comprising the compound of Exemplary Embodiment A4, and a pharmaceutically acceptable carrier.

Exemplary Embodiment A12. A pharmaceutical composition comprising the compound of Exemplary Embodiment A5, and a pharmaceutically acceptable carrier.

Exemplary Embodiment A13. A pharmaceutical composition comprising the compound of Exemplary Embodiment A6, and a pharmaceutically acceptable carrier.

Exemplary Embodiment A14. A pharmaceutical composition comprising the compound of Exemplary Embodiment A7, and a pharmaceutically acceptable carrier.

Exemplary Embodiment A15. A method of treating or preventing an NLRP3-related disease or disorder, comprising administering to a subject at least one therapeutically effective amount of a compound of Exemplary Embodiment A1.

Exemplary Embodiment A16. The method of Exemplary Embodiment A1, wherein the NLRP3-related disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease , kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or individuals who carry germline or somatic non-silent mutations in identified NLRP3 Among NLRP3-related diseases.

Exemplary Embodiment A17. The method of Exemplary Embodiment A16, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amine) Pyrido[3,4-d]pyridazin-1-yl)phenol.

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

Exemplary Embodiment A19. The method of Exemplary Embodiment A16, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-piran-4 -yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

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

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

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

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

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

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

Exemplary Embodiment A26. The method of Exemplary Embodiment A23, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-piran-4 -yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

Exemplary Embodiment A27. The method of Exemplary Embodiment A23, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-piran-4 -yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

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

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

Exemplary Embodiment A30. A method of treating or preventing an NLRP3-related disease or condition selected from: Parkinson's disease, Alzheimer's disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache/pain and traumatic brain injury, the method comprising administering to the individual at least one therapeutically effective amount of a pharmaceutical composition such as Exemplary Embodiment A8. Example

For exemplary purposes, neutral (free base) compounds described herein were synthesized and tested in the Examples. It will be understood that the neutral compounds disclosed herein can be prepared using techniques routine in the art ( e.g. , by saponification of esters to carboxylate salts, or by hydrolysis of amide to form the corresponding carboxylic acid, and then converting the carboxylic acid acid to carboxylate) into the corresponding pharmaceutically acceptable salts of these compounds.

Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz and 300.3 K as stated, 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.

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

Abbreviation: DCM Dichloromethane DMF N,N-dimethylformamide DMSO DMSO dppf 1,1′-bis(diphenylphosphino)ferrocene ESI electrospray dissociation EtOAc or EA Ethyl acetate tOH ethanol FA Formic acid h hours Hex Hexane HPLC HPLC IPA Isopropyl alcohol LCMS Liquid Chromatography-Mass Spectrometry MeCN or ACN Acetonitrile OH Methanol min minute mw microwave m/z mass/charge PE Petroleum ether Preparative HPLC Preparative high performance liquid chromatography rt room temperature RT Residence time THF Tetrahydrofuran Y Yield 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] pyridazine -1 -yl ) phenol ( compound 1B * )

Example 1 follows Plan A.

Step 1 : 1- chloro -N-(4,4- dimethyloxolan- 3- yl ) pyrido [3,4-d] pyridazin -4- amine and 4- chloro -N-( Synthesis of 4,4- dimethyloxolan -3- yl ) pyrido [3,4-d] pyridazin -1- amine. At 130°C, add 1,4-dichloropyrido[3,4-d]pyridazine (250 mg, 1.25 mmol, 1 equivalent), DMF (3 mL) and Na ₂ CO ₃ ( 423.91 mg, 4 mmol, 3.2 equivalents). The final reaction mixture was irradiated with microwave radiation at 130°C for 40 min. After the reaction was completed, the residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (MeCN) aqueous solution, 0% to 100% gradient within 30 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This yielded 1-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine as a yellow oil and 4-chloro- N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-1-amine (150 mg, mixture of two isomers). LCMS: (ES, m/z): RT=0.735 min, m/z=279[M+1] ⁺ .

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] pyridazine -1 -yl ) phenol ( compound 1B*) . At 80°C, add 1-chloro-N-(4,4-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazine-4- to a 25 mL round bottom flask. A mixture of 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 mg, 0.69 mmol, 1.3 equiv), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) ( Pd(dppf)Cl ₂ ) (78.75 mg, 0.10 mmol, 0.2 equiv), Na ₂ CO ₃ (171.11 mg, 1.61 mmol, 3 equiv), dioxane (6 mL) and H ₂ O (1.2 mL). The final reaction mixture was heated at 80 °C for 2 h. After the reaction was completed, the reaction mixture was concentrated, and the residue was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, acetonitrile (MeCN) aqueous solution, 0% to 100% gradient within 30 min; Detector, UV 254 nm). After the reaction was completed, the reaction mixture was concentrated, and the crude product was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01): column, XBridge Prep Phenyl OBD Column, 19*250 mm, 5µm; mobile phase , water (10 mmol/L NH ₄ HCO ₃ ) and acetonitrile (MeCN) (25% MeCN to 45% in 12 min); detector, UV 254). This yielded 5-chloro-2-(1-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-4-yl as a crude pale yellow solid. )phenol (3.2 mg, 1.5% yield) and 5-chloro-2-(4-{[-4,4-dimethyloxolan-3-yl]amine} as a pale yellow crude solid Pyrido[3,4-d]pyridazin-1-yl)phenol ( Compound 1A ) (32 mg, 15% yield). Then use the following conditions (column, Chiral ART Cellulose-SA, 4.6*50 mm, 3 um; mobile phase, methyl tertiary butyl ether (MtBE) (0.2% formic acid (FA)) and isopropyl: dichloride Methane (IPA:DCM) = 1:1 (50% IPA:DCM=1:1 for 4 min; detector, UV 254) for 20 mg 5-chloro-2-(4-{[-4, 4-Dimethyloxolan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol ( compound 1A ) was chiral separated to obtain a light yellow solid. 5-Chloro-2-(4-{[(3R)-4,4-dimethyloxolan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl )phenol (also referred to herein as (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine- 1-yl)phenol) ( compound 1* ) (RT = 1.12 min, 5.4 mg, 2.69% yield) and 5-chloro-2-(4-{[(3S)-4,4- as a light yellow solid 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). Arbitrarily specified stereochemistry.

(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 (400 MHz, methanol-d4) δ 9.77 (d, J = 1.0 Hz, 1H), 8.87 (d, J = 5.7 Hz, 1H), 7.59 - 7.50 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.8 Hz, 2H), 5.10 - 4.98 (m, 1H), 4.47 - 4.30 (m, 1H), 3.99 - 3.86 (m, 1H), 3.75 (d, J = 8.4 Hz, 1H), 3.68 (d, J = 8.4 Hz, 1H), 1.32 (s, 3H), 1.16 (s, 3H).

(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 (400 MHz, methanol-d4) δ 9.81 - 9.74 (m, 1H), 8.87 (d, J = 5.7 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.38 (d, J = 8.0 Hz , 1H), 7.06 (d, J = 7.7 Hz, 2H), 5.13 - 4.98 (m, 1H), 4.50 - 4.33 (m, 1H),4.00 - 3.87 (m, 1H), 2.45 (d, J = 8.3 Hz, 1H), 2.08 (d, J = 8.3 Hz, 1H), 1.32 (s, 3H), 1.16 (s, 3H). 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] da Azin -1- yl ) phenol ( compound 3*) and (R)-5- chloro -2-(4-((3,3- dimethyltetrahydro -2H- pyran -4- yl ) amine ) Pyrido [3,4-d] pyridazin -1- yl ) phenol ( Compound 3B*)

Example 2 follows Plan B.

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

Step 2 : Synthesis of 1-(4- chloro -2- methoxyphenyl ) pyrido [3,4-d] pyridazin -4- ol. To a 250 mL round bottom flask, add 4-(4-chloro-2-methoxybenzyl)pyridine-3-carboxylic acid (5 g, 17.1 mmol, 1 equiv) and SOCl ₂ (50 mL). The resulting mixture was stirred at 70 °C for 2 h. The reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (DCM) (50 mL) and added to NH ₂ NH ₂ .H ₂ O (3.43 g, 68.6 mmol, 4 equiv), methanol (MeOH) (50 mL) at 0°C. in solution. 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 (4g, 90% purity) was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD Column, 19*250 mm, 10µm; mobile phase, Water (10 mmol/L NH ₄ HCO ₃ ) and acetonitrile (MeCN) (39% MeCN maintained within 17 min); detector, UV 254/220 nm. This gave 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol as an off-white solid (2.0 g, 40.6% yield). LCMS: (ES, m/z): RT=0.723 min, m/z=288.0 [M +H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.90 (s, 1H), 9.50 (s, 1H), 8.94 (d, J = 5.5 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H) , 7.33 (d, J = 1.9 Hz, 1H), 7.23 - 7.15 (m, 2H), 3.75 (s, 3H).

Step 3 : Synthesis of 4- chloro -1-(4- chloro -2- methoxyphenyl ) pyrido [3,4-d] pyridazine. Add 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2.5 g, 8.69 mmol, 1 equivalent) and POCl ₃ to a 250 mL round bottom flask. (40 mL) and pyridine (4 mL). The resulting mixture was stirred at 100 °C for 3 h. The reaction progress was monitored by LCMS. Quench the reaction with 500 mL sodium bicarbonate (aq.) and 500 mL EtOAc at 0°C. The resulting mixture was extracted with EtOAc (3x500 mL). The combined organic layers were dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. This gave 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine as a brown solid (1.5 g, 56.4% yield). LCMS (ES, m/z): RT=0.845 min, m/z=306.0 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.84 - 9.68 (m, 1H), 9.12 (d, J = 5.7 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.32 - 7.25 (m, 1H), 3.74 (s, 3H).

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

Step 5 : 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] da Azin -1- yl ) phenol ( compound 3*) and (R)-5- chloro -2-(4-((3,3- dimethyltetrahydro -2H- pyran -4- yl ) amine ) Synthesis of pyrido [3,4-d] pyridazin -1- yl ) phenol ( Compound 3B*) . To a 20 vial was added the reaction mixture from step 4, sodium (ethylsulfanyl) (1054.30 mg, 12.53 mmol, 25 equiv) and DMSO (8 mL) at room temperature. The resulting mixture was stirred at 120°C under nitrogen atmosphere for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with MeCN (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions (column, C18 gel; mobile phase, MeCN aqueous solution (10 mmol/L NH ₄ HCO ₃ ), 0% to 100% gradient in 30 min; detection device, UV 254 nm), producing a product that is an off-white solid. The product (90 mg, 98.2% purity) was analyzed by preparative HPLC under the following conditions (preparative HPLC-064: column, CHIRALPAK IG, 2*25 cm, 5 um; mobile phase, Hex and MeOH:DCM=1: 1 (maintain 50% MeOH:DCM=1:1 within 23 minutes; detector, UV 254nm) for purification to obtain 5-chloro-2-(4-{[(4R)-3,3-) as an off-white solid Dimethyloxan-4-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (also referred to herein as (R)-5-chloro-2-(4 -((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol) ( Compound 3B* ) (RT = 1.50 min, 27.8 mg, 14.3% yield) and 5-chloro-2-(4-{[(4S)-3,3-dimethyloxan-4-yl]amine as an off-white solid yl}pyrido[3,4-d]pyridazin-1-yl)phenol (also referred to herein as (S)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H) -pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol) ( compound 3* ) (RT = 3.28 min, 24.4 mg, 12.5% yield). Arbitrarily specified stereochemistry.

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 (400 MHz, DMSO- d ₆ ) δ 10.24 (s, 1H), 9.89 (s, 1H), 8.86 (d, J = 5.6 Hz, 1H), 7.38 - 7.20 (m, 3H), 7.03 ( d, J = 7.4 Hz, 2H), 4.81 - 4.70 (m, 1H), 4.05 - 3.89 (m, 1H), 3.54 - 3.42 (m, 2H), 3.25 (d, J = 11.3 Hz, 1H), 1.99 - 1.90 (m, 1H), 1.75 - 1.66 (m, 1H), 1.14 (s, 3H), 0.87 (s, 3H).

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 (400 MHz, DMSO- d ₆ ) δ 10.24 (s, 1H), 9.88 (s, 1H), 8.86 (d, J = 5.6 Hz, 1H), 7.40 - 7.17 (m, 3H), 7.03 ( d, J = 7.5 Hz, 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, 4.8 Hz, 1H), 1.73 - 7.65 (m, 1H), 1.13 (s, 3H), 0.87 (s, 3H). 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- methyl phenol ( compound 5) and (S)-2-(4-((5,5 -dimethyltetrahydrofuran -3- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl ) -5- Methylphenol ( compound 5B)

Example 3 follows Plan A.

Add 1-chloro-N-(5,5-dimethyloxolan-3-yl)pyrido[3,4-d]pyridazin-4-amine to a 8 mL sealed tube at 80°C. (120 mg, 0.430 mmol, 1 equivalent), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (201 mg, 0.860 mmol, 2 equiv), Pd(dppf)Cl ₂ (94.5 mg, 0.130 mmol, 0.300 equiv), dioxane (2 mL) and H ₂ O (0.4 mL). 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 obtain crude product (140 mg), which was prepared by Type HPLC (column: Xselect CSH C18 OBD Column 30*150mm 5 m, n; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ; mobile phase B: MeCN; flow rate: 60 mL/min; gradient: 11 34% B to 34% B within min, 34% B; wavelength: 254 nm; RT1 (min): 10.2) was purified to obtain a mixture of compounds 5A and 5B (65 mg), which was analyzed by preparative chiral-HPLC ( Column: CHIRAL 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) was further purified to obtain (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amine) Pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol ( compound 5 ) (28.4 mg, 18.8% yield) (RT(min): 9.63) and (S)-2- (4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol ( Compound 5B ) (23.7 mg , 15.7% yield) (RT(min): 13.52). Absolute stereochemistry was determined by X-ray crystallography.

(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 (400 MHz, methanol- d ₄ ) δ 9.70 (d, J = 1.0 Hz, 1H), 8.85 (d, J = 5.7 Hz, 1H), 7.57 (m, J = 5.7, 1.0 Hz, 1H) , 7.28 (d, J = 7.7 Hz, 1H), 6.91 - 6.83 (m, 2H), 5.05 - 4.97 (m, 1H), 4.41 (m, J = 9.1, 6.7 Hz, 1H), 3.92 (m, J = 9.1, 5.9 Hz, 1H), 2.45 (m, J = 12.8, 8.1 Hz, 1H), 2.40 (s, 3H), 2.08 (m, J = 12.7, 6.8 Hz, 1H), 1.45 (s, 3H) , 1.35 (s, 3H).

(S)-2-(4-((5,5- dimethyltetrahydrofuran -3- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl )-5- methylphenol ( Compound 5B) LCMS (ES, m/z): RT=1.23 min, m/z=351.1[M+H] ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.70 (d, J = 1.0 Hz, 1H), 8.85 (d, J = 5.7 Hz, 1H), 7.57 (m, J = 5.7, 1.0 Hz, 1H) , 7.28 (d, J = 7.7 Hz, 1H), 6.91 - 6.83 (m, 2H), 5.07 - 4.97 (m, 1H), 4.41 (m, J = 9.1, 6.6 Hz, 1H), 3.92 (m, J = 9.1, 5.8 Hz, 1H), 2.45 (m, J = 12.8, 8.0 Hz, 1H), 2.40 (s, 3H), 2.08 (m, J = 12.7, 6.8 Hz, 1H), 1.45 (s, 3H) , 1.35 (s, 3H).

Table A shows a scheme for preparing the compounds of the present disclosure, and Table B provides NMR data. Table A. Compound number structure MS (ESI ; m/z ; M+H) plan 1* (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 371.1 Plan A (Example 1) 1A* 5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 371.1 Plan A (Example 1) 1B* (S)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 371.1 Plan A (Example 1) 2 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazine-1- base) phenol 378.2 Plan A 3B* (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol 385.2 Plan B (Example 2) 3A 5-Chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 385.2 Plan B (Example 2) 3* (S)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol 385.2 Plan B (Example 2) 4* (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol 385.1 Scheme B Compound 4*: column, CHIRALPAK IE, 2*25 cm, 5 um; mobile phase: hexane and MeOH:DCM=1:1 (maintain 25% MeOH:DCM=1:1 within 17 minutes); detection detector, UV 254. RT = 2.45 minutes 4A 5-Chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 385.1 Scheme B Compounds 4*, 4A and 4B* were synthesized following Scheme B and Example 2 using 2,2-dimethyltetrahydro-2H-pyran-4-amine as the amine (i) reagent in step 4. 4B* (R)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol 385.1 Scheme B Compound 4B*: column, CHIRALPAK IE, 2*25 cm, 5 um; mobile phase, Hex- and MeOH:DCM=1:1 (maintain 25% MeOH:DCM=1:1 within 17 minutes); detection detector, UV 254. RT = 3.12 minutes 5 (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol 351.1 Plan A (Example 3) 5A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol 351.1 Plan A (Example 3) 5B (S)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol 351.1 Plan A (Example 3) 6* (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol 420.2 Scheme A Compound 6*: Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile phase A: Hexane (Hex) (0.5% 2M NH ₃ -MeOH), Mobile phase B: EtOH:DCM=1:1 ;Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 8 minutes; Wavelength: 220/254 nm RT(min): 5.27 6A 2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl) phenol 420.2 Scheme A Compounds 6*, 6A and 6B* were synthesized following Scheme A and Example 1 using (4-methylmorpholin-2-yl)methanamine as the amine (i) reagent in step 1. 6B* (R)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol 420.2 Scheme A Compound 6B*: Column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH ₃ -MeOH), mobile phase B: EtOH:DCM=1:1; flow rate: 20 mL/min; Gradient: 50% B to 50% B in 8 minutes; Wavelength: 220/254 nm; RT(min): 7.30 7* (S)-5-Chloro-2-(4-((tetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol Comparative Example 1 USSN 17/528,928 343.1 Plan A 8 5-Chloro-2-(4-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol Comparative Example 2 USSN 17/528,928 357.0 Plan A Table B. ^1H NMR table Compound number ¹ H NMR 1* 1H NMR (400 MHz, methanol-d ₄ ) δ 9.77 (d, J = 1.0 Hz, 1H), 8.87 (d, J = 5.7 Hz, 1H), 7.59 - 7.50 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.8 Hz, 2H), 5.10 - 4.98 (m, 1H), 4.47 - 4.30 (m, 1H), 3.99 - 3.86 (m, 1H), 3.75 (d, J = 8.4 Hz, 1H), 3.68 (d, J = 8.4 Hz, 1H), 1.32 (s, 3H), 1.16 (s, 3H). 1B* ¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.81 - 9.74 (m, 1H), 8.87 (d, J = 5.7 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.7 Hz, 2H), 5.13 - 4.98 (m, 1H), 4.50 - 4.33 (m, 1H),4.00 - 3.87 (m, 1H), 2.45 (d, J = 8.3 Hz, 1H), 2.08 (d, J = 8.3 Hz, 1H), 1.32 (s, 3H), 1.16 (s, 3H). 2* ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.18 (s, 1H), 9.84 (s, 1H), 8.86 (d, J = 5.6 Hz, 1H), 7.69 (t, J = 6.0 Hz, 1H) , 7.47 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 5.6 Hz, 1H), 7.26 - 6.90 (m, 3H), 3.82 (d, J = 5.9 Hz, 2H), 1.25 (s, 6H). 3B* ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.24 (s, 1H), 9.89 (s, 1H), 8.86 (d, J = 5.6 Hz, 1H), 7.38 - 7.20 (m, 3H), 7.03 ( d, J = 7.4 Hz, 2H), 4.81 - 4.70 (m, 1H), 4.05 - 3.89 (m, 1H), 3.54 - 3.42 (m, 2H), 3.25 (d, J = 11.3 Hz, 1H), 1.99 - 1.90 (m, 1H), 1.75 - 1.66 (m, 1H), 1.14 (s, 3H), 0.87 (s, 3H). 3* ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.24 (s, 1H), 9.88 (s, 1H), 8.86 (d, J = 5.6 Hz, 1H), 7.40 - 7.17 (m, 3H), 7.03 ( d, J = 7.5 Hz, 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, 4.8 Hz, 1H), 1.73 - 7.65 (m, 1H), 1.13 (s, 3H), 0.87 (s, 3H). 4* ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.70 (s, 1H), 8.86 (d, J = 5.7 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H), 4.80 - 4.71 (m, 1H), 3.95 - 3.80 (m, 2H), 2.23 -2.10 (m, 2H), 1.70 - 1.57 (m, 2H) , 1.40 (s, 3H), 1.31 (s, 3H). 4B* ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.68 (d, J = 1.0 Hz, 1H), 8.85 (d, J = 5.7 Hz, 1H), 7.52 - 7.50 (m, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.12 - 7.01 (m, 2H), 4.84 - 4.76 (m, 1H), 3.97 - 3.80 (m, 2H), 2.21 - 2.13 (m, 2H), 1.70 - 1.57 (m, 2H), 1.41 (s, 3H), 1.31 (s, 3H). 5 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.70 (d, J = 1.0 Hz, 1H), 8.85 (d, J = 5.7 Hz, 1H), 7.57 (m, J = 5.7, 1.0 Hz, 1H) , 7.28 (d, J = 7.7 Hz, 1H), 6.91 - 6.83 (m, 2H), 5.05 - 4.97 (m, 1H), 4.41 (m, J = 9.1, 6.7 Hz, 1H), 3.92 (m, J = 9.1, 5.9 Hz, 1H), 2.45 (m, J = 12.8, 8.1 Hz, 1H), 2.40 (s, 3H), 2.08 (m, J = 12.7, 6.8 Hz, 1H), 1.45 (s, 3H) , 1.35 (s, 3H). 5B ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.70 (d, J = 1.0 Hz, 1H), 8.85 (d, J = 5.7 Hz, 1H), 7.57 (m, J = 5.7, 1.0 Hz, 1H) , 7.28 (d, J = 7.7 Hz, 1H), 6.91 - 6.83 (m, 2H), 5.07 - 4.97 (m, 1H), 4.41 (m, J = 9.1, 6.6 Hz, 1H), 3.92 (m, J = 9.1, 5.8 Hz, 1H), 2.45 (m, J = 12.8, 8.0 Hz, 1H), 2.40 (s, 3H), 2.08 (m, J = 12.7, 6.8 Hz, 1H), 1.45 (s, 3H) , 1.35 (s, 3H). 6* ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.66 (s, 1H), 8.87 (d, J = 5.7 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 5.7 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 4.03 (t, J = 8.0 Hz, 1H), 3.99 - 3.92 (m, 1H), 3.87 (dd, J = 13.8, 4.7 Hz, 1H), 3.82 - 3.65 (m, 2H), 3.00 (d, J = 11.4 Hz, 1H), 2.74 (d, J = 11.7 Hz, 1H), 2.34 (s, 3H), 2.23 (td, J = 11.7, 3.4 Hz, 1H), 2.04 (td, J = 10.9 Hz, 1H). 6B* ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.66 (s, 1H), 8.87 (d, J = 5.7 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 5.7 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 4.04 (s, 1H), 4.02 - 3.92 (m, 1H), 3.87 (m, 1H), 3.83 - 3.65 (m, 2H), 3.00 (d, J = 11.3 Hz, 1H), 2.74 (d, J = 11.8 Hz, 1H), 2.35 (s, 3H), 2.24 (td, J = 11.6, 3.4 Hz, 1H ), 2.05 (t, J = 10.8 Hz, 1H). 7* Comparison example 1 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.82 (s, 1H), 8.87 (d, J = 5.6 Hz, 1H), 7.94 (d, J = 5.8 Hz, 1H), 7.43 - 7.27 (m, 2H), 7.04 (d, J = 7.1 Hz, 2H), 4.87-4.80 (m, 1H), 4.11 - 3.91 (m, 2H), 3.85 - 3.72 (m, 2H), 2.40 - 2.26 (m, 1H) , 2.22 - 2.06 (m, 1H). 8Comparison Example 2 ¹ H NMR (400 MHz, DMSO-d6) δ 9.90 (d, J = 0.9 Hz, 1H), 9.13 (d, J = 5.5 Hz, 1H), 7.67 - 7.65 (m, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.18 - 7.02 (m, 2H), 3.77 (s, 2H), 3.62 (s, 2H), 0.86 - 0.63 (m, 4H). Example 4. 5-( difluoromethoxy )-2-(4-((5,5- dimethyltetrahydrofuran -3- yl ) amino ) pyrido [3,4-d] pyridazine -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*)

Example 4 follows Plan A.

Step 1. Synthesis of 1- bromo -4-( difluoromethoxy )-2- methoxybenzene. At room temperature, add 4-bromo-3-methoxyphenol (5 g, 24.62 mmol, 1 equivalent), acetonitrile (MeCN) (10 mL), and bromodifluoromethylphosphonic acid to a 100 mL round-bottomed flask. Diethyl ester (13.15 g, 49.25 mmol, 2 equivalents) and KOH (2.76 g, 49.25 mmol, 2 equivalents), H ₂ O (10 mL). 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 (1x10 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (PE/EA) (4:1) to obtain the title compound (3.9 g, 61.3% yield). LCMS, ESI: RT= 1.35 min, m/z =253[M+H] ⁺ .

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) at room temperature Add triethylamine (2639.37 mg, 26.08 mmol, 3 equivalents) and 4,4,5,5-tetramethyl-1,3,2-dioxaborane (5563.40 mg, 43.47 mmol, 5 equivalents). ). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 0.5 h. To the above mixture, 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). The resulting mixture was stirred at 80°C under nitrogen atmosphere for an additional 2 h. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL) at 0°C. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (1x20 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to obtain the crude title compound, which was used directly in the next step. LCMS, ESI: RT= 0.75 min, m/z =219[M+H] ⁺ .

Step 3. Synthesis of 1- chloro -N-(5,5- dimethyloxolan- 3- yl ) pyrido [3,4-d] pyridazin -4- amine. Add 1,4-dichloropyrido[3,4-d]pyridazine (800 mg, 3.99 mmol, 1 equivalent), 5,5-dimethyloxolane-3- to a 20 mL sealed tube. Amine (552.79 mg, 4.79 mmol, 1.2 equiv), Na ₂ CO ₃ (1270.94 mg, 11.99 mmol, 3 equiv) and dimethylformamide (10 mL). 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 5 times. The combined mixture was filtered and the filter cake was washed with EtOAc (3x20 mL). The filtrate was concentrated under reduced pressure. The crude product was analyzed by preparative HPLC (2#SHIMADZU (HPLC-01): column, XBridge Prep Phenyl OBD Column, 19*250 mm, 5µm; mobile phase, water (50 mmol/L NH ₄ HCO ₃ ) and acetonitrile (MeCN) (12% MeCN rose to 22% within 10 min, maintained at 22% within 2 min); detector, UV254nm) was purified to obtain 1-chloro-N-(5,5-dimethyloxolane) Alk-3-yl)pyrido[3,4-d]pyridazin-4-amine (2 g, 32.3% yield). LCMS, ESI: RT= 0.73 min, m/z = 279.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.83 (d, J = 1.0 Hz, 1H), 9.07 (d, J = 5.6 Hz, 1H), 8.07 (d, J = 5.8 Hz, 1H), 7.88 (dd, J = 5.6, 0.9 Hz, 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).

Step 4. 1-(4-( Difluoromethoxy )-2- methoxyphenyl )-N-(5,5 -dimethyltetrahydrofuran -3- yl ) pyrido [3,4-d] Synthesis of pyridazine -4- amine . To stirred 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 ) were added Na ₂ CO ₃ (1596.36 mg, 15.06 mmol, 3 equivalents) and Pd(dppf)Cl ₂ (735.02 mg, 1 mmol, 0.2 equivalents). The resulting mixture was stirred at 80°C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, acetonitrile (MeCN) aqueous solution, 40% to 50% gradient in 10 min; detector, UV 254 nm) to obtain the title compound ( 1.20 g, 57% yield). LCMS, ESI: RT= 0.66 min, m/z = 417.1 [M+H] ⁺ .

Step 5.5-( difluoromethoxy )-2-(4-((5,5 -dimethyltetrahydrofuran -3- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl ) Synthesis of phenol . To the stirred 1-(4-(difluoromethoxy)-2-methoxyphenyl)-N-(5,5-dimethyltetrahydrofuran-3-yl)pyrido[ To a solution of 3,4-d]pyridazin-4-amine (1100 mg, 2.64 mmol, 1 equiv) in dimethylformamide (10 mL) was added sodium (ethylsulfanyl) (666.53 mg, 7.92 mmol, 3 equivalents). The resulting mixture was stirred at 120 °C for 1 h. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (3x5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; mobile phase A: water (0.05% trifluoroacetic acid (TFA)), mobile phase B: MeCN; flow rate: 60 mL /min; Gradient: 18% B to 28% B, 28% B in 10 min; Wavelength: 254 nm; RT(min): 8.4) Purification gave the title compound ( Compound 9A ) (751.6 mg, 55.1% yield) . LCMS, ESI: RT= 0.67 min, m/z =403.1[M+H] ⁺ ; ¹ H NMR (400 MHz, methanol- d ₄ ) 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 separated via chiral HPLC , and the stereochemistry was assigned based on extrapolation from that of compound 5 and compound 5B .

(S)-5-( difluoromethoxy )-2-(4-((5,5- dimethyltetrahydrofuran -3- yl ) amino ) pyrido [3,4-d] pyridazine -1 -Isolation of 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 (400 MHz, methanol-d4) δ 9.99 (d, J = 1.3 Hz, 1H), 9.14 (d, J = 5.5 Hz, 1H), 7.72 - 7.71 (m, 1H), 7.47 (d, J = 8.4 Hz, 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, 6.0 Hz, 1H), 1.46 (s , 3H), 1.37 (s, 3H); LCMS: 403.5 [M+H] ⁺ .

(R)-5-( difluoromethoxy )-2-(4-((5,5- dimethyltetrahydrofuran -3- yl ) amino ) pyrido [3,4-d] pyridazine -1 -Isolation of 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 (400 MHz, methanol- d ₄ ) δ 10.03 - 9.98 (m, 1H), 9.14 - 9.13 (m, 1H), 7.72 - 7.71 (m, 1H), 7.47 (d, J = 8.4 Hz, 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] ⁺ . Example 5. 2-(4-((6,6- dimethyltetrahydro -2H- pyran -3- yl ) amino ) pyrido [3,4-d] da Azin -1- yl )-5- methylphenol ( compound 10A) , (S)-2-(4-((6,6- dimethyltetrahydro -2H- piran -3- yl ) amine ) 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*)

Example 5 follows Plan B.

Step 1. Synthesis of 4-(2- methoxy -4- methylbenzoyl ) pyridine -3- carboxylic acid. At -78°C, add furo[3,4-c]pyridine-1,3-dione (10 g, 67.06 mmol, 1 equivalent) and THF (100 mL) dropwise to a 250 mL 3-neck round-bottom flask. and (2-methoxy-4-methylphenyl)magnesium bromide (9 g, 40.24 mmol, 0.6 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. 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= 0.570 min, m/z=272 [M+1] ⁺ .

Step 2. Synthesis of 1-(2- methoxy -4- methylphenyl ) pyrido [3,4-d] pyridazin -4- ol. To a 250 mL round bottom flask, add 4-(2-methoxy-4-methylbenzyl)pyridine-3-carboxylic acid (2 g, 7.37 mmol, 1 equiv) and SOCl ₂ (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 equiv) 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 ((preparative HPLC-059): column, CHIRAL ART Cellulose-SC, 2*25 cm, 5 um; mobile phase, Hex (0.5% 2M NH ₃ -MeOH) and MeOH:DCM=1:1 (maintain 60% MeOH:DCM=1:1 within 10 min); detector, UV 254) purified to obtain the title compound (1.30g, 66% yield) . LCMS: (ES, m/z): RT= 0.880 min, m/z=268[M+1]+ ^. 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.49 (d, J = 0.9 Hz, 1H), 8.93 (d, J = 5.5 Hz, 1H), 7.25 (d, J = 7.6 Hz , 1H), 7.17 (d, J = 5.5, 0.9 Hz, 1H), 7.06 (s, 1H), 6.98 - 6.91 (m, 1H), 3.70 (s, 3H), 2.43 (s, 3H).

Step 3. Synthesis of 4-(2- methoxy -4- methylbenzoyl ) pyridine -3- carboxylic acid. At room temperature, add 1-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazin-4-ol (800 mg, 2.99 mmol, 1 equiv), POCl ₃ (10 mL) and pyridine (1 mL). 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 addition to an aqueous solution of _NaHCO3 (500 mL) and ethyl acetate (EtOAc) (500 mL) at 0°C. The resulting mixture was extracted with EtOAc (3x500 mL). The combined organic layers were washed with _{H2O (} 1x500 mL), dried over _Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure to give the title compound (300 mg, 35.1% yield). LCMS: (ES, m/z): RT= 0.837 min, m/z=286[M+1]+ _. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (d, J = 1.0 Hz, 1H), 9.10 (d, J = 5.7 Hz, 1H), 7.59 - 7.46 (m, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 1.4 Hz, 1H), 7.08 - 6.95 (m, 1H), 3.69 (s, 3H), 2.47 (s, 3H).

Step 4. N-(6,6- dimethyloxan- 3- yl )-1-(2- methoxy -4- methylphenyl ) pyrido [3,4-d] da Synthesis of oxazine -4- amine. To stir 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 ) were added to the solution in 6,6-dimethyloxane-3-amine (81.39 mg, 0.630 mmol, 1.2 equivalents) and triethylamine (TEA) (159.4 mg, 1.58 mmol, 3 equivalents). 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 analyzed by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), 10% to 50% gradient in 10 min; detection (UV 254 nm) to obtain the title compound (180 mg, 77.5% yield). LCMS: (ES, m/z): RT= 0.663min, m/z = 378[M+H] ⁺ .

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- piran -3- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl )-5- methylphenol ( Compound 10B*) . To stirred N-(6,6-dimethyloxan-3-yl)-1-(2-methoxy-4-methylphenyl)pyrido[3,4-d] To a solution of pyridazin-4-amine (50 mg, 0.026 mmol, 1 equiv) in DMF (1.5 mL) was added sodium (ethylsulfanyl) (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 completed, the resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with EtOAc (2x10 mL) and concentrated under vacuum. The product was analyzed by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: MeCN; flow rate: 60 mL/min; gradient: 33% B to 43% B, 43% B in 10 min; wavelength: 254 nm; RT1 (min): 9.5) purification to obtain the title compound ( compound 10A ). Compound 10* and compound 10B* were then separated via chiral HPLC. Arbitrarily specified stereochemistry.

(S)-2-(4-((6,6- dimethyltetrahydro -2H- pyran -3- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl )- Isolation of 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, 27.6% yield). LCMS: (ES, m/z): RT= 1.372 min, m/z = 365 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d6) δ 9.74 (s,1H), 9.65 (s, 1H), 8.85 (dd, J = 5.8, 2.2 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 5.7 Hz, 1H), 7.20 (d, J = 7.6 Hz, 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, 9.6 Hz, 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).

(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*25 cm, 5 μm; mobile phase A: hexane (0.2% 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): 3.82 ; (5.4 mg, 11.2% yield). LCMS: (ES, m/z): RT= 1.36 min, m/z = 365 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.64 (s, 1H), 8.85 (d, J = 5.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 5.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H) , 6.84 - 6.76 (m, 2H), 4.39 (s, 1H), 3.87 (dd, J = 11.4, 4.7 Hz, 1H), 3.53 (t, J = 10.5 Hz, 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). 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 *)

Example 6 follows Plan A.

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

Step 2.2-(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- piper) Synthesis of pyrran -4- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl )-5-( trifluoromethyl ) phenol ( compound 11B*) . To a 20 mL vial, add 1-chloro-N-(2,2-dimethyloxan-4-yl)pyrido[3,4-d]pyridazin-4-amine (250 mg, 0.85 mmol , 1 equivalent), Na ₂ CO ₃ (271.51 mg, 2.56 mmol, 3 equivalents), Pd(dppf)Cl ₂ (187.44 mg, 0.25 mmol, 0.3 equivalents), dioxane (2.5 mL) and H ₂ O (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 phase flash chromatography (column, C18 silica gel; mobile phase, MeCN aqueous solution, 30% to 60% gradient in 10 min; detector, UV 254 nm) to obtain crude product compound 11A (200 mg , 80% purity), which was analyzed by preparative HPLC (column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and MeCN (10 min 35% MeCN (increased to 45%); detector, UV 254nm) was purified to obtain purified compound 11A (120 mg, 98% purity), which was analyzed by chiral preparative HPLC (column, CHIRALPAK ID, 2 *25 cm, 5 um; mobile phase, hexane (0.2% formic acid) and ethanol (EtOH) (maintain 10% EtOH within 20 min); detector, UV 254nm) purification, obtained RT is 1.66 min (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* ); and (R)-2-(4-((2,2-dimethyltetrahydro-2H-) with RT of 2.37 min Piran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (24.3 mg, 5.33% yield) ( Compound 11B* ) . Arbitrarily specified stereochemistry.

(S)-2-(4-((2,2- dimethyltetrahydro -2H- pyran -4- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl )- 5-( Trifluoromethyl ) phenol ( compound 1 1* ) : LCMS: (ES, m/z): RT=1.21 min, m/z=419.0[M+H] ⁺ ; ¹ H NMR (400 MHz, Methanol - d ₄ ) δ 9.71 (d, J = 1.0 Hz, 1H), 8.86 (d, J = 5.7 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.52 - 7.46 (m, 1H) , 7.37 - 7.31 (m, 1H), 7.28 (d, J = 1.7 Hz, 1H), 4.86 - 4.75 (m, 1H), 3.99 - 3.88 (m, 1H), 3.91 - 3.82 (m, 1H), 2.24 - 2.10 (m, 2H), 1.75 - 1.64 (m, 1H), 1.67 - 1.58 (m, 1H), 1.41 (s, 3H), 1.32 (s, 3H).

(R)-2-(4-((2,2- dimethyltetrahydro -2H- pyran -4- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl )- 5-( Trifluoromethyl ) phenol ( Compound 11B* ) : LCMS: (ES, m/z): RT=1.21 min, m/z=419.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, methanol - d ₄ ) δ 9.71 (d, J = 1.0 Hz, 1H), 8.86 (d, J = 5.7 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.37 - 7.31 (m, 1H), 7.28 (d, J = 1.7 Hz, 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). 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- piran -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*)

Example 7 follows Plan A.

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

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 equivalent) in dioxane (10 mL) was added to room temperature under a nitrogen atmosphere. Triethylamine (512.27 mg, 5.04 mmol, 3 equivalents) was treated for 30 min, and then Pd(OAc) ₂ (37.88 mg, 0.17 mmol, 0.1 equivalents) 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 under nitrogen atmosphere for 2 h. The reaction was quenched with ice/water (10 mL) at 0°C. The aqueous layer was extracted with EtOAc (50 mL x 3). The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo to give the title compound (1 g crude), which was used in the next step without further purification. GCMS: m/z = 202.06.

Step 3. 1-[4-( Difluoromethyl )-2- methoxyphenyl ]-N-(2,2 -dimethyloxan -4- yl ) pyrido [3,4 -d] Synthesis of pyridazine -4- amine. To the stirred 2-[4-(difluoromethyl)-2-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborane To a solution of (135.86 mg, 0.47 mmol, 1 equiv) in 1,4-dioxane (9 mL) and H ₂ O (1.8 mL) was added Na ₂ CO ₃ (152.05 mg, 1.43 mmol, 3 equiv) and Pd(dppf) _Cl2 (104.97 mg, 0.14 mmol, 0.3 equiv). The resulting mixture was stirred at 80°C under nitrogen atmosphere for 2 h. The reaction was diluted with water (20 mL) at 0°C. The aqueous layer was extracted with EtOAc (3x50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN aqueous solution, 10% to 50% gradient in 10 min; detector, UV 254 nm) to obtain the title compound (176 mg, 88.8% yield). LCMS: (ES, m/z): RT= 0.65 min, m/z = 415.40 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.84 (d, J = 5.60 Hz, 1H), 7.67 (d, J = 6.90 Hz, 1H), 7.52 (d, J = 7.70 Hz, 1H), 7.40 (s, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.21 - 7.12 (m, 1H), 6.44 (q, J = 7.0 Hz, 1H), 3.76 (d, J = 5.50 Hz, 3H), 3.74 (s, 2H), 1.91 (d, J = 12.90 Hz, 4H ), 1.27 - 1.14 (m, 6H).

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- piran -4- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl ) phenol ( compound 16*) and (R)-5-( difluoromethyl )-2-(4-((2, Synthesis of 2 -dimethyltetrahydro -2H- pyran- 4- yl ) amino ) pyrido [ 3,4-d] pyridazin -1- yl ) phenol ( compound 16B*) . To the stirred 1-[4-(difluoromethyl)-2-methoxyphenyl]-N-(2,2-dimethyloxan-4-yl)pyrido[3, To a solution of 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 (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was subjected to reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN aqueous solution (10mmol/L NH ₄ HCO ₃ ), 25% to 45% gradient in 10 min; detector, UV 254 nm) After purification, compound 16A (43 mg, 96% purity, 88.8% yield) was obtained, which was analyzed by preparative chiral HPLC (column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: Hex (0.2% FA), mobile phase B: IPA:DCM=1:1; flow rate: 20 mL/min; gradient: 30% B to 30% B in 15 min; wavelength: 254/220 nm; RT1(min) :10.29) was further purified to obtain (R)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-piran-4-yl) with RT of 14.32 min )amino)pyrido[3,4-d]pyridazin-1-yl)phenol ( compound 16B* ) (16.5 mg, 11.4% yield) and (S)-5-(difluoro) with RT of 10.29 min Methyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ( Compound 16* ) (18.5 mg, 12.3% yield). Arbitrarily specified stereochemistry.

(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 (400 MHz, DMSO-d6) δ 10.14 (s, 1H ), 9.78 (s, 1H), 8.85 (d, J = 5.6 Hz, 1H), 7.66 (s, 1H), 7.46 (d, J = 7.60 Hz, 1H), 7.29 (d, J = 5.6 Hz, 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).

(S)-5-( difluoromethyl )-2-(4-((3,3- dimethyltetrahydro -2H- pyran -4- yl ) amino ) pyrido [3,4-d ] pyridazin -1- yl ) phenol ( compound 16* ) : LCMS: (ES, m/z): RT=1.12 min, m/z = 401.20[M+H]+; ¹ H NMR (400 MHz, DMSO -d6) δ 10.14 (s, 1H), 9.78 (s, 1H), 8.85 (d, J = 5.6 Hz, 1H), 7.66 (s, 1H), 7.46 (d, J = 7.60 Hz, 1H), 7.29 (d, J = 5.6 Hz, 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). 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- piran -4- yl ) amine ) ) pyrido [3,4-d] pyridazin -1- yl ) phenol ( compound 18A*) , 5- chloro -2-(4-(((3R,4R)-3- methyltetrahydro -2H- Piran -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*)

Example 8 follows Plan B.

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

Step 2 : Synthesis of 1-(4- chloro -2- methoxyphenyl ) pyrido [3,4-d] pyridazin -4- ol. To a 250 mL round bottom flask, add 4-(4-chloro-2-methoxybenzyl)pyridine-3-carboxylic acid (5 g, 17.1 mmol, 1 equiv) and SOCl ₂ (50 mL). The resulting mixture was stirred at 70 °C for 2 h. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was dissolved in DCM (50 _mL ) and added to a solution of _NH2NH2.H2O (3.43 g, 68.6 mmol, 4 equiv), _MeOH (50 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 (4g, 90% purity) was purified by preparative HPLC (2#SHIMADZU (HPLC-01): column, XBridge Shield RP18 OBD Column, 19*250 mm, 10µm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and MeCN (39% MeCN maintained in 17 min; detector, UV 254/220 nm) were purified to obtain the title compound (2.0 g, 40.6% yield). LCMS: (ES, m/z): RT=0.723 min, m/z=288.0 [M +H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.90 (s, 1H), 9.50 (s, 1H), 8.94 (d, J = 5.5 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H) , 7.33 (d, J = 1.9 Hz, 1H), 7.23 - 7.15 (m, 2H), 3.75 (s, 3H).

Step 3 : Synthesis of 4- chloro -1-(4- chloro -2- methoxyphenyl ) pyrido [3,4-d] pyridazine. Add 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2.5 g, 8.69 mmol, 1 equivalent) and POCl ₃ to a 250 mL round bottom flask. (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 sodium bicarbonate (aq.) and 500 mL EtOAc at 0°C. The resulting mixture was extracted with EtOAc (3x500 mL). The combined organic layers were dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (1.50 g, 56.4% yield). LCMS (ES, m/z): RT=0.845 min, m/z=306.0[M+1] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.84 - 9.68 (m, 1H), 9.12 (d, J = 5.7 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.32 - 7.25 (m, 1H), 3.74 (s, 3H).

Step 4 : 1-(4- chloro - 2- methoxyphenyl )-N-(3- methyltetrahydro -2H- piran -4- yl ) pyrido [3,4-d] pyridazine- 4- Synthesis of amines. To a 20 mL vial, add 3-methyloxane-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). The resulting mixture was stirred at 80°C under nitrogen atmosphere overnight. The reaction progress was monitored by LCMS. The residue was purified by reverse-phase flash chromatography (column, C18 gel; mobile phase, MeCN aqueous solution, 0% to 100% gradient in 30 min; detector, UV 254 nm) to obtain cis and trans forms. The title compound was a mixture of stereoisomers of formula (150 mg, 88.7% yield). LCMS: (ES, m/z): RT= 0.688 min, m/z=385[M+1]+.

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

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

5- Chloro -2-(4-(((3R,4R)-3- methyltetrahydro -2H- pyran -4- yl ) amino ) pyrido [3,4-d] pyridazine -1- Base ) phenol ( compound 18* ) : LCMS: (ES, m/z): RT= 0.631min, m/z=371[M+1]+; ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.72 (d, J = 1.0 Hz, 1H), 8.86 (d, J = 5.7 Hz, 1H), 7.52 (d, J = 5.7 Hz, 1H), 7.45 - 7.32 (m, 1H), 7.05 (d, J = 7.3 Hz, 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 = 6.6 Hz, 3H).

5- Chloro -2-(4-(((3S,4S)-3- methyltetrahydro -2H- pyran -4- yl ) amino ) pyrido [3,4-d] pyridazine -1- Base ) phenol ( compound 18D* ) : LCMS: (ES, m/z): RT= 1.202 min, m/z=371[M+1]+; ¹ H NMR (400 MHz, methanol- d ₄ ) 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 :

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

5- Chloro -2-(4-(((3R,4S)-3- methyltetrahydro -2H- pyran -4- yl ) amino ) pyrido [3,4-d] pyridazine -1- Base ) phenol ( compound 18C* ) : LCMS: (ES, m/z): RT= 1.032min, m/z=371[M+1]+; ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.78 (d, J = 1.0 Hz, 1H), 8.86 (d, J = 5.7 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.38 (d, J = 8.0 Hz, 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 = 2.7 Hz, 1H), 2.58 - 2.47 (m, 1H) , 2.29 - 2.12 (m, 1H), 1.83 - 1.72 (m, 1H), 1.13 (d, J = 7.1 Hz, 3H).

5- Chloro -2-(4-(((3S,4R)-3- methyltetrahydro -2H- pyran -4- yl ) amino ) pyrido [3,4-d] pyridazine -1- Base ) phenol ( compound 18A* ) : LCMS: (ES, m/z): RT= 1.032 min, m/z=371[M+1]+; ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.78 (d, J = 1.0 Hz, 1H), 8.86 (d, J = 5.7 Hz, 1H), 7.59 - 7.48 (m, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.10 - 6.97 (m, 2H), 4.79 - 4.52 (m, 1H), 4.07 (d, J = 11.9 Hz, 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 = 7.1 Hz, 3H).

Additional compounds provided in Table C below followed the protocols and examples described herein. 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 ] pyridazine- 1- yl )-3,5- dimethylphenol ( compound 24B*) Scheme 9A Process 9B Process 9C

Example 9 follows Plan A.

Step 1 : Add 1,4-dichloropyrido[3,4-d]pyridazine (500 mg, 2.50 mmol, 1 equivalent), 5,5-dimethyloxolane- 3-amine (201.53 mg, 1.75 mmol, 0.7 equiv), Na ₂ CO ₃ (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 four times. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with methanol (MeOH). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (MeCN) aqueous solution, 10% to 80% gradient in 25 min; detector, UV 254 nm, to obtain The crude product was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; mobile phase, water (10 mmol/ L NH ₄ HCO ₃ ) and acetonitrile (23% to 35% in 8 min); detector, UV 254nm, obtained 1-chloro-N-(5,5-dimethyloxolane-3- (1.2 g, 28% yield). LCMS: (ES, m/z): RT = 0.62 min, m/z=279.0[M+H] ⁺ .

Step 2 : Purify the stereoisomeric mixture from step 1 by chiral HPLC under the following conditions: column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH _in in methanol), mobile phase B: isopropanol/dichloromethane (1:1); flow rate: 20 mL/min; gradient: 70% B to 70% B in 14.5 min; wavelength: 254/220 nm; RT1( min) ((R)-1-chloro-N-(5,5-dimethyltetrahydrofuran-3-yl)pyrido[3,4-d]pyridazin-4-amine): 4.81; RT2 (min) : 11.33 (S)-1-chloro-N-(5,5-dimethyltetrahydrofuran-3-yl)pyrido[3,4-d]pyridazin-4-amine; sample solvent: methanol/dichloromethane (1:1); injection volume: 1 mL, obtaining (R)-1-chloro-N-(5,5-dimethyltetrahydrofuran-3-yl)pyrido[3,4-d]pyridazine-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] ⁺ ), arbitrarily assigned stereochemistry.

Step 3 : Add 2-bromo-3,5-dimethylphenol (600 mg, 2.98 mmol, 1 equivalent), dioxane (6 mL), and triethylamine (905.92 mg, 8.95 mmol, 3 equiv) and 4,4,5,5-tetramethyl-1,3,2-dioxaborane (1909.55 mg, 14.92 mmol, 5 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 min. To the above mixture were added palladium(II) acetate (Pd(OAc) ₂ ) (67 mg, 0.29 mmol, 0.1 equivalent), 2-(dicyclohexylphosphino)biphenyl (Cy-JohnPhos) (209.18 mg, 0.59 mmol) , 0.2 equivalent). The resulting mixture was stirred at 80°C under nitrogen atmosphere for 1 h. 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 x 10 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to obtain 2-hydroxy-4,6-dimethylphenylboronic acid (800 mg, 81% yield), which was used in the next step without further purification.

Step 4. Add 2-hydroxy-4,6-dimethylphenylboronic acid (214.37 mg, 1.29 mmol, 3 equivalents) and intermediate A* (120 mg, 0.43 mmol, 1 equivalent) and water to an 8 mL vial. (0.2 mL), Na ₂ CO ₃ (138.19 mg, 1.29 mmol, 3 equivalents), [1,1′-bis(diphenylphosphino)ferrocene] complex of palladium(II) dichloride and dichloromethane compound (Pd(dppf)Cl ₂ CH ₂ Cl ₂ ) (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 reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile aqueous solution, 10% to 50% gradient in 10 min; detector, UV 254 nm, to obtain crude product ( 70 mg), which was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile Phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 35% B, 35% B in 10 min; wavelength: 254 nm; RT1(min): 9.5, giving 2-(4-((( R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethylphenol ( compound 24* ) ( 41.90 mg, 27% yield). Arbitrarily designated by the Department of Stereochemistry. LCMS: (ES, m/z): RT ₁ = 1.43 min, m/z = 365.2[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.81 (d, J = 0.9 Hz, 1H), 9.21 (d, J = 2.3 Hz, 1H), 8.82 (d, J = 5.6 Hz, 1H), 7.84 - 7.82 (m, 1H), 7.13 - 7.03 (m, 1H), 6.65 (d, J = 6.9 Hz, 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 = 3.1 Hz, 3H), 1.37 (d, J = 3.2 Hz, 3H), 1.26 ( s, 3H).

Step 5. Add 2-hydroxy-4,6-dimethylphenylboronic acid (214.37 mg, 1.29 mmol, 3 equivalents), intermediate B* (120 mg, 0.43 mmol, 1 equivalent), and water to an 8 mL vial. (0.2 mL), Na ₂ CO ₃ (138.19 mg, 1.29 mmol, 3 equivalents), [1,1′-bis(diphenylphosphino)ferrocene] complex of palladium(II) dichloride and dichloromethane compound (Pd(dppf)Cl ₂ CH ₂ Cl ₂ ) (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 reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile aqueous solution, 10% to 50% gradient in 10 min; detector, UV 254 nm, to obtain crude product ( 70 mg), which was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile Phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 35% B, 35% B in 10 min; wavelength: 254 nm; RT1(min): 9.5, giving 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). Arbitrarily designated by the Department of Stereochemistry. LCMS: (ES, m/z): RT ₁ = 1.43 min, m/z = 365.2[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.81 (d, J = 0.9 Hz, 1H), 9.21 (d, J = 2.3 Hz, 1H), 8.82 (d, J = 5.6 Hz, 1H), 7.84 - 7.82 (m, 1H), 7.13 - 7.03 (m, 1H), 6.65 (d, J = 6.9 Hz, 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 = 3.1 Hz, 3H), 1.37 (d, J = 3.2 Hz, 3H), 1.26 ( s, 3H). Example 10. 5- Chloro -2-(4-(((2R,4R)-2- methyltetrahydro -2H- pyran -4- yl ) amino ) pyrido [3,4-d] pyridazine -1- yl ) phenol ( compound 25A*) , 5- chloro -2-(4-(((2S,4S)-2- methyltetrahydro -2H- piran -4- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl ) phenol ( compound 25B*) , 5- chloro -2-(4-(((2S,4R)-2- methyltetrahydro - 2H- piran- 4- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl ) phenol ( compound 25C*) and 5- chloro -2-(4-(((2R,4S)-2- methyl Synthetic Scheme 10A of tetrahydro -2H- pyran -4- yl ) amino ) pyrido [3,4-d] pyridazin -1- yl ) phenol ( compound 25D*)

Example 10 follows Plan B.

Step 1 : At -78°C, add furo[3,4-c]pyridine-1,3-dione (3 g, 20.12 mmol, 1 equivalent) and tetrahydrofuran (THF) into a 250 mL 3-neck round-bottom flask. ) (30 mL) and (4-chloro-2-methoxyphenyl)magnesium bromide (0.5 mol/L) (24.16 mL, 12.07 mmol, 0.6 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction progress was monitored by LCMS. The reaction was quenched by adding ice water (300 mL) at 0°C. The resulting mixture was concentrated in vacuo. The precipitated solid was collected by filtration and washed with water (3x 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=0.633 min, m/z=292.0[M+1] ⁺ .

Step 2 : Add 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (2.5 g, 8.56 mmol, 1 equivalent) and SOCl ₂ (25 mL) to a 250 mL round-bottomed flask. . The resulting mixture was stirred at 70 °C for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (DCM) (30 mL) and added to NH ₂ NH ₂ .H ₂ O (80%) (2.39 g, 34.24 mmol, 4 equiv) in methanol (MeOH) ( 50 mL) in solution. 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 preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD Column, 19*250 mm, 10µm; mobile phase, Water (10 mmol/L NH ₄ HCO ₃ ) and acetonitrile (41% maintained in 19 min); detector, UV 254/220 nm, obtained 1-(4-chloro-2-methoxyphenyl)pyrido [3,4-d]pyridazin-4-ol (1.2 g, 49% yield). LCMS: (ES, m/z): RT=0.678 min, m/z=288.0[M+1] ⁺ .

Step 3 : Add 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (1.2 g, 4.16 mmol, 1 equivalent) to a 250 mL round bottom flask. and POCl ₃ (25 mL) and pyridine (2.5 mL). The resulting mixture was stirred at 110 °C for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was diluted with ethyl acetate (EtOAc) (20 mL). The resulting mixture was slowly poured into a mixture of EtOAc (1 L) and saturated sodium bicarbonate (aq.) (1 L) at 0°C. The aqueous layer was extracted with EtOAc (2x1L). The combined organic layers were dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to obtain 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (800 mg, 63% yield) . LCMS: (ES, m/z): RT=0.801 min, m/z=306.0[M+1] ⁺ .

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

Step 5. Add sodium ethanethiolate (EtSNa) (654.78 mg, 7.80 mmol, 15 equiv) directly to the reaction solution from step 4. The resulting mixture was stirred at 120°C under air atmosphere for 1 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile aqueous solution, 15% to 18% gradient in 15 min; detector, UV 254 nm and 220 nm, to obtain The cis and trans forms of 5-chloro-2-{4-[(2-methyloxan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol Mixture of formula isomers (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 minutes; wavelength: 254 nm; RT1 (min): 10), obtaining a mixture of cis and trans isomers 5-Chloro-2-{4-[(2-methyloxan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (120 mg, 99 % purity). LCMS: RT= 0.62 min, m/z = 371 [M+H] ⁺ .

Step 6. Combine 5-chloro-2-{4-[(2-methyloxan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol The mixture of isomers (120 mg) was purified by preparative chiral 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 minutes; 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) to obtain compounds 25A* and 25B * Mixture of compounds (55 mg, 98% purity), compound 25C* (11.2 mg, 99.8% purity), and compound 25D* (10.6 mg, 99.9% purity); any specified stereochemistry.

Compound 25C* : LCMS: RT = 0.61 min, m/z = 371 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 9.80 (d, J = 1.0 Hz, 1H), 8.87 (d, J = 5.6 Hz, 1H), 7.53 (dd, J = 5.7, 1.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.10 - 7.02 (m, 2H), 4.73 - 4.66 (m, 1H), 4.11 - 3.86 (m, 3H), 2.18 (d, J = 13.9 Hz, 1H) , 2.12 - 1.97 (m, 2H), 1.58 (ddd, J = 14.0, 10.0, 4.0 Hz, 1H), 1.35 (d, J = 6.3 Hz, 3H).

Compound 25D* : LCMS: RT = 0.62 min, m/z = 371 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 9.80 (d, J = 1.0 Hz, 1H), 8.87 (d, J = 5.7 Hz, 1H), 7.53 (dd, J = 5.7, 1.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.10 - 7.02 (m, 2H), 4.73 - 4.66 (m, 1H), 4.11 - 3.86 (m, 3H), 2.18 (d, J = 13.9 Hz, 1H) , 2.12 - 1.97 (m, 2H), 1.76 (ddd, J = 14.0, 10.0, 4.0 Hz, 1H), 1.26 (d, J = 6.3 Hz, 3H).

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

Compound 25A* : LCMS: RT = 0.91 min, m/z = 371 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 9.69 (d, J = 1.0 Hz, 1H), 8.85 (d, J = 5.7 Hz, 1H), 7.51 (dd, J = 5.7, 1.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 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 = 13.3 Hz, 1H), 1.72 (qd, J = 12.3, 4.7 Hz, 1H), 1.44 (q, J = 11.6 Hz, 1H), 1.27 (d, J = 6.2 Hz, 3H).

Compound 25B* : LCMS: RT = 0.91 min, m/z = 371 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 9.72 (d, J = 1.0 Hz, 1H), 8.68 (d, J = 5.7 Hz, 1H), 7.54 (dd, J = 5.7, 1.0 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.09 - 7.02 (m, 2H), 4.63 - 4.53 (m, 1H), 4.13 - 4.04 (m, 1H), 3.73 - 3.62 (m, 2H), 2.30 - 2.22 (m, 1H), 2.21 - 2.13 (m, 1H), 1.72 (qd, J = 12.3, 4.6 Hz, 1H), 1.44 (q, J = 11.7 Hz, 1H), 1.24 (d, J = 6.2 Hz , 3H). Example 11. 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- Synthetic scheme 11A of d] pyridazin -1- yl )-5- methylphenol ( compound 26B*) Process 11B

Example 11 follows Plan A.

Step 1. Add chlorom-cresol (3 g, 21.04 mmol, 1 equivalent), acetonitrile (20 mL), K ₂ CO ₃ (8.72 g, 63.12 mmol, 3 equivalents) and iodine to a 40 mL vial at room temperature. Methane (MeI) (8.96 g, 63.12 mmol, 3 equiv). 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 and dissolved with petroleum ether/ethyl acetate (18:1) to obtain 1-chloro-3-methoxy-5-toluene (3.1 g, 94% yield) . LCMS: RT=1.04min, m/z =157.0 [M+H] ⁺ .

Step 2. In a 100-mL three _- round-bottom flask, add 1-chloro-3-methoxy-5-toluene (3 g, 19.16 mmol, 1 equivalent) to tetrahydrofuran ( THF) (5 mL) was added dropwise a solution of tertiary butyllithium (1.6 M in hexane, 20 mL, 1.7 equiv). The reaction mixture was stirred at -78 °C for 1 h. A solution of triisopropyl borate (5.40 g, 28.73 mmol, 1.50 equiv) in THF (10 mL) was then added dropwise and the mixture was stirred at -20 °C for a further 2 h. The reaction was monitored by LCMS. The reaction was quenched with saturated _NH4Cl (10 mL) and 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 in vacuo. 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] ⁺ .

Step 3. At room temperature, add 2-chloro-6-methoxy-4-methylphenylboronic acid (287.60 mg, 1.40 mmol, 4 equivalents), dioxane (1.5 mL), H ₂ O (0.3 mL), Intermediate A* from Example 9 (100 mg, 0.36 mmol, 1 equiv), Na ₂ CO ₃ (114.06 mg, 1.08 mmol, 3 equiv) and [1,1′-bis(di Phenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (Pd(dppf) ₂ Cl ₂ CH ₂ Cl ₂ ) (79.2 mg, 0.11 mmol, 0.3 equiv). The resulting mixture was stirred at 80 °C under _N2 atmosphere for 2 h. The reaction was monitored by LCMS. The reaction was quenched with water (5 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile aqueous solution, 10% to 50% gradient in 20 min; detector, UV 254 nm, to obtain 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=1.01min, m/z =399.0 [M ₊ H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). Arbitrarily specified stereochemistry.

Step 4. Add 1-(2-chloro-6-methoxy-4-methylphenyl)-N-[(3R)-5,5-dimethyloxa to a 8 mL vial at room temperature. Cyclopentan-3-yl]pyrido[3,4-d]pyridazin-4-amine (80 mg, 0.20 mmol, 1 equiv), DMSO (1 mL), and sodium (ethylsulfanyl) (168.69 mg, 2.01 mmol, 10 equivalents). The resulting mixture was stirred at 120 °C for 2 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile aqueous solution, 10% to 40% gradient in 10 min; detector, UV 254/220 nm, to obtain crude The product (70 mg, 90% purity) was purified by preparative HPLC under the following conditions (column: Xselect CSH F-Phenyl OBD Column, 19*250 mm, 5 μm; mobile phase A: water (0.05% tris Fluoroacetic 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; compound 26A* (25 mg , 25% yield). LCMS: RT ₁ =1.08 min, m/z = 385.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.15 (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 = 7.8 Hz, 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 = 2.5 Hz, 3H), 1.26 (s, 3H).

Step 5. To a 8 mL vial, add Intermediate B* from Example 9 (80.0 mg, 0.29 mmol, 1 equiv), dioxane (0.5 mL), H ₂ O (0.1 mL), 2 -Chloro-6-methoxy-4-methylphenylboronic acid (173 mg, 0.86 mmol, 3 equivalents), Na ₂ CO ₃ (91.3 mg, 0.86 mmol, 3 equivalents) and [1,1′-bis( Diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (Pd(dppf) ₂ Cl ₂ CH ₂ Cl ₂ ) (63 mg, 0.09 mmol, 0.3 equiv). The resulting mixture was stirred at 60°C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The reaction was quenched with water (5 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 x 20 mL). The combined organic layers were washed with brine (15 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica; mobile phase, acetonitrile in water, 15% to 40% gradient in 20 min; detector, UV 220/254 nm. This yields 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- d ₆ ) 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). Arbitrarily designated by the Department of Stereochemistry.

Step 6. Add 1-(2-chloro-6-methoxy-4-methylphenyl)-N-[(3S)-5,5-dimethyloxa to a 8 mL vial at room temperature Cyclopentan-3-yl]pyrido[3,4-d]pyridazin-4-amine (80 mg, 0.20 mmol, 1 equiv), dimethylformamide (DMF) (1 mL) and (B Sodium sulfanyl) (168.69 mg, 2.01 mmol, 10 equiv). The resulting mixture was stirred at 120 °C for 2 h. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with DMF (4 mL). After filtration, the filtrate was concentrated under reduced pressure. The filtrate was purified by preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep Phenyl OBD Column, 19*250 mm, 5µm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and acetonitrile (30% to 40% within 10 min); detector, UV 220/254 nm, obtained compound 26B* (20 mg, 20% yield). LCMS, ESI: RT=0.85 min, m/z =385.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, methanol- d ₄ ) 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). Example 12. Biological Activity of Compounds of the Present Disclosure

The biological activity of the disclosed compounds is determined using assays described herein. Human whole blood - NLRP3

Lithium heparin-coated tubes were used to collect blood from volunteers. Distribute blood samples onto a 96-well plate using 90 µl per well. Priming was performed by adding 5 µl LPS (O26:B6; Sigma L-2654) at a final concentration of 1 µg/ml in a humidified incubator at 37°C, 5% CO2 for 4.5 hours. Thirty minutes before NLRP3 activation, 5 µl of 20X compound solution or vehicle (2% DMSO) was added to each well, and the plate was incubated in a humidified incubator at 37°C, 5% CO2 on a shaker (450 rpm). Then activate by adding 3.3 µl 31X ATP solution per well. At the end of the 30 min stimulation, the plates were centrifuged (800 g, 10 min, room temperature) and the plasma from each well was frozen at -80°C. IL-1β levels in supernatants were analyzed using a mesoscale discovery assay (MSD K151TUK) according to the manufacturer's instructions. Human whole blood was drawn from healthy volunteers after obtaining written informed consent. Brain level (kp and kpu,u) - NLRP3

Total brain to plasma ratios were assessed in vivo in CD1 mice following oral administration of compounds. Blood was collected at several time points up to 24 h and transferred into plastic microcentrifuge tubes containing EDTA-K2 as anticoagulant. Blood samples were centrifuged at 4000<i>g for 5 min at 4°C to obtain plasma, which was then frozen immediately before analysis and stored at -75 ± 15°C. At approximately 1 minute, the animals were terminally anesthetized with increasing concentrations of CO2 gas. At selected time points, whole brains were removed from the skull, rinsed in cold PBS to remove blood, dried with clean gauze, then frozen in liquid nitrogen and stored at -75±15°C before analysis. At the time of analysis, brain samples were homogenized with PBS at a ratio of tissue weight (g) to PBS volume (mL) of 1:3. After separation on a HALO 160A ES-C18, 2.7µm 2.1 × 50mm column, plasma and brain drug levels were quantified by LC/MS/MS on an AB Sciex Triple Quad 5500+ instrument. Quantitation was performed using calibration curves prepared in blank plasma or blank brain homogenate. The software WinNonlin (Phoenix™) was used to perform pharmacokinetic analysis of concentration versus time data (including AUC _inf and AUC _last ). The Kp ratio (ratio of total brain concentration to total plasma concentration) was calculated as (AUC _tot,br )/(AUC _tot,pl ).

Unbound brain exposure was estimated as Kp _uu , which is the free brain/free plasma concentration ratio (C _u,br /C _u,pl ). The C _u,br /C _u,pl ratio was obtained by using the in vitro determined F _u,br and F _u,pl from the in vivo total brain plasma ratio (C _tot,br /C _tot,pl ).

Plasma protein binding and brain homogenate protein binding were measured by equilibrium dialysis in HT dialysis plates. Soak the dialysis membrane in ultrapure water for 60 minutes to separate the bands, then in 20% ethanol for 20 minutes, and finally in dialysis buffer for 20 minutes. Assemble the dialysis device 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 in an incubator at 37°C and 5% CO2 at 100 rpm for 6 hours. At the end of the incubation, compound concentrations in both chambers were measured by LC-MS/MS on an AB Inc Triple QuadTM 5500 after separation on an XSelect Hss T3 2.5µ (2.1×30 mm) column. The free fraction (Fu) was calculated as (peak area to buffer chamber/peak area to plasma chamber).

Kp _uu is calculated as (AUC _tot,br x F _u,br )/(AUC _tot,pl x F _u,pl ). Activity information

Table D assigns each compound a code indicating potency in the human whole blood (hWB) NLRP3 assay: A or B. According to the code, A means IC ₅₀ value ≤ 1.0 µM; B means IC ₅₀ value > 1.0 µM. Corresponding original activity data is also included.

The table below also assigns the kp and kpu, u value codes for each compound: A or B. According to the code, A represents a value of >0.3, and B represents a value of < 0.3. The kp value was calculated by measuring whole brain drug levels (AUC) at 24 h in mice dosed with 20 mpk PO and dividing by the plasma AUC. Then kpu,u was calculated after correcting the kp value with mouse plasma protein binding and mouse brain homogenate binding. Kpu,u value >0.3 indicates brain penetration, and Kpu,u value less than or equal to 0.3 indicates non-brain penetration. ND=Not determined. Also includes the corresponding original kp and kpu,u data. Form D. Activity information Compound number hWB IC ₅₀ hWB IC ₅₀ kp kp kpu,u kpu,u 1* A 1.0 A 0.90 A 0.31 1B* B 1.8 ND ND ND ND 2 A 0.16 B 0.24 A 2.2 3* A 0.19 A 0.58 A 2.2 3B* B 11 ND ND ND ND 4* A 0.66 A 0.81 A 0.89 4B* B 1.7 ND ND ND ND 5 A 0.22 A 0.44 A 0.94 5B A 0.21 ND ND ND ND 6* A 0.43 A 0.66 A 2.3 6B* B 1.26 ND ND ND ND 9* A 0.26 A 0.40 A 0.63 9B* A 0.061 B 0.24 A 0.52 10* B 1.4 A 0.35 A 0.51 10B* B 7.9 ND ND ND ND 11* B 1.4 A 0.96 A 1.3 11B* B 10 ND ND ND ND 12* A 0.82 A 0.33 A 1.3 12B* B 3.2 ND ND ND ND 13* A 0.22 A 0.60 A 0.77 13B* B 9.8 ND ND ND ND 14* A 0.51 A 0.64 A 0.33 14B* B 3.6 ND ND ND ND 15* B 1.2 A 0.83 A 2.2 15B* B 18 ND ND ND ND 16* B 1.8 A 0.48 A 0.59 16B* B 12 ND ND ND ND 17* A 0.33 A 0.69 A 1.9 17B* B 2.4 ND ND ND ND 18A* B 1.1 A 0.73 A 0.30 18* A 0.89 A 0.68 A 0.47 18C* B 1.2 ND ND ND ND 18D* B 6.2 ND ND ND ND 19* B 1.4 A 1.4 A 0.81 19B* B 1.2 ND ND ND ND 20* A 0.89 A 0.61 A 0.46 20B* B 3.4 ND ND ND ND twenty one* A 0.46 A 0.30 A 0.76 21B* B 2.3 ND ND ND ND twenty two* A 0.96 A 1.1 A 0.34 22B* B 5.9 ND ND ND ND twenty three* A 0.12 B 0.24 A 0.33 23B* ND ND B 0.28 B 0.09 twenty four* A 0.33 B 0.05 ND ND 24B* ND ND ND ND ND ND 25A* A 0.58 A 1.1 B 0.1 25B* A 0.85 ND ND ND ND 25C* B 1.4 A 0.65 B 0.099 25D* B 1.2 A 1.0 B 0.20 26* A 0.90 B 0.10 B 0.17 26B* B 1.3 ND ND ND ND 7* Comparison example 1 A 0.80 B 0.13 B 0.15 8Comparison Example 2 A 0.20 B 0.18 B 0.11 Compare examples

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

Furthermore, as shown in Table D above, the inhibitors of the NLPR3 protein described in US Application No. 17/528,928 exhibit this unexpected and insignificant activity. The selected NLPR3 inhibitors of the present disclosure were found to exhibit stronger brain penetration properties in a head-to-head comparison with the compounds of USSN 17/528,928 application, with similar NLPR3 inhibitory activity in the blood, as shown in Table D. In order to illustrate more clearly in the above table, compounds 1* , 2 , 3* , 4* , 5 and 6 of the disclosure are compared with 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 them exhibits "B" brain levels and does not have brain penetration, thus making the compounds of the present application more useful for treating NLPR3-mediated CNS diseases.

It was further found that the solubility of the compound of formula ( I ) can be improved by replacing the R ³ halogen moiety, such as a chlorine group, with a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group (where alkyl or alkyl- independently substituted with 0, 1, 2 or 3 halogen atoms) while still maintaining a Kpu,u greater than 0.3. See , for example, Table E below. Compare, for example , the solubility of Comparative Example ³ (Compound 105 of USSN 17/528,928) with a chlorine R moiety to Compounds 9* , 9B* and 5 in phosphate buffer solution (PBS, pH 7.4): Compound 9* and Compound 9B * Both cause a 7-fold increase in solubility moving from the chlorine R ³ moiety to the -OCHF ₂ R ³ moiety; compound 5 causes a 27-fold increase in solubility moving from the chlorine R ³ moiety to the -CH ₃ R ³ moiety; and each remains well brain penetration. Incorporation of m-non-hydrogen groups into the R ^moiety of compound 5 , such as compound 21* (m-fluoro moiety), compound 26* (m-chloro moiety), and compound 24* (m _- CH group), results in a further increase in solubility; compare Compound 21* (increased 37-fold), compound 26* (increased 42-fold) and compound 24* (increased 43-fold) and Comparative Example 3 . Compounds that do not have brain penetration but have improved properties such as solubility may be used to treat systemic (non-CNS) NLPR3-mediated diseases. Table E. compound kp kpu,u Solubility (PBS, pH 7.4) uM Comparative Example of (R)-5-chloro-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 3 ( Compound 105 of USSN 17/528,928 ) A(0.4) A (0.43) PBS (pH 7.4): 6.7 uM Compound 9B* B(0.24) A(0.52) PBS (pH 7.4): 45 uM (7-fold increase) Compound 9* A (0.40) A (0.63) PBS (pH 7.4): 45 uM (7-fold increase) Compound 5 A(0.44) A(0.94) PBS (pH 7.4): 180 uM (27-fold increase) Compound 21* B(0.30) A (0.76) PBS (pH 7.4): 250 uM (37-fold increase) Compound 26* B(0.10) B(0.17) PBS (pH 7.4): 280 uM (42-fold increase) Compound 24* B(0.05) ND PBS (pH 7.4): 290 uM (43-fold increase) equivalent

The details of one or more embodiments of the disclosure are set forth in the accompanying 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 desired methods and materials are described herein. Other features, objects and advantages of the present disclosure will be apparent from the detailed description and patent claims. In the specification and appended claims, the singular includes plural referents unless the context clearly dictates otherwise. 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. All patents and publications cited in this specification are incorporated by reference.

The foregoing description is given for purposes of illustration only, and is not intended to limit the disclosure to the precise form disclosed other than by reference to the appended claims.

Claims (42)

A compound of formula ( I ): ( I ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, wherein: A is 5 to 8 membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl contains at least one O ring atom; R ¹ is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; R ² is halogen or C ₁ -C ₆ alkyl; or R ¹ and R ² together with the atoms to which they are connected form a 3 to 4-membered carbocyclic ring; R ³ is -OH, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy ; X is H, -OH, halogen, -NH2 _, -NH( _C1 - _C6alkyl ), -N( _C1 - _C6alkyl ) ₂ or _C1 - _C6alkyl ; and ^R4 is H, C ₁ -C ₆ alkyl, or -C(O)(C ₁ -C ₆ alkyl); and p is 0 or 1, where each instance of alkyl, alkyl-, or carbocyclic ring is independently 0, 1, 2 or 3 halogen atoms are substituted, and when R ³ is Cl, then Not for . For example, the compound of claim 1, or its pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug, wherein A contains A 5-membered monocyclic heterocycloalkyl group with an O ring atom. For example, the compound of claim 1 or claim 2, or its pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or prodrug, A is a 6-membered monocyclic heterocycloalkyl group containing one O ring atom. Such as the compound of any one of claims 1-3, or its pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, tautomer, isotopically labeled compound or precursor Medicine, where p is 1. Such as the compound of any one of claims 1-4, or its pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, tautomer, isotopically labeled compound or precursor Drug, wherein p is 1; R ¹ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; and R ² is C ₁ -C ₆ alkyl. Such as the compound of any one of claims 1-5, or its pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, tautomer, isotopically labeled compound or precursor medicine, wherein R ³ is not halogen. Such as the compound of any one of claims 1-6, or its pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, tautomer, isotopically labeled compound or precursor medicine, wherein R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. Such as the compound of any one of claims 1-5, or its pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, tautomer, isotopically labeled compound or precursor medicine, wherein R ³ is Cl, methyl, -CF ₃ , -CHF ₂ or -OCHF ₂ . Such as the compound of any one of claims 1-8, or its pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound or precursor medicine, in which R ⁴ is H. Such as the compound of any one of claims 1-9, or its pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, tautomer, isotopically labeled compound or precursor medicine, where X is H or F. A compound as in any one of the preceding claims, wherein the compound has formula ( Ia ) or ( Ib ): ( Ia ) or ( Ib ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. The compound of any one of the preceding claims, wherein the compound has formula (II-a) , (II-b) , (II-c) , (II-d) , (II-e) or (II-f ) : ( II-a ), ( II-b ), ( II-c ), ( II-d ), ( II-e ) or ( II-f ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. The compound of any one of the preceding claims, wherein the compound has formula (III-a) , (III-b) or (III-c) : ( III-a ), ( III-b ) or (III-c), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, where: m is 0 to 2; and n is an integer from 1 to 2. The compound of any one of the preceding claims, wherein the compound has formula (III-d) , (III-e) or (III-f) : ( III-d ), ( III-e ) or ( III-f ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs, where: m is 0 to 2; and n is an integer from 1 to 2. The compound of any one of the preceding claims, wherein the compound has formula (IV-a) , (IV-b) or (IV-c) : ( IV-a ), ( IV-b ) or ( IV-c ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. The compound of any one of the preceding claims, wherein the compound has formula (IV-a1) , (IV-b1) or (IV-c1) : ( IV-a1 ), ( IV-b1 ) or (IV-c1), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. The compound of any one of claims 1-13, wherein the compound has formula (Va) , (Vb) , (Vc) , (V-a') , (V-b') or (V-c') : ( Va ), ( Vb ), ( Vc ), ( V-a' ), ( V-b' ) or ( V-c' ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. The compound of any one of claims 1-13, wherein the compound has formula (VI-a) , (VI-b) , (VI-c) , (VI-d) , (VI-e) , (VI -f) , (VI-g) or (VI-h) : ( VI-a ), ( VI-b ), ( VI-c ), ( VI-d ), ( VI-e ), ( VI-f ), ( VI-g ) or ( VI-h ), or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. For example, the compound of claim 1 has the formula: 1A 5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3A 5-Chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ; 4A 5-Chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ; 5A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 9A 5-(Difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ; 10A 2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methyl phenol; 11A 2-(4-((2,2-dimethyltetrahydro-2H-piran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol; 12A 6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3-methylphenol; 13A 2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methyl phenol; 14A 2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methyl phenol; 15A 2-(4-((3,3-dimethyltetrahydro-2H-piran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol; 16A 5-(Difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine- 1-yl)phenol; 17A 5-(Difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine- 1-yl)phenol; 18B 5-Chloro-2-(4-((3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 19A 2-(4-((4-oxaspiro[2.4]heptan-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl) phenol; 20A 5-(Difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazine- 1-yl)phenol; 21A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5-methylphenol; 22A 2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; or its pharmaceutically acceptable salts or isotope-labeled compounds. For example, the compound of claim 1 is: 1* ®-5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 1B (S)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3B* (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 3* (S)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 4* (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 4B* (R)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 5 (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 5B (S)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 9B* (R)-5-(difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 9* (S)-5-(difluoromethoxy)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazine-1 -base)phenol; 10* (S)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 10B* (R)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 11* (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol; 11B* (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol; 12* (R)-6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3- methylphenol; 12B* (S)-6-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-fluoro-3- methylphenol; 13B* (R)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 13* (S)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 14B* (R)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 14* (S)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-methylphenol; 15* (S)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol; 15B* (R)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)- 5-(trifluoromethyl)phenol; 16B* (R)-5-(difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; 16* (S)-5-(difluoromethyl)-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; 17* (S)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; 17B* (R)-5-(difluoromethyl)-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; 18A* 5-Chloro-2-(4-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 18* 5-Chloro-2-(4-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 18C* 5-Chloro-2-(4-(((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 18D* 5-Chloro-2-(4-(((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 19B* (S)-2-(4-((4-oxaspiro[2.4]heptan-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol; 19* (R)-2-(4-((4-oxaspiro[2.4]heptan-6-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(tri Fluoromethyl)phenol; 20B* (R)-5-(difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; 20* (S)-5-(difluoromethyl)-2-(4-((6,6-dimethyltetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d ]pyridazin-1-yl)phenol; twenty one* 2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5- methylphenol; 21B* 2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3-fluoro-5- methylphenol; 22B* (S)-2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl base) phenol; twenty two* (R)-2-(4-((2,2-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl base) phenol; or its pharmaceutically acceptable salts or isotope-labeled compounds. A compound having the formula: 2 5-(Difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 6A 2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl) phenol; or its pharmaceutically acceptable salts or isotope-labeled compounds. For example, the compound of claim 1 has the formula: twenty four* 2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethyl base phenol; 24B* 2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethyl base phenol; 25A* 5-Chloro-2-(4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 25B* 5-Chloro-2-(4-(((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 25C* 5-Chloro-2-(4-(((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 25D* 5-Chloro-2-(4-(((2R,4S)-2-methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazine-1- base) phenol; 26* 3-Chloro-2-(4-(((R)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5- methylphenol; 26B* 3-Chloro-2-(4-(((S)-5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5- methylphenol; or its pharmaceutically acceptable salts or isotope-labeled compounds. Such as the compound of claim 1, wherein the compound is not , or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, tautomers, isotopically labeled compounds or prodrugs. For example, the compound of claim 1, wherein the compound is not: 1A ; 5-Chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3A 5-Chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ; 4A 5-Chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol ;or 5A 2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol, or its pharmaceutically acceptable salts or isotope-labeled compounds. Such as the compound of any one of claims 1-21, 23 and 24, wherein the Kpu,u of the compound is greater than 0.3. The compound of any one of claims 1-21, 23 or 24, wherein the Kpu,u of the compound is greater than 0.3 to about 10. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof , isotopically labeled compounds or prodrugs, and one or more pharmaceutically acceptable carriers. A method of regulating NLRP3, the method comprising administering to an individual a compound as claimed in any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof substances, tautomers, isotopically labeled compounds or prodrugs, or pharmaceutical compositions as claimed in claim 27. A method of treating or preventing a disease or condition, the method comprising administering to an individual a compound as claimed in any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, or hydrate thereof , stereoisomers, tautomers, isotopically labeled compounds or prodrugs, or pharmaceutical compositions as claimed in claim 27. Such as the compound of any one of claims 1-26, or its pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, tautomer, isotopically labeled compound or precursor Medicines, or pharmaceutical compositions as claimed in claim 27, for the treatment or prevention of diseases or conditions. Such as the compound of any one of claims 1-26, or its pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, tautomer, isotopically labeled compound or precursor The use of drugs in the manufacture of medicaments for the treatment or prevention of disease or condition. Such as the compound of any one of claims 1-26, or its pharmaceutically acceptable salt, solvate, clathate, hydrate, stereoisomer, tautomer, isotopically labeled compound or precursor The purpose of medicine is to treat or prevent a disease or condition. The method, compound or use of any one of claims 29-32, wherein the disease or disorder is an NLRP3-related disease or disorder. The method, compound or use of any one of claims 28-33, wherein the system is human. Such as the method, compound or use of any one of claims 29-34, wherein the disease or condition is inflammation, autoimmune disease, cancer, infection, central nervous system disease or condition, metabolic disease, cardiovascular disease, respiratory disease , kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, psychological disease, graft-versus-host disease, allodynia, or NLRP3-related disease. Such as the method, compound or use of claim 35, wherein the central nervous system disease or disorder is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, muscle atrophy Lateral sclerosis or multiple sclerosis. For example, claim 35 for the method, compound or use, wherein the kidney disease is acute kidney disease, chronic kidney disease or rare kidney disease. For example, the method, compound or use of claim 35, wherein the skin disease is psoriasis, hidradenitis suppurativa (HS) or atopic dermatitis. The method, compound or use of claim 35, wherein the rheumatic disease is dermatomyositis, Still’s disease or juvenile idiopathic arthritis. The method, compound or use of claim 35, wherein the NLRP3-related disease is in an individual determined to carry a germline or somatic non-silent mutation in NLRP3. The method, compound or use of claim 40, wherein the NLRP3-related disease in an individual determined to carry a germline or somatic non-silent mutation in NLRP3 is cryptopyrin-related autoinflammatory syndrome. For example, the method, compound or use of claim 41, wherein the cryptopyrin-related autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome or neonatal multiple systemic inflammatory disease.