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WO2023183943A1 - Dérivés de pyrido-[3,4-d]pyridazine-amine utiles en tant que dérivés de nlrp3 - Google Patents

Dérivés de pyrido-[3,4-d]pyridazine-amine utiles en tant que dérivés de nlrp3 Download PDF

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Publication number
WO2023183943A1
WO2023183943A1 PCT/US2023/064967 US2023064967W WO2023183943A1 WO 2023183943 A1 WO2023183943 A1 WO 2023183943A1 US 2023064967 W US2023064967 W US 2023064967W WO 2023183943 A1 WO2023183943 A1 WO 2023183943A1
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WO
WIPO (PCT)
Prior art keywords
compound
pyrido
amino
pyridazin
disease
Prior art date
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Ceased
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PCT/US2023/064967
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English (en)
Inventor
Stéphane DORICH
Amandine Chefson
Stéphane CIBLAT
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Ventus Therapeutics US Inc
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Ventus Therapeutics US Inc
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Filing date
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Priority claimed from US17/704,983 external-priority patent/US11618751B1/en
Priority to KR1020247034096A priority Critical patent/KR20250005125A/ko
Priority to EP23722227.8A priority patent/EP4499638A1/fr
Priority to PE2024002059A priority patent/PE20250605A1/es
Priority to AU2023238121A priority patent/AU2023238121A1/en
Priority to CA3246681A priority patent/CA3246681A1/fr
Priority to JP2025502799A priority patent/JP2025510414A/ja
Application filed by Ventus Therapeutics US Inc filed Critical Ventus Therapeutics US Inc
Priority to IL315842A priority patent/IL315842A/en
Priority to CN202380037553.1A priority patent/CN119137121A/zh
Priority to US18/190,920 priority patent/US12331048B2/en
Publication of WO2023183943A1 publication Critical patent/WO2023183943A1/fr
Priority to US18/763,277 priority patent/US12312351B2/en
Priority to US18/785,350 priority patent/US12398136B2/en
Priority to US18/799,636 priority patent/US20240409540A1/en
Priority to MX2024011697A priority patent/MX2024011697A/es
Anticipated expiration legal-status Critical
Priority to CONC2024/0013702A priority patent/CO2024013702A2/es
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present disclosure is directed to inhibitors of NLR family pyrin domain containing 3 (NLRP3) proteins.
  • the inhibitors described herein are useful in the treatment of diseases and disorders associated with the modulation of NLRP3 proteins.
  • the invention is concerned with compounds and pharmaceutical compositions inhibiting NLRP3, methods of treating diseases and disorders associated with NLRP3 using said compounds and pharmaceutical compositions, and methods of synthesizing said compounds and compositions.
  • PRRs paternrecognition receptors
  • PAMPs pathogen-associated molecular patterns
  • DAMPs damage-associated molecular patterns
  • the inflammasomes represent a class of PRRs that are crucial components of the irmate immune response. Activation of the inflammasomes trigger a cascade of events that releases IL-ip, IL-18, and promotes an inflammatory’ form of cell death called pyroptosis induced by the activation of Gasdermin. Pyroptosis is a unique form of inflammatory’ cell death that leads to the release of not only cytokines but also other intracellular components that promote a broader immune response both of the innate and acquired immune system. Thus, inflammasome activation is a major regulatory’ of the inflammatory’ cascade.
  • NLRP3 is the most characterized inflammasome and has been shown to be critical in innate immunity and inflammatoiy responses. While several other NLR complexes, such as NLRC4, are activated under very specific circumstances, NLRP3 can be activated by numerous stimuli and should be seen as a sensor of intracellular homeostatic imbalance. Therefore, its precise functioning is essential. In addition to playing a role in host immune defense, dysregulation of NLRP3 lias been linked to the pathogenesis of many inflammatoiy disorders.
  • NLRP3 byperactivation has been demonstrated pre-clinically to play a critical role in a plethora of inflammatoty and degenerative diseases including, NASH, atherosclerosis and other cardiovascular diseases, Alzheimer’s disease, Parkinson’s disease, diabetes, gout, and numerous other autoinflammatory diseases.
  • CAPS cryopyrin-associated periodic syndromes
  • the present disclosure provides, inter alia, a compound of Formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrag thereof, wherein:
  • A is a 5- to 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises 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 ] and R 2 , together with the atoms to which they are attached, form a 3 - or 4-membered carbocyclic ring;
  • R 3 is -OH, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • X is H, -OH, halogen, -NHz, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , or C]-C & alkyl;
  • R 4 is H, C 1 -C 6 alkyd, or -C(O)(Cj-C& alkyl); and p is 0 or 1, wherein each instance of alkyl, alk-, or carbocyclic is independently substituted with 0, 1, 2, or 3 halogen atoms, and when R 3 is C1, then
  • the compound of Formula (I) is not
  • the compound has a Kpu,u of > 0.3.
  • the present disclosure provides, inter alia, suitable compounds selected from Tables 1 or 2, and pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, or tautomers thereof. [0010] In another aspect, the present disclosure provides, inter alia, suitable compounds selected from:
  • compositions comprising (R)-5- chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-l-yl)phenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • compositions comprising 5- (difluoromethyl)-2-(4-((2-(methoxy-d3)-2-metliylpropyl)amino)pyrido[3,4-d]pyridazin-l-yl)phenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • compositions comprising (R)-5- chIoro-2-(4-((3,3-dimetbyltetrabydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-l-yl)phenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • compositions (S)-5-chloro-2-(4- ((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-l-yl)phenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • compositions comprising (R)-2-(4- ((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-l-yl)-5-metlwlphenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • compositions comprising (S)-2-(4- (((4-metiiylmorphoIin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-l-yl)-5-(trifluoromeEhyl)phenol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the present disclosure provides compounds obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in Schemes 1 and 2),
  • the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-11).
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutical! ⁇ ' effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides a method of treating or preventing an NLRP3-related disease or disorder selected from Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache/pain, and traumatic brain injury.
  • the method comprises administering to the subject at least one therapeutically effective amount of the compound disclosed herein,
  • the disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of tire central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psy chological disease, graft versus host disease, allodynia, or an NLRP3 -related disease in a subject that lias been determined to cany a germline or somatic non-silent mutation in NLRP3.
  • the disease or disorder of the central nervous system is Parkinson’s disease, Alzheimer’s disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.
  • the kidney disease is an acute kidney disease, a chronic kidney disease, or a rare kidney disease.
  • the skin disease is psoriasis, iiidradenitis suppurativa (HS), or atopic dermatitis.
  • the rheumatic disease is dermatomyositis, Still’s disease, or juvenile idiopathic arthritis.
  • the NLRJP3 -related disease in a subject that lias been determined to cany' a germline or somatic non-silent mutation in NLRP3 is ciyopyrin-associated autoinflammatoiy syndrome.
  • cryopyrin-associated autoinflammatoiy syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal onset multisystem inflammatory disease.
  • the present disclosure provides a method of preparing a compound of the present disclosure.
  • the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.
  • the present disclosure relates to phthalazine derivatives, pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers (e.g., single stereoisomers, mixtures of stereoisomers, or racemic mixtures of stereoisomers), tautomers, prodrugs, and isotopically labeled compounds thereof, which may inhibit NLRP3 activity and are accordingly useful in methods of treatment of the human or animal body.
  • Certain compounds of this invention demonstrate surprising and unexpected superiority w ith regard to brain penetration.
  • the present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders in which NLRP3 is implicated, such as inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allody nia, or an NLRP3-related disease in a subject that lias been determined to cany a germline or somatic non-silent mutation in NLRP3.
  • disorders in which NLRP3 is implicated such as inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an o
  • alkyl 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 groups and C 3 , C4, C5 or C6 branched saturated aliphatic hydrocarbon groups.
  • C 1 -C 6 alkyl is intends to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkyl groups.
  • alkyl examples include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, I-propyl, n-butyl, s -butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl.
  • a straight drain or branched alkyl has six or fewer carbon atoms (e.g. , C 1 -C 6 for straight chain, C:i-Ct> for branched chain), and in another embodiment, a straight drain or branched alkyl has four or fewer carbon atoms.
  • An alkyl group may be an “optionally substituted alkyl”, which refers to an unsubstituted alkyl or alky i having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hvdroxyd, alkylcarbonyloxy, arylcarbonyloxy, alkoxycaibonyloxy, aiyloxycarbonyloxy, carboxylate, alkylcarbonyl, aiylcarbonyl, alkoxy carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl thiocarbonyl, alkoxvl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, aiylamino, diaiylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkyhhio
  • optionally substituted moieties include both the unsubstituted moieties and the moieties having one or more of the designated substituents.
  • substituted heterocycloalkyl includes those substituted with one or more alky l groups, such as 2,2,6,6-tetramethyI-piperidinyl and 2,2,6,6-tetraroethyI-l,2,3,6- tetrahydropyridinyl .
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • the terra “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups.
  • a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., CI-CG for straight chain, C3-C.5 for branched chain).
  • C2-C6 includes alkenyl groups containing two to six carbon atoms.
  • CS-CG includes alkenyl groups containing three to six carbon atoms.
  • optionally substituted alkenyl refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyd, alkenyl, alkynyl, halogen, hydroxyl, alkydcarbonyloxy, asylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxv, carboxylate, alkylcarbonyl, asylcarbonvl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, pbosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diaryiamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkyitbio, arylthio, thiocarboxylate,
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight chain alkynvl groups (e.g., ethynyl, propynvl, butynyl, pentynyl, hexynyl, heptynyl, octynvl, nonynyl, decynyl), and branched alkynyl groups.
  • a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, Ca-Ce for branched chain).
  • C 1 -C 6 includes alkynyl groups containing two to six carbon atoms.
  • C3-C6 includes alkynyl groups containing three to six carbon atoms.
  • “Ca-Ca alkenylene linker” or“C2-C6 alkyuyleue linker” is intended to include C2, Ca, C), Cs or Ca drain (linear or branched) divalent unsaturated aliphatic hy drocarbon groups.
  • Ca-Ce, alkenylene linker is intended to include C2., C3, C4, C5 and C6 alkenylene linker groups.
  • optionally substituted alkynyl refers to unsubstituted alkynyl or alky nyl having designated substituents replacing one or more hy drogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynvl, halogen, hydroxyl, alkylcarbonyloxy', aiylcarbonyloxy, alkoxy carbonyloxy', aryloxycarbonyloxv, carboxylate, alkylcarbonyl, arykarbonyl, alkoxy carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialky lamino, aryiamino, diaiyiamino and alkylaiylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydiyl, alkylthio, aiyl
  • optionally substituted moieties include both the unsubstituted moieties and the moieties having one or more of the designated substituents.
  • 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-tetrahydropyridinyI .
  • cyano refers to a nitrile radical (e.g., -CN).
  • cycloalkyl or “carbocyclic” or “carbocyclyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or Cs-C?,).
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepty l, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.
  • heterocycloalky l refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more ring heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 ring heteroatoms, or e.g. , 1, 2, 3, 4, 5, or 6 ring heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise.
  • ring heteroatoms such as O, N, S, P, or Se
  • heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinvl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indohnvl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazohdinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranvl, morpholinyl, tetrabydrothiopyranvl, 1,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]
  • the term “optionally substituted heterocycloalkyl” refers to unsubstituted beterocycloalkyl having designated substituents replacing one or more hydrogen atoms on one or more carbon or heteroatom.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcatbonyloxy, arylcarbonyloxy, alkoxy carbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxy carbonyl, aminocarbonyl, alkylarmnocarbonyl, dialkyiaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphorate, phosphinate, amino (including aikylarmno, dialkylamino, arylamino, diary larnino and alkylarylarmno), acylamino (including alkyl), acylamino
  • hydroxy or “hydroxyl” includes groups with an -OH or -O'.
  • halo or “halogen” refers to fluoro, chloro, bromo and iodo.
  • haloalkyl or “haloalkoxyl” refers to an alkyl or alk- moiety of the alkoxyl substituted with one or more halogen atoms.
  • alkoxy or “alkoxyl” includes substituted and unsubstituted alkyl groups covalently linked to an oxygen atom.
  • alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy', ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy , arylcarbonyloxy, alkoxy carbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonvl, dialkyiaminocarbonyl, alkylthiocarbonyi, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diaiylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined al a single point (e.g. , biphenyl), or fused (e.g., naphthyl).
  • the aryl group may be optionally substituted by one or more substituents, e.g. , 1 to 5 substituents, at any point of attachment.
  • 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, - ⁇ -(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C & ) alkynyl, -OH, - OP(O)(OH) 2 , -OC(O)(C 1 -C 6 ) alkyd, -C(O)(C 1 -C 6 ) alkyl, -OC(O)O(C 1 -C 6 ) alkyl, -NH 2 , NH((C 1 -C 3 ) alkyl), N((C 1 -C 6 ) alkyl),, -S(O) 2 -(C 1 -C 6 ) alkyl, -
  • the substituents can themselves be optionally substituted.
  • the ary l groups herein defined may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring.
  • Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indeny 1, tetrahydronaphthaienyl, tetrahydrobenzoarmulenyl, 10,ll-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like.
  • heteroaryl means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, the remaining ring atoms being C.
  • Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, Se, or B.
  • Heteroaryl as herein defined also means a tricyclic beteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B.
  • the aromatic radical is optionally substituted independently with one or more substituents described herein.
  • Examples include, but are not limited to, furyl, thieny l, pyrrolyl, pyridyl, pyrazolyl, py rimidinyl, imidazoly l, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, tbiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, tbiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2- b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyra
  • the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring, e.g., a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo.
  • a fully unsaturated aromatic ring e.g., a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is
  • a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein.
  • exemplary ring systems of these heteroaryl groups include, for example, mdolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, clirornanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzotliiazine, 3,4-dihydro-lH-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyi, indolinyl, oxindolyl, indolyl, l,6-dihydrO"7H-pyrazoio[3,4-c]pyridm-7-onyl, 7,8-dihydro-6H- pvrido[3,2-b]pyrrolizinyl,
  • the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcasbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenyicaibonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino,
  • Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxypbenyl such as benzo[d][l,3]dioxole-5-yI).
  • alicyclic or heterocyclic rings which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxypbenyl such as benzo[d][l,3]dioxole-5-yI).
  • compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • tliat compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M.
  • any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition.
  • the treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models.
  • any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless othe rwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition.
  • the treatment includes treatment of human or non-human animals including rodents and other disease models, As used herein, the term “subject” is interchangeable with the term “subject in need thereof’, both of which refer to a subject having a disease or having an increased risk of developing the disease. A “subject” includes a mammal.
  • the mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the mammal is a human.
  • a subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein.
  • a subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein.
  • a subject in need thereof can be one who lias an increased risk of developing such disease or disorder relative to the population at large (i.e. , a subject who is predisposed to developing such disorder relative to the population at large).
  • a subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or lias not yet responded to treatment).
  • the subject may be resistant at start of treatment or may become resistant during treatment.
  • the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein.
  • the subject in need thereof received at least one prior therapy.
  • the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition.
  • Treating” or “treatment” of a state, disorder or condition therefore includes: (1 ) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted w ith or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the slate, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or al least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • a compound of the present disclosure can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.
  • the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.
  • the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof
  • the dosage will also depend on the route of administration.
  • routes 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 the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is general! ⁇ ' safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include tire following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents: antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethvlenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • a compound or pliarmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment.
  • a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches.
  • the dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects.
  • the state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.
  • the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combinatio n of therapeutics selected for administration.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill mid judgment of the clinician.
  • the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophy lactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 5 O (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LDWEDso.
  • Pharmaceutical compositions that exhibit large therapeutic indices are desired.
  • the dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • Dosage and administration are adjusted to provide sufficient levels of the active ageni(s) or to maintain the desired effect.
  • Factors which may be taken into account include the seventy of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
  • compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations tliat can be used pharmaceutically.
  • the appropriate formulation is dependent upon the route of administration chosen.
  • 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 dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent tliat easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the iike.
  • isotonic agents for example, sugars, polyalcohols 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 an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorpora ting the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation are vacuum drying and freeze-dry ing that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable earner. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tabiets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the active compounds can be prepared with pharmaceutically acceptable carriers tliat will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, poly glycolic acid, collagen, polyorthoesters, and poly lactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
  • the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of tiie recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy , among other factors affecting the selected dosage.
  • the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder.
  • Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day.
  • An effective amount of a pharmaceutical agent is that which provides an objectively’ identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression.
  • the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.
  • the pliarmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional uon-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from Bon-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited io, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2- hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edelic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,
  • the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.
  • salts include hexanoic acid, cyclopentane propionic 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-l-caiboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
  • the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamme, diethanolamine, triethanolamine, tromethamine, N -methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • an organic base such as ethanolamme, diethanolamine, triethanolamine, tromethamine, N -methylglucamine, and the like.
  • the ratio of the compound to the cation or anion of the salt can be 1 : 1 , or any ratio other than 1 : 1, e.g., 3:1, 2: 1, 1:2, or 1:3.
  • the compounds, or pharmaceutically acceptable salts thereof are administered orally, nasally, transdermally, pulmonary, inhal at tonally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly , intravenously, rectally, intrapleurally, intrathecally and parenterally.
  • the compound is administered orally .
  • One skilled in the art will recognise the advantages of certain routes of administration.
  • the dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity' of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drag required to prevent, counter, or arrest the progress of the condition.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition.
  • the present disclosure provides, inter alia, a compound of Formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein:
  • A is a 5- to 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises at least one O ring atom;
  • R ! is halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy
  • R 2 is halogen or Ci-Ce alkyl; or R l and R 2 , together with the atoms to which they are attached, form a 3 - or 4-membered carbocyclic ring;
  • R 3 is -OH, halogen, C 1 -C 6 alkyd, or C 1 -C 6 alkoxy;
  • X is H, -OH, halogen, -NH2, -NHfCi-Cg alkyl), -N(C 1 -C 6 alkyd)?., or Ct-Ck alkyl;
  • R 4 is H, C]-Cs alkyd, or -C(O)(C 1 -C 6 alkyl); and p is 0 or 1, wherein each instance of alkyl, alk-, or carbocyclic is independently substituted with 0, 1, 2, or 3 halogen atoms; and when R 3 is CI, then is not
  • the compound of Formula (I) is not or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I) wherein p is 1; R l is C 1 -C 6 alkyl or Ci- C? alkoxy'; and R 2 is C 1 -C 6 alkyl.
  • A is a 5- to 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises of at least one O ring atom. In some embodiments, A is a 5- to 8- membered monocyclic heterocvcloalkyl, wherein the heterocycloalkyd comprises one O ring atom. [0108] In some embodiments, A is a 5-membered monocyclic heterocycloalkyl, wherein the heterocvcloalkyl comprises of at least one O ring atom. In some embodiments, A is a 5-membered monocyclic heterocvcloalkyl, wherein the heterocycloalkyl comprises one O ring atom.
  • A is a 6-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises of at least one O ring atom. In some embodiments, A is a 6-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises one O ring atom.
  • A is a 7-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises of at least one O ring atom. In some embodiments, A is a 7-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises one O ring atom.
  • A is a 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises of at least one O ring atom. In some embodiments, A is a 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises one O ring atom.
  • p is 0 or 1.
  • p is 0. In some embodiments, p is 1.
  • R 1 is halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, wherein the alkyl or alkoxy’ is independently substituted with 0, 1, 2, or 3 halogen atoms.
  • R 1 is halogen, C 1 -C 6 alkyd, or C 1 -C 6 alkoxy’, wherein the alkyd or alkoxy’ is substituted with 1 , 2, or 3 halogen atoms.
  • R 1 is halogen, Ci-Ce alkyl, or C 1 -C 6 alkoxy.
  • R 1 is halogen
  • R 1 is F, Cl, Br, or I.
  • R 1 is F. In some embodiments, R 1 is Ci. In some embodiments, R 1 is Br. In some embodiments, R 1 is I.
  • R 1 is C 1 -C 6 alkyl substituted with 0, 1, 2, or 3 halogen
  • R 1 is C 1 -C 6 alkyl substituted with 1, 2, or 3 halogen.
  • R 1 is Ci-Ce alkvl.
  • R l is methyl substituted with 0, 1, 2, or 3 halogen.
  • R 1 is ethyl substituted with 0, 1, 2, or 3 halogen.
  • R 1 is propyl substituted with 0, 1, 2, or 3 halogen.
  • R 1 is butyl substituted w ith 0, 1, 2, or 3 halogen.
  • R 1 is pentyl substituted with 0, 1, 2, or 3 halogen.
  • R 1 is hexyd substituted with 0, 1, 2, or 3 halogen.
  • each R 1 is isopropyl substituted with 0, 1, 2, or 3 halogen.
  • R 1 is isobuty l substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 1 is isopentyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 1 is isohexyl substituted with 0, 1, 2, or 3 halogen. Io some embodiments, R 1 is secbutyl substituted with 0, 1 , 2, or 3 halogen. In some embodiments, R 1 is secpentyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 1 is sechexyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 1 is tertbutyl substituted with 0, 1, 2, or 3 halogen,
  • R 1 is methyl substituted with 1, 2, or 3 halogen.
  • R ! is ethyl substituted with 1, 2, or 3 lialogen.
  • R ! is propyl substituted with 1, 2, or 3 lialogen.
  • R ! is butyl substituted with 1, 2, or 3 lialogen.
  • R 1 is pentyl substituted with 1, 2, or 3 halogen.
  • Ri is hexyl substituted with 1, 2, or 3 halogen.
  • each R 1 is isopropyl substituted with 1, 2, or 3 halogen.
  • R 1 is isobutyl substituted with 1, 2, or 3 halogen. In some embodiments, R 1 is isopentyl substituted with 1, 2, or 3 halogen. In some embodiments, R 1 is isohexyl substituted with 1, 2, or 3 halogen. In some embodiments, R 1 is secbutyl substituted with 1, 2, or 3 halogen. In some embodiments, R 1 is secpentyl substituted with 1, 2, or 3 halogen. In some embodiments, R s is sechexyl substituted with 1, 2, or 3 halogen. In some embodiments, R ! is tertbutyl substituted with 1, 2, or 3 halogen.
  • R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R' is propyl. In some embodiments, R 1 is butyl. In some embodiments, R' is pentyl. In some embodiments, R ] is hexyl. In some embodiments, each R 1 is isopropyl. In some embodiments, R 1 is isobutyl. In some embodiments, R l is isopentyl. In some embodiments, R l is isohexyl. In some embodiments, R 1 is secbutyl. In some embodiments, R l is secpentyl. In some embodiments, R 1 is sechexyd. In some embodiments, R‘ is tertbutyl.
  • R 1 is Ci-Ch alkoxy substituted with 0, I, 2, or 3 halogen.
  • R 1 is Ci-Ch alkoxy substituted with I , 2, or 3 halogen.
  • R 1 is C i-Ch alkoxy.
  • R 1 is Ci alkoxy substituted with 0, 1, 2, or 3 halogen.
  • R 1 is Ch: alkoxy substituted with 0, 1, 2, or 3 halogen.
  • R 1 is Cs alkoxy substituted with 0, 1, 2, or 3 halogen.
  • R ! is Q alkoxy substituted with 0, 1, 2, or 3 halogea
  • R ! is Cs alkoxy substituted with 0, 1, 2, or 3 halogen.
  • R l is Cs alkoxy substituted with 0, 1, 2, or 3 halogen.
  • R 1 is Ci alkoxy substituted with 1, 2, or 3 halogea
  • R 1 is C2 alkoxy substituted with I, 2, or 3 halogen.
  • R l is Ch alkoxy substituted with 1, 2, or 3 halogea
  • R [ is Ch alkoxy substituted with I , 2, or 3 halogen.
  • R 1 is Cs alkoxy substituted with 1, 2, or 3 halogen.
  • R 1 is C& alkoxy substituted with 1, 2, or 3 halogen.
  • R l is C] alkoxy. In some embodiments, R 1 is C2 alkoxy. In some embodiments, R 1 is Cs alkoxy. In some embodiments, R 1 is Ch alkoxy. In some embodiments, R 1 is Cs alkoxy. In some embodiments, R 1 is Cs alkoxy,
  • R 2 is halogen or C 1 -C 6 alkyl substituted with 0, I, 2, or 3 halogen. [0133[ In some embodiments, R 2 is halogen or C 1 -C 6 alkyl substituted with I, 2, or 3 halogen. [0134] In some embodiments, R 2 is halogen or C 1 -C 6 alkyl.
  • R 2 is halogen
  • R 2 is F, Cl, Br, or I.
  • R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is I. [0138J In some embodiments, R 2 is C]-C & alkyl substituted with 0, 1 , 2, or 3 halogen. [0339J In some embodiments, R 2 is C]-C & alkyl substituted with 1, 2, or 3 halogen.
  • R z is Ci-Ca alkyl.
  • R 2 is methyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 2 is ethyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 2 is propyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 2 is butyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 2 is pentyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 2 is hexyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 2 is isopropyl substituted with 0, 1, 2, or 3 halogen.
  • R 2 is isobutyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 2 is isopentyl substituted with 0, 1, 2, or 3 lialogen. In some embodiments, R 2 is isohexyl substituted with 0, 1, 2, or 3 lialogen. In some embodiments, R 2 is secbutyl substituted with 0, 1, 2, or 3 lialogen. In some embodiments, R 2 is secpentyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 2 is sechexyl substituted w ith 0, 1, 2, or 3 lialogen. In some embodiments, R 2 is tertbuty l substituted with 0, 1 , 2, or 3 halogen.
  • R 2 is methyl substituted with 1, 2, or 3 halogen. In some embodiments, R 2 is ethyl substituted with 1, 2, or 3 lialogen. In some embodiments, R 2 is propyl substituted with 1, 2, or 3 halogen. In some embodiments, R 2 is butyl substituted with 1, 2, or 3 halogen. In some embodiments, R 2 is pentyl substituted with 1, 2, or 3 lialogen. In some embodiments, R 2 is hexyl substituted with 1, 2, or 3 lialogen. In some embodiments, R 2 is isopropyl substituted with 1, 2, or 3 halogen.
  • R 2 is isobutyl substituted with 1, 2, or 3 lialogen. In some embodiments, R 2 is isopentyl substituted with 1, 2, or 3 lialogen. In some embodiments, R 2 is isohexyl substituted with 1, 2, or 3 lialogen. In some embodiments, R 2 is secbutyl substituted with 1, 2, or 3 halogen. In some embodiments, R 2 is secpentvl substituted with 1, 2, or 3 halogen. In some embodiments, R 2 is sechexyl substituted with 1, 2, or 3 halogen. In some embodiments, R 2 is tertbutyl substituted with I, 2, or 3 halogen.
  • R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is hexyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is isobutyl. In some embodiments, R 2 is isopentyl. In some embodiments, R 2 is isohexyl. In some embodiments, R 2 is secbutyl. In some embodiments, R 2 is secpentyl. In some embodiments, R 2 is sechexyl. In some embodiments, R 2 is tertbutyl.
  • 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.
  • R 1 and R 2 together with the atoms to wiuch they are attached, form a 3- or 4-membered carbocyclic ring substituted with 1, 2, or 3 lialogen atoms.
  • R 1 and R 2 together with the atoms to which they are attached, form a 3- or 4-membered carbocyclic ring.
  • 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.
  • 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.
  • R 1 and R 2 together with the atoms to which they are attached, form a
  • R ! and R 2 together with the atoms to which they are attached, form a
  • 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.
  • R ! and R 2 together with the atoms to which they are attached, form a 4-membered carbocyclic ring.
  • p is 1 and each of R 1 and R 2 is independent! ⁇ ' 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 independent! ⁇ ' C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, wherein R ] and R z are attached to the same carbon atom on Ring A.
  • 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 attached to the same carbon atom on Ring A.
  • R 3 is -OH, halogen, Ci-Cr, alkyl, or Ci-C& alkoxy, wherein the alkyl or alkoxy is independently substituted with O, 1, 2, or 3 halogea
  • R 3 is -OH, halogen, Ci-Cr, alkyl, or Ci-C& alkoxy, wherein the alkyl or alkoxy is substituted with 1, 2, or 3 halogen.
  • R 3 is -OH, halogen, Ci-Ce alkyl, or C 1 -C 6 alkoxy.
  • R 3 is -OH.
  • R 3 is halogen
  • R 3 is Br. In some embodiments, R 3 is Cl. In some embodiments, R 3 is F. In some embodiments, R 3 is I.
  • R 3 is not halogen.
  • R 3 is C] -C & alky! or Ci -Cs alkoxy’.
  • R 3 is Ci-Ca alkyl substituted with 0, 1, 2, or 3 halogen.
  • R 3 is Ci-Ca alkyl substituted with I, 2, or 3 halogen.
  • R 3 is Cj-Ct. alkyl.
  • R 3 is methyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 3 is ethyl substituted with 0, 1, 2, or 3 halogea In some embodiments, R 3 is propyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 3 is butyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 3 is pentyl substituted with 0, I, 2, or 3 halogen. In some embodiments, R 3 is hexyl substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 3 is isopropyl substituted with 0, 1, 2, or 3 halogen.
  • R 5 is isobutvl substituted with 0, 1, 2, or 3 halogen.
  • R 2 independently is isopentyl substituted with 0, 1, 2, or 3 halogen.
  • R 3 is isohexyl substituted with 0, 1 , 2, or 3 halogen.
  • R 3 is secbutyl substituted with 0, 1, 2, or 3 halogen.
  • R 3 is secpentyl substituted with 0, 1, 2, or 3 halogen.
  • R 3 is sechexyl substituted with 0, 1, 2, or 3 halogen.
  • R 3 is tertbutyl substituted with 0, 1 , 2, or 3 halogen.
  • R 3 is methyl substituted with 1, 2, or 3 halogen. In some embodiments, R 3 is ethyl substituted with 1, 2, or 3 halogea In some embodiments, R 3 is propyl substituted with 1, 2, or 3 halogen. In some embodiments, R 3 is butyl substituted with 1, 2, or 3 halogen. In some embodiments, R 3 is pentyl substituted with 1, 2, or 3 halogen. In some embodiments, R 3 is hexyl substituted with 1, 2, or 3 halogen.
  • R 3 is isopropyl substituted with 1, 2, or 3 halogea In some embodiments, R 3 is isobutvl substituted with 1, 2, or 3 halogea In some embodiments, R 2 independently is isopentyl substituted with 1, 2, or 3 halogen. In some embodiments, R 3 is isohexyl substituted with 1, 2, or 3 halogen. In some embodiments, R 3 is secbutyl substituted with 1, 2, or 3 halogen. In some embodiments, R 3 is secpentyl substituted with 1, 2, or 3 halogen. In some embodiments, R 3 is sechexyl substituted with 1, 2, or 3 halogen. In some embodiments, R 3 is tertbutyl substituted with 1, 2, or 3 halogen.
  • R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is pentyl. In some embodiments, R 3 is hexyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is isobutyl. In some embodiments, R 2 independently is isopentyl. In some embodiments, R 3 is isohexyl. In some embodiments, R 3 is secbutyl. In some embodiments, R 3 is secpentyl. In some embodiments, R 3 is sechexyl. In some embodiments, R 3 is tertbutyl.
  • R 3 is C 1 -C 6 alkoxy substituted with 0, 1, 2, or 3 halogea [0170 j In some embodiments, R 3 is C 1 -C 6 alkoxy substituted with 1, 2, or 3 halogen. [0171] In some embodiments, R 3 is C 1 -C 6 alkoxy.
  • R 3 is methoxy' substituted with 0, 1 , 2, or 3 halogen. In some embodiments, R 3 is ethoxy substituted with 0, 1, 2, or 3 halogea In some embodiments, R 3 is propoxy substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 3 is butoxy' substituted with 0, 1 , 2, or 3 halogen. In some embodiments, R ! is pentoxy substituted with 0, 1, 2, or 3 halogen. In some embodiments, R 3 is hexoxy substituted with 0, 1, 2, or 3 halogen,
  • R 3 is methoxy substituted with 1, 2, or 3 lialogen, In some embodiments, R 3 is ethoxy substituted with 1, 2, or 3 halogen. In some embodiments, R 3 is propoxy substituted with 1, 2, or 3 lialogen. In some embodiments, R 3 is butoxy substituted with 1, 2, or 3 halogea In some embodiments, R 3 is pentoxy substituted with 1, 2, or 3 lialogen. In some embodiments, R 3 is hexoxy substituted with 1, 2, or 3 halogen.
  • R 3 is methoxy. In some embodiments, R 3 is ethoxy'. In some embodiments, R 3 is propoxy. In some embodiments, R 3 is butoxy. In some embodiments, R 3 is pentoxy. In some embodiments, R 3 is hexoxy.
  • R 3 is Cl, methyl, -CF?, -CHF?, or -OCHF2.
  • R 3 is -CF?, -CHF?, or -OCHF2.
  • R J is -CFs.
  • R 3 is -CHF?.
  • R 3 is -OCHF?.
  • X is H, -OH, halogen, -NH?, -Nl-tyC 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)?., or Ci-Ce alkyl.
  • X is -OH, halogen, -NH?, -NHiCi-Ce alkyl), -N(Ci-C 6 alkyl)?, or C 1 -C 6 alkyl.
  • X is H.
  • X is halogen
  • X is Br, Cl, F, or I.
  • X is Br. In some embodiments, X is CI. In some embodiments, X is F. In some embodiments, X is I.
  • X is -OH.
  • X is -NH?. In some embodiments, X is -NH(C 1 -C 6 alkyl).
  • X is -NH(Ci alkyl). In some embodiments, X is -NH(C? alkyl). In some embodiments, X is -NH(C? alkyl). In some embodiments, X is -NH(C 4 alkyl). In some embodiments, X is -NH(Cs alkyl). In some embodiments, X is -NH(Cs alkyl).
  • X is -N(C 1 -C 6 alkyl)?.
  • X is -N(Ci alkyl)?. In some embodiments, X is -N(C? alkyl)?. In some embodiments, X is -N(C? alkyl)?. In some embodiments, X is -N(C 4 alkyl)?. In some embodiments, X is -N(Cs alkyl)?. In some embodiments, X is -N(Cs alkyl)?.
  • X is Ci-Cg alkyl.
  • 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, Xis isohexyl. In some embodiments, X is secbutyl. In some embodiments, X is secpentyl. In some embodiments, X is sechexyl. In some embodiments, Xis tertbutyl.
  • X is H or F.
  • R 4 is H, C 1 -C 6 alkyl, C?-C 6 alkenyl, Cb-Cg alkynyl, or -C(O)(Ci-C6 alkyl).
  • R 4 is Ci-C 6 alkyl, C?-C ! 6 alkenyl, C2-C.5 alkynyl, or -C(O)(Ci-C'6 alkyl).
  • R 4 is H.
  • R 4 is Ci-C& alley 1.
  • R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. In some embodiments, R 4 is butyl. In some embodiments, R 4 is pentyl. In some embodiments, R 4 is hexyl. In some embodiments, each R 4 is isopropyl. In some embodiments, R 4 is isobutyl. In some embodiments, R 4 is isopentyl. In some embodiments, R 4 is isohexyl. In some embodiments, R 4 is secbutyl. In some embodiments, R 4 is secpentyl. In some embodiments, R 4 is sechexyl. In some embodiments, R 4 is tertbutyl, [0197] In some embodiments, R 4 is - ⁇ ' ⁇ );(( -( alkyl).
  • R 4 is -C(O)(Ci alkyl). In some embodiments, R 4 is -C(O)(C2 alkyl). In some embodiments, R 4 is -C(O)(C3 alkyl). In some embodiments, R 4 is -C(O)(C4 alkyl). In some embodiments, R 4 is -C(O)(C-5 alkyl). In some embodiments, R 4 is -C(O)(Ct, alkyl).
  • each instance of alkyl, alk-, or carbocyclic is independently substituted with 0, 1, 2, or 3 halogen atoms.
  • each instance of alkyl is substituted with 0, 1, 2, or 3 halogen atoms.
  • each instance of alk- is substituted with 0, 1, 2, or 3 halogen atoms.
  • each instance of carbocyclic is substituted with 0, 1, 2, or 3 halogen atoms.
  • R 4 is hydrogen.
  • R 3 is halogen, Ci-Ce alkyl, or C t-C& alkoxy, e.g., -Cl, -CHF2, -CF3, -CH3, or - OCHF2.
  • the compound of Formula (I) is of Formula (I-a) or (I-b): pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • the phenyl ring system of formula (a) is of formula (a-1), (a-2), or (a-3), wherein X is hydrogen, halogen or C 1 -C 6 alkyl, e.g., -II, -F, -Cl, or -CH3.
  • R 4 is hydrogen.
  • Rf is halogen, Ci-Cj, alkyl, or Cj-Ce alkoxy, e.g., -Cl, -CHF2, -CFa, -CFI-j, or - OCHF2.
  • R 3 is Ci-Ct, alkyl or Ci-Ce alkoxy, e.g, -CHF2, -CF-j, -CH3, or -OCHF2.
  • R 3 is C 1 -C 6 alkyl, e.g., -CHF?, -CF3, or -CH3.
  • the amine ring system of formula (b) is of formula (b-1).
  • R 1 is -CH? and R 2 is -CH3.
  • the compound of Formula (I) is of Formula (Il-a), or (II-c): pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • X is halogen or C 1 -C 6 alkyl, e.g., -F, -Cl, or -CHj.
  • R 4 is hydrogen.
  • R 3 is halogen, C 1 -C 6 alkyl, or Ci-C* alkoxy, e.g., -Cl, - CHF?., -CF3, -CH3, or -OCHF2.
  • R 3 is Ci-C6 alkyl or Cj-Ce alkoxy, e.g., -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3 is Ci-Cg alkyl, e.g., -CHF2, - CF-j, or -CH3. In certain embodiments, the amine ring system of formula (b) is of formula (b- 1), In certain embodiments, R 1 is -CH3 and R 2 is -CH3.
  • the compound of Formula (I) is of Formula (IM), (Il-e), or (Il-f): pharmaceutically acceptable salt, solvate, clathratf hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • X is halogen or C 1 -C 6 alkyl, e.g., -F, -Ci, or -CHj.
  • R 4 is hydrogen.
  • R 3 is halogen, Ct-Ce alkyl, or Ci-C* alkoxy, e.g., -Cl, - CHFj, -CF3, -CH3, or -OCHF2.
  • R 3 is Ci-C6 alkyl or Cj-Ce alkoxy, e.g., -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3 is Ci-Cg alkyl, e.g., -CHF2, -
  • the amine ring system of formula (b) is of formula (b- 1), In certain embodiments, R 1 is -CH3 and R is -CH3.
  • the compound of Formula (I) is of Formula (III-a), (III-b), or s lll-ci clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, w herein m is an integer from 0 to 2 and n is an integer from 1 to 2.
  • m is 0, 1, or 2.
  • m is 1 or 2.
  • n is 0, 1, or 2.
  • n 1 or 2.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • the phenyl ring system of formula (a) is of formula (a-1), (a-2), or (a-3), wherein X is hydrogen, halogen or C 1 -C 6 alkyl, e.g., - H, -F, -Cl, or -CH?,.
  • R 4 is hydrogen.
  • R 3 is halogen, Ci-Ce alkyl, or Ci-C « alkoxy, e.g., -Cl, -CHF 2 , -CF 3 , -CH 3 , or -OCHF?.
  • R 3 is Cj-Ce alkyl or Ci-Ce alkoxy, e.g. , -CHF 2 , -CFj, -CH 3 , or -OCHF 2 .
  • R 3 is C i-C& alkyl, e.g., -CHF?, -CFj, or -CH?.
  • R 1 is -CH?
  • R 2 is -CH?.
  • the compound of Formula (I) is of Formula (IJI-d), (III-e), or (Ill-f): pharmaceutically acceptable salt, solvate, clathrate. hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein m is an integer from 0 to 2 and n is an integer from 1 to 2.
  • the phenyl ring system of formula (a) is of formula (a-1), (a-2), or (a-3), wherein X is hydrogen, halogen or Cj-Cs alkyl, e.g., - H, -F, -Cl, or -CH?.
  • R 4 is hydrogen.
  • R 3 is halogen, Ci-C £ , alkyl, or Ci-Ce alkoxy, e.g., -Cl, -CHF 2 , -CF?,, -CH?, or -OCHF 2 .
  • R 3 is Ci-C £ , alkyl or Ci-C £ , alkoxy, e.g., -CHF 2 , -CF 3 , -CH 3 , or -OCHF 2 .
  • R 3 is C 1 -C 6 alkyl, e.g., -CHF 2 , -CF 3 , or -CH?.
  • the compound of Formula (I) is of Formula (IV-a), (IV -to), or (IV-c):
  • the phenyl ring system of formula (a) is of formula (a-1), (a-2), or (a-3), wherein X is hydrogen, halogen or Ci-C-6 alkyl, e.g.. -H, -F, -Cl, or -CH3.
  • R 4 is hydrogen.
  • R J is halogen, Cj-Ce alkyl, or Ci-Ce alkoxy, e.g, -Cl, -CHF2, -CF?, -CH3, or -OCHF2.
  • Ci-Ce alkyl or Ci-Cg alkoxy e.g. , -CHF?., -CF3, -CH3, or -OCHF2.
  • R 3 is Ct-Cg alkyl, e.g. , -CHF?., -CF3, or -CH?.
  • R 1 is -CH3 and R z is -CH?.
  • the compound of Formula (I) is of Formula (IV-al), (IV-bl), or (IV- cl): clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • the phenyl ring system of formula (a) is of formula (a-1), (a-2), or (a-3), wherein X is hydrogen, halogen or Ci-Ce alkyl, e.g., -H, -F, -Cl, or -CH?.
  • R 4 is hydrogen.
  • R J is halogen, Cj-Ce alkyl, or Ci-Ce alkoxy, e.g, -Cl, -CHF?, -CF?, -CH?, or -OCHF2.
  • R J is Ci-Ce alkyl or Ci-Cg alkoxy, e.g. , -CHF?, -CF?, -CH?, or -OCHF2.
  • R 3 is Ct-Cg alkyl, e.g , -CHF? thread -CF?, or -CH?.
  • the compound of Formula (I) is of Formula (V-a), (V-b), or (V-c):
  • the compound of Formula (I) is of Formula (V-a’), (V-b’), or (V-c’): clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • the phenyl ring system of formula (a) is of formula (a-1), (a-2), or (a-3), wherein X is hydrogen, halogen or Ci-Cj, alkyl, e.g, -H, -F, -Cl, or -CH3.
  • R 3 is halogen, Ci-Ce alkyl, or Ci-Ct, alkoxy, e.g., -Ci, -CHF2, -CF3, -CH-j, or - OCHF2.
  • R’ is C 1 -C 6 alkyl or Ci-Ce alkoxy, e.g., -CHF2, -CF3, -CH 3 , or -OCHF2.
  • R J is C 1 -C 6 alkyl, e.g., -CHF2, -CF3, or -CII3.
  • R 1 is -CH3 and R 2 is -CH3.
  • the compound of Formula (I) is of Formula (Vl-a), (Vl-b), ( VI-c),
  • the phenyl ring system of formula (a) is of formula (a-1), (a-2), or (a-3), wherein X is hydrogen, halogen or Cj-Cr. alkyl, e.g., -H, -F, -Cl, or -CH3.
  • R 4 is hydrogen.
  • R 3 is halogen, Ci-C-6 alkyl, or Ci-Ce alkoxy, e.g., -Cl, -CHF?, -CF3, -CH3, or - OCHF2.
  • R 3 is C 1 -C 6 alkyl or Ci-Ce alkoxy, e.g., -CHF2, -CF3, -CH3, or -OCHF2. In certain embodiments, R 3 is C 1 -C 6 alkyl, e.g., -CHF2, -CF3, or -CH3. In certain embodiments, R J is -CH3 and R 2 is -CH3.
  • the compound of Formula (I) is of Formula (Vl-al ), (VI-M), (VI-cl),
  • Vl-dl (Vl-el), (Vl-fl), (Vl-gl), or (VI-M):
  • the phenyl ring system of formula (a) is of formula (a-1), (a-2), or (a-3), wherein X is hydrogen, halogen or C1-C& alkyl, e.g., -H, -F, -Cl, or -CH3.
  • R* is hydrogen.
  • R 3 is halogen, Cs-Ce alkyl, or C 1 -C 6 alkoxy, e.g., -Cl, -CHF?., -CF?, -CH?, or - OCHF2.
  • R 3 is Ci-Cc, alkyl or Ci-Cr, alkoxy, e.g. , -CHF2, -CF?, -CH?, or -OCHF2.
  • R J is Ci-Cg alkyl, e.g. , -CHF?, -CF?, or -CH?.
  • the compound is selected from a compound described in Table 1, or a phannaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrag thereof.
  • the compound is selected from a compound described in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound is selected from a compound described in Table 1, or a solvate thereof.
  • the compound is selected from a compound described in Table 1, or a clathrate thereof.
  • the compound is selected from a compound described in Table 1, or a hydrate thereof.
  • the compound is selected from a compound described in Table 1, or a stereoisomer thereof.
  • the compound is selected from a compound described in Table 1, or a tautomer thereof.
  • the compound is selected from a compound described in Table 1, or an isotopically labeled compound thereof.
  • the compound is selected from a compound described in Table 1, or a prodrug thereof.
  • the compound is selected from a compound described in Table 1. Stereochemistry which has been arbitrarily assigned is signified with an Asterix (*)
  • the compound is a pharmaceutically acceptable salt of a compound described in Table 1.
  • the compound is a prodrug of a compound described in Table 1,
  • the compound is an isotopic derivative of any one of the compounds described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound is an isotopic deriva tive of a prodrug of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1 .
  • the compound is selected from a compound described in Table 2, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • the compound is selected from a compound described in Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound is selected from a compound described in Table 2, or a solvate thereof.
  • the compound is selected from a compound described in Table 2, or a clathrate thereof.
  • the compound is selected from a compound described in Table 2, or a hydrate thereof.
  • the compound is selected from a compound described in Table 2, or a stereoisomer thereof.
  • the compound is selected from a compound described in Table 2, or a tautomer thereof.
  • the compound is selected from a compound described in Table 2, or an isotopically labeled compound thereof.
  • the compound is selected from a compound described in Table 2, or a prodrug thereof.
  • the compound is selected from a compound described in Table 2. Stereochemistry which has been arbitrarily assigned is signified with an Asterix (*).
  • the compound is a pharmaceutically acceptable salt of a compound described in Table 2.
  • the compound is a prodrug of a compound described in Table 2,
  • the compound is an isotopic derivative of any one of the compounds described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of a prodrug of any one of the compounds described in Table 2, or a pharmaceutically acceptable salt thereof. [0259] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2.
  • the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.
  • the present disclosure provides, inter aha, compounds selected from
  • the compound is (R)-5-cbloro-2-(4-((4,4-dimethyltetrahydrofiiran-3- yl)amino)pyrido[3,4-d]pyridazin-l-yl)phenol.
  • the compound is 5-(difluorometiiyl)-2-(4-((2-(metiioxy-d3)-2- methylpropyl)amino)pyrido[3,4-d]pyridazin-l"yl)phenoL
  • the compound is (R)-5-chioro-2-(4-((3,3-dimetliyltetraliydro-2H-pyran- 4-yl)amino)pyrido[3,4-d]pyridazin-I-yl)phenol.
  • the compound is (S)-5-chloro-2-(4-((2,2-diinethyItetrahydro-2H-pyran- 4-yl)amino)pyrido[3,4-d]pyridazin-I-yl)phenol.
  • the compound is (R)-2-(4-((5,5-dimethyltetrahvdrofuran-3- yl)amino)pyrido[3,4-d]pyridazin-l-yl)-5-methylphenol.
  • the compound is (S)-2-(4-(((4-methylmorpholin-2- yl)methyl)amino)pyrido[3,4-d]pyridazin-l-yl)-5-(trifluorometby])pbenol.
  • the compound is a pharmaceutically acceptable salt of any one of the compounds described herein.
  • the present disclosure provides a compound being an isotopic derivative (also referred to herein as an isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.
  • the compound is an isotopic derivative of any one of the compounds described herein and prodrugs and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of the compounds described herein and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of prodrugs of the compounds described herein and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of the compounds described herein.
  • the isotopic derivative can be prepared using any of a variety of art- recognized techniques.
  • the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the isotopic derivative is a deuterium labeled compound.
  • the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.
  • isotopic derivative refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled.
  • an isotopic derivative of a compound disclosed herein is isotopically enriched with regard to, or labeled with, one or more isotopes as compared to the corresponding disclosed compound.
  • the isotopic derivative is enriched with regard to, or labeled with, one or more atoms selected from 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 S.
  • the isotopic derivative is a deuterium labeled compound (i.e., being enriched with 2 H with regard to one or more atoms thereof).
  • the compound is a 18 F labeled compound.
  • the compound is a l23 I labeled compound, a S24 I labeled compound, a l23 I labeled compound, a 129 I labeled compound, a 13 l I labeled compound, a S35 I labeled compound, or any combination thereof.
  • the compound is a 33 S labeled compound, a 34 S labeled compound, a 35 S labeled compound, a 3b S labeled compound, or any combination thereof.
  • the iS F, l23 1, 124 I, l23 I, 129 I, ]3 l I, l33 I, 32 S, 34 S, 3 'S, and/or 36 S labeled compound can be prepared using any of a variety of art-recognized techniques.
  • the deuterium labeled compound can generally be prepared by carry ing out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a 18 F, 123 I, l24 I, i2 ’1, 129 I, l31 1, 135 I, 3z S, 34 S, ! ’S, and/or 36 S labeled reagent for a non-isotope labeled reagent.
  • a compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned i8 F, i23 I, 124 1, 125 I, i29 I, 131 1, 135 1, 32 S, 34 S, 35 S, and 3£ 'S atom(s) is within the scope of the invention. Further, substitution with isotope (e.g., 18 F, 123 1, 124 1, 129 I, 131 1, 135 1, 32 S, 34 S, 35 S, and/or 3b S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, bydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, mi ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • mi ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • the compound of Formula (I) is not:
  • the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed ‘'diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”
  • chiral center refers to a carbon atom bonded to four nonidentical substituents.
  • chiral isomer means a compound with at least one chiral center.
  • Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.”
  • a stereoisomer may be characterized by the absolute configura tion (R or S) of tliat chiral center.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew.
  • geometric isomer means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cycIobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rales.
  • tliat the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood tliat not all isomers may have the same level of activity.
  • tautomer is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed.
  • keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
  • Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”
  • the compounds of tliis disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Some of the compounds of the disclosure may- have geometric isomeric centers (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflamniasome inhibitory activity.
  • any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein.
  • Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).
  • the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt, likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetrametliylanmionium ion or diethylamine ion.
  • the substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.
  • the compounds of the present disclosure can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • hydrates include rnonohydrates, dihydrates, etc.
  • solvates include ethanol solvates, acetone solvates, etc.
  • solvate means solvent addition forms that contain either stoichiometric or non-stoicbiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. 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 the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H20.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • derivative refers to compounds that have a common core structure and are substituted with various groups as described herein.
  • solvated forms such as, for example, hydrated forms.
  • a suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.
  • tautomeric fo rms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidme, nitroso/oxime, thioketone/enethiol, and nrtro/aci-nitro.
  • the compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrag which is broken down in the human or animal body to release a compound of the disclosure.
  • a prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure.
  • a prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property -modifying group can be attached. Examples of prodrugs ingorge derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.
  • the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically -produced compound or a metabolically -produced compound.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity .
  • Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, el 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-drags,” by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al.. Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Cbem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Deliveiy Systems,” A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drag Design,” Pergamon Press, 1987.
  • a suitable pharmaceutically acceptable prodrag of a compound of any one of tbe Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce tlie parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include Ci-Cio alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-Cio alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C 1 -C 6 alkyl)2carbamoyl, 2 -dialkylaminoacetyl and 2- carboxyacetyl groups.
  • Ci-Cio alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
  • Ci-Cio alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C 1 -C 6 alkyl)2carbamoyl, 2 -dialkylaminoacetyl and 2- carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy' group include a-acyloxyalkyl groups such as acetoxvmethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of die Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4 alkylamine such as methylamine, a (C1-C4 alkylh-amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4 alkoxv-CA-CA alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4 alkylamine such as benzylamine and ammo acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a C1-4 alkylamine such as methylamine
  • a (C1-C4 alkylh-amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein tlrat possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci-Cio alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-l-ylmethyl and 4-(C;-C4 alkyl)piperazin-l -ylmethyl,
  • the in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites tlrat are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein.
  • tlie in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).
  • Protocol A A suitable general route for the preparation of a compound of the application is using Protocol A and can be described in Scheme 1 herein.
  • Step one involves an SxAr reaction between an amine (i) and an aryl dicliloride (ii), to provide the target chloroaiyl intermediate (iii).
  • Step two involves cross-coupling between intermediate (iii) and the desired boronic acids or boronates (iv), optionally followed by deprotection of an alkyl ether (e.g., a methyl ether) on the phenyl ring, to generate the desired compound (v).
  • Amine (i), and dichloride (ii), and boronic acid or boronate (iv) are either commercially available or known in the chemical literature, unless otherwise indicated.
  • Step One involves opening commercially available 3,4-pyridmedicarboxylic acid anhydride (vii) with a Grignard reagent to obtain carboxylic acid (viii).
  • Step two features chlorination, then condensation with hydrazine to furnish pyridazinol (ix).
  • Step three then involves another chlorination to furnish key intermediate (x), which in turn may be engaged in step four as a an SNAr reaction with an amine (i) to form azaphthalazines (xi).
  • Step five then features a methyl ether deprotection then provides analogs (xii).
  • Compounds designed, selected and/or optimized by methods described above and herein, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity.
  • the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein 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 U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.
  • in vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure.
  • These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, binding assays, cellular assays (cell lines, primary' cells and whole blood), in vitro cell viability assays, as well assays for determining NLRP3 potency , unbound clearance, solubility, permeability, metabolic stability (e.g., in hepatocytes), and CYP inhibition and timedependent inhibition (TD1) assays (e.g., for de-risking potential adverse in vivo drug-drug interactions).
  • enzymatic activity assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, binding as
  • the biological assay is described in the Examples, Assay Methods section. In some embodiments, the Assay Methods section refers to Example 12.
  • the compounds of the instant disclosure may be tested for their human-NLRP3 inhibition activity using known procedures, such as the methodology reported in Coll et al. Nat Med. (2015) 21(3):248-255. See also the Examples, Assay Methods section.
  • the compounds of the instant disclosure may be tested for their human NLRP3 potency using known procedures. See, e.g., the human whole blood NLRP3 assay described in the Assay Method section of the Examples.
  • the compounds of the instant disclosure may further be tested for brain penetrance. See, e.g., the kp and kpu,u NLRP3 assay described in the Assay Method section of tire Examples.
  • the compounds of the instant disclosure may be tested for unbound clearance (Clu) following known procedures, such as described in Miller et al., J. Med. Chem. (2020) 63: 12156-12170.
  • unbound clearance (Clu) may be calculated by dividing total clearance (‘CL’ in mL/min/kg) as measured in blood or plasma by the unbound fraction in plasma (fu).
  • the permeability of compounds of the instant disclosure may be determined following known procedures, such as described in Wang et al. J Mass Spectrom. (2000) 35:71-76.
  • permeability across cell membranes may be measured using either Caco-2 or MDCK-MDR1 cell lines in Transwell plates, after measuring the compound in both apical and basolateral chambers, and reported as an apparent permeability Papp A-B in 10" b env's.
  • the solubility of compounds of the instant disclosure may 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.
  • physiologically relevant media such as phosphate buffered solution (PBS, pH 7.4) or simulated gastric fluid (SGF)
  • PBS phosphate buffered solution
  • SGF simulated gastric fluid
  • Thermodynamic solubility in physiologically relevant media may be measured by LC-MS/MS, after a twenty-four hour incubation, followed by filtration, and reported in mg/mL.
  • Optimized solubility may be beneficial for manufacturing and further processing of the compound.
  • optimized solubility allows for a more efficient in vitro analysis of the compound, including data collection around the compound’s safety, drug-drug interactions, potency, selectivity, metabolism, and permeability.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described in Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodmg thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described In Table 2, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present disclosure provides a pharmaceutical composition comprising al least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and one or more pharmaceutically acceptable earners or excipients.
  • the pharmaceutical composition comprises one or more carrier, filler, vehicle, excipient, solubility enhancing agent, chelating agent, or a combination thereof
  • the present disclosure provides a pharmaceutical composition comprising at least one compound described in Table 1.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound described in Table 2.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound described herein,
  • the pharmaceutical composition comprises a compound described in Table 1 and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a compound described in Table 2 and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a compound of Formula I as described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises (R)-5- chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-l-yi)phenoi as described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises 5- (difluorometbyl)-2-(4-((2-(methoxy r -d3)-2-methyIpropyl)amino)pyrido[3,4-d]pyridazin-l-yl)phenol as described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises (R)-5- chloro-2.-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)py rido[3,4-d]pyridazin-l-yl)phenol as described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises (S)-5- chloro-2-(4-( (2,2-dimethyItetrahydro-2H-py ran-4-y l)amino )py ndo [3 ,4-d]pyridazin- 1 -yl)phenol described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises (R)-2- (4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazm-l-yl)-5-methylphenol as described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises (S)-2- (4-(((4-methylmorphoIin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-l-yl)-5-(trifluoromethyI)phenoI as described herein and a pharmaceutically acceptable earner.
  • the compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of present disclosure can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle.
  • the aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient.
  • Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity /suspending agent, buffer, and pH modifying agent, and a mixture thereof.
  • Any suitable solubility enhancing agent can be used.
  • solubility enhancing agent examples include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P- cyclodextrin, methyl-p-cyclodextrin, randomly methylated-P-cyclodextrin, ethyiated-p-cyclodextrin, triacetyl-p-cyclodextrin, peracetylated-p-cyclodextrin, carboxymethyl-p-cyclodextrin, hydroxy ethyl- P-cyclodextrin, 2-hydroxy-3-(trimethylammonto)propyl-P-cyclodextrin, ghicosyl-P-cyclodextrin, sulfated p-cyclodextrin (S-P-CD), maltosyl-p-cyclodextrin, p-cyclodextrin sulfobutyl ether, branched- P-cyclodextrin, branche
  • Any suitable chelating agent can be used.
  • a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and teirasodiuin edetate, and mixtures thereof.
  • a preservative examples include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorbexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methy lparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hy droxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorbexidine glucon
  • the aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic- pressure).
  • the tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.
  • the aqueous vehicle may also contain a viscosity /suspending agent.
  • Suitable viscosity /suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinvl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.
  • the formulation may contain a pH modifying agent.
  • the pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid.
  • the aqueous vehicle may also contain a buffering agent to stabilize the pH.
  • the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and e-aminocaproic acid, and mixtures thereof.
  • the formulation may further comprise a wetting agent.
  • wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), poly ethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.
  • Oral compositions generally' include an inert diluent or an edible pharmaceutically acceptable earner. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the fo rm of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin: an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide: a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide: a sweetening agent
  • composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or cawier.
  • compositions of the disclosure may be in a fo rm suitable for oral use (for example as tablets, lozenges, liard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, sy rups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intrapentoneal or intramuscular dosing or as a suppository for rectal dosing).
  • a fo rm suitable for oral use for example as tablets, lozenges, liard or soft capsules, aqueous or oily suspensions
  • compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent an inflammasome related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to heat an inflammasome related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • the present disclosure provides a method of modulating NLRP3 activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of modulating NLRP3 activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof
  • the present disclosure provides a method of inhibiting NLRP3 activity (e.g., in vitro or in vivo ⁇ , comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of inhibiting NLRP3 activity (e.g,, in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder inhibited by NLRP3 as disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable sal t thereof or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing a disease or disorder inhibited by NLRP3 as disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodnig thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to tire subject a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of the present disclosure.
  • the disease or disorder is a disease or disorder in which NL.RP3 activity is implicated.
  • the disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory’ disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3 -related disease in a subject that lias been determined to cany a germline or somatic non-silent mutation in NLRP3.
  • the present disclosure provides a method of treating or preventing inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3 -related disease in a subject that has been determined to cam' a gennline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating inflammation, an autoimmune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory' disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3-related disease in a subject that has been determined to cany a gennline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3-related disease in a subject that Sias been determined to cany a germline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating inflammation, an autoimmune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3 -related disease in a subject that has been determined to cany a germline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof for use in modulating NLRP3 activity (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting NLRP3 activity (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting NLRP3 (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use as an antagonist for NLRP3 (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in trea ting or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating NLRP3 activity (e.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating NLRP3 (e.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting NLRP3 activity (e.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting NLRP3 (c.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of the present di sclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treati ng or preventing a disease or disorder disclosed herein,
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for modulating NLRP3 activity (e.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable sal t thereof for inhibiting NLRP3 ac tivi ty (e.g., in vitro or in vivo ).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for modulating NLRP3 (e.g., in vitro or in vivo ).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for inhibiting NLRP3 (e.g., in vitro or in vivo ).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating a disease or disorder disclosed herein.
  • the disease or disorder is associated with implicated NLRP3 activity.
  • the disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3 -related disease in a subject that has been determined to cany a germline or somatic non-silent mutation in NLRP3,
  • the disease or disorder is inflammation.
  • the disease or disorder is an auto-immune disease.
  • the disease or disorder is a cancer.
  • the disease or disorder is an infection.
  • the disease or disorder is a disease or disorder of the central nervous system.
  • the disease or disorder is a metabolic disease.
  • the disease or disorder is a cardiovascular disease.
  • the disease or disorder is a respiratoiy disease
  • the disease or disorder is a kidney disease.
  • the disease or disorder is a liver disease.
  • the disease or disorder is an ocular disease.
  • the disease or disorder is a skin disease.
  • the disease or disorder is a lymphatic disease.
  • the disease or disorder is a rheumatic disease.
  • the disease or disorder is a psychological disease.
  • the disease or disorder is graft versus host disease.
  • the disease or disorder is allodvnia.
  • the disease or disorder is an NLRP3-related disease.
  • the disease or disorder of the central nervous system is Parkinson’s disease, Alzheimer’s disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.
  • the respiratory disease is steroid-resistant asthma.
  • the respiratory disease is severe steroid-resistant asthma.
  • the kidney disease is an acute kidney disease, a chronic kidney disease, or a rare kidney disease.
  • the skin disease is psoriasis, hidradenitis suppurativa (US), or atopic dermatitis.
  • the rheumatic disease is dermatomyositis. Still’s disease, or juvenile idiopathic arthritis.
  • the NLRP3-related disease in a subject that bas been determined to cany a germline or somatic non-silent mutation in NLRP3 is ciyopyrin-associated autoinflammatory syndrome.
  • the ciyopyrin-associated autoinflammatory' syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal onset multisystem inflammatory' disease.
  • the compound is brain penetrant, e.g., having a Kpu,u of > 0.3.
  • Compounds with a Kpu.u of less than or equal to 0,3 are not brain penetrant. In some embodiments, the compound is not brain penetrant.
  • the compound has a Kpu,u of greater than 0.3 to about 9. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 8. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 7. In some embodiments, the compound lias a Kpu.u of greater than 0,3 to about 6. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 5, In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 4. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 3. In some embodiments, the compound lias a Kpu.u of greater than 0.3 to about 2. In some embodiments, the compound has a Kpu,u of greater than 0.3 to about 1.
  • the compound has a Kpu,u of about 2. In some embodiments, the compound has a Kpu,u of about 2.5.
  • the compound has a Kpu,u of about 3. In some embodiments, the compound has a Kpu.u of about 3.5.
  • the compound has a Kpu,u of about 4. In some embodiments, the compound has a Kpu.u of about 4.5.
  • the compound has a Kpu,u of about 5. In some embodiments, the compound has a Kpu,u of about 5.5.
  • the compound has a Kpu,u of about 6. In some embodiments, the compound lias a Kpu,u of about 6.5.
  • the compound has a Kpu,u of about 7. In some embodiments, the compound lias a Kpu,u of about 7.5.
  • the compound has a Kpu,u of about 8. In some embodiments, the compound lias a Kpu.u of about 8.5.
  • the compound lias a Kpu.u of about 10.
  • the compound is metabolically stable, e.g., having a half-life in mouse or human liver microsomes or hepatocytes of greater than 20 minutes, greater than 30 minutes, greater than 40 minutes, greater than 50 minutes, greater tlian 60 minutes, or between about 30 minutes to about 120 minutes.
  • Compounds of the present disclosure may be administered alone as a sole therapy or can be administered in addition with one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e. by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced).
  • the benefit experienced by an individual may be increased by administering a compound of the instant disclosure with another therapeutic agent (which also includes a therapeutic regimen) that also lias therapeutic benefit.
  • the compound of die disclosure need not be administered via the same route as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route.
  • the compound of the disclosure may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously.
  • the initial administration may be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • a combination for use in the treatment of a disease in which inflammasome activity is implicated comprising a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another suitable agent.
  • composition which comprises a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with a suitable, in association with a pharmaceutically acceptable diluent or carrier.
  • the compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc,); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g,, by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary ); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsuiar, subcapsular, infraorbital, intraperitoneal,
  • A is a 5” to 8-membered monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises 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 atached, form a 3- to 4-membered carbocyclic ring:
  • R 3 is -OH, halogen, C 1 -C 6 alkyd, or C 1 -C 6 alkoxy;
  • X is H, -OH, halogen, -NH2, -NHtCt-CT alkyl), -N(C]-C& alkyd)?, or Ci-Cg alkyl;
  • R 4 is H, C 1 -C 6 alkyl, or -C(O)(C 1 -C 6 alkyl); and p is 0 or 1, wherein each instance of alkyl, alk-, or carbocyclic is independently substituted with 0, 1 , 2, or
  • Exemplary Embodiment 2 The compound of Exemplary' Embodiment 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrag thereof, wherein A is a 5-membered monocyclic heterocycloalkyl comprising one O ring atom.
  • Exemplary Embodiment 3 The compound of Exemplary Embodiment 1 or Exemplary’ Embodiment 2, or a pharmaceutically’ acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrag thereof, wherein A is a 6-membered monocyclic heterocycloalkyl comprising one O ring atom.
  • Exemplary Embodiment 4 The compound of any one of Exemplary Embodiments 1 -3, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein p is 1.
  • Exemplary Embodiment 5. The compound of any one of Exemplary Embodiments 1 -4, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein p is 1; R‘ is C 1 -C 6 alkyl or Ct-C« alkoxy; and R 2 is Cj- C 6 alkyl.
  • Exemplary Embodiment 6 The compound of any one of Exemplary Embodiments 1 -5, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, 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, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein R 3 is C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • Exemplary Embodiment 8 The compound of any one of Exemplary Embodiments 1-5, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein R 3 is Ci, methyl, -CFs, -CHF2, or -OCHF2.
  • Exemplary Embodiment 9 The compound of any one of Exemplary Embodiments 1-8, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein R 4 is H.
  • Exemplary Embodiment 10 The compound of any one of Exemplary Embodiments 1-9, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein X is H or F.
  • Exemplary Embodiment 12 The compound of any one of the preceding Exemplary Embodiments, wherein the compound is of Formula (Il-a), (Il-b), (II-c), (Il-d), (Il-e), or (Il-f):
  • Exemplary Embodiment 13 The compound of any one of the preceding Exemplary Embodiments, wherein the compound is of Formula (Ill-a), (lll-b), or (III-c): clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein m is an integer from 0 to 2 and n is an integer from 1 to 2.
  • Exemplary Embodiment 14 The compound of any one of the preceding Exemplary Embodiments, wherein the compound is of Formula (Ill-d), (Ill-e), or (Ill-f): pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, wherein m is an integer from 0 to 2 and n is an integer from 1 to 2.
  • Exemplary Embodiment 15 The compound of any one of the preceding Exemplary Embodiments, wherein die compound is of Formula (IV-a), (IV-b), or (IV-e): clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 16 The compound of any one of the preceding Exemplary Embodiments, wherein the compound is of Formula (IV-al), (TV -bl), or (IV-cl): clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 17 The compound of any one of Exemplary Embodiments 1-13, wherein the compound is of Formula (V-a), (V-b), (V-c), (V-a’), (V-b’), or (V-c’):
  • Exemplary Embodiment 18 The compound of any one of Exemplaiy Embodiments 1-13, pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 20 The compound of Exemplary Embodiment 1 of the formula:
  • Exemplary Embodiment 23 The compound of Exemplary Embodiment 1, wherein the compound is not clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 24 The compound of Exemplary Embodiment 1, wherein the compound is not:
  • Exemplary Embodiment 25 The compound of any one of Exemplary Embodiments 1-21, 23 and 24, wherein the compound has a Kpu,u greater than 0.3.
  • Exemplary Embodiment 26 The compound of any one of Exemplary Embodiments 1-21, 23, or 24, wherein the compound has a Kpu,u greater titan 0.3 to about 10.
  • Exemplary Embodiment 27 A pharmaceutical composition comprising the compound of any one of Exemplary Embodiments 1-2.6, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or pnodrug thereof, and one or more pharmaceutically acceptable carriers.
  • Exemplary Embodiment 28 A method of modulating NLRP3, the method comprising administering to the subject a compound of any one of Exemplary Embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of Exemplary Embodiment
  • Exemplary Embodiment 29 A method of treating or preventing a disease or disorder, the method comprising administering to the subject a compound of any one of Exemplary Embodiments 1 -26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of Exemplary Embodiment 27.
  • Exemplary Embodiment 30 The compound of any one of Exemplary Embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of Exemplary Embodiment 27, for use in treating or preventing a disease or disorder.
  • Exemplary Embodiment 31 Use of the compound of any one of Exemplary Embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, in the manufacture of a medicament, for the treatment or prevention of a disease or disorder.
  • Exemplary Embodiment 32 Use of the compound of any one of Exemplary Embodiments 1-26, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, for the treatment or prevention of a disease or disorder.
  • Exemplary Embodiment 33 The method, compound, or use of any one 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 one of Exemplary Embodiments 2.8-33, wherein the subject is a human.
  • Exemplary Embodiment 35 The method, compound, or use of any one of Exemplary' Embodiments 2.8-34, wherein the disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3-related disease.
  • the disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NL
  • Exemplary Embodiment 36 The method, compound, or use of Exemplary Embodiment 35, wherein the disease or disorder of the central nervous system is Parkinson’s disease, Alzheimer’s disease, traumatic brain injujy, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.
  • the disease or disorder of the central nervous system is Parkinson’s disease, Alzheimer’s disease, traumatic brain injujy, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.
  • Exemplary Embodiment 37 The method, compound, or use of Exemplary Embodiment 35, wherein the kidney disease is an acute kidney disease, a chronic kidney disease, or a rare kidney disease.
  • Exemplary Embodiment 38 The method, compound, or use of Exemplary Embodiment 35, wherein the skin disease is psoriasis, hidrademtis suppurativa (HS), or atopic dermatitis.
  • the skin disease is psoriasis, hidrademtis 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 a subject that lias been 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 NL RP3 -related disease is in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3 is cryopyrin-associated autoinflammatoiy syndrome.
  • Exemplary Embodiment 42 The method, compound, or use of Exemplary Embodiment 35, wherein the cryopyrin-associated autoinflammatoiy syndrome is familial cold autoinflammatoiy syndrome, Muckle-Wells syndrome, or neonatal onset multisystem inflammatory disease.
  • Exemplary Embodiment 44 The compound of Exemplary Embodiment 43, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-l- yl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 45 The compound of Exemplary Embodiment 43, wherein the compound is 5-(difluoromethyl)“2-(4-((2-(methoxy-d3)"2-methylpropyl)amino)pyrido[3,4- d]pyridazin-l-yl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 46 The compound of Exemplary Embodiment 43, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyItetrahydro-2H-pyran-4-yl)amino)pyrido[3,4- d]pyridazin-l-yl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrag thereof.
  • Exemplary Embodiment 47 The compound of Exemplary' Embodiment 43, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amlno)pyrido[3,4- d]pyridazin-i-yl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrag thereof.
  • 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-l-yl)-5- methylphenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 49 The compound of Exemplary Embodiment 43, wherein the compound is (S)-2-(4-(((4-metliylmoipholin-2-yi)metliyl)aniino)pyrido[3,4-d]pyridazin-l-yi)-5- (trifluoromethyl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 50 A pharmaceutical composition comprising a compound of Exemplary Embodiment 43, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and a pharmaceutically acceptable earner.
  • Exemplary Embodiment 51 A pharmaceutical composition comprising a compound of Exemplary Embodiment 44, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof, and a pharmaceutically acceptable carrier.
  • Exemplary Embodiment 52 A pharmaceutical composition comprising a compound of Exemplary' Embodiment 45, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, orprodmg thereof, and a pharmaceutically acceptable earner.
  • Exemplary Embodiment 53 A pharmaceutical composition comprising a compound of Exemplary’ Embodiment 46, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrag thereof, and a pharmaceutically acceptable carrier.
  • Exemplary Embodiment 54 A pharmaceutical composition comprising a compound of Exemplary Embodiment 47, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrag thereof, and a pharmaceutically acceptable earner.
  • Exemplary Embodiment 55 A pharmace utical composition comprising a compound of Exemplar ⁇ ' Embodiment 48, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, orprodrug thereof, and a pharmaceutically acceptable carrier.
  • Exemplary Embodiment 56 A pharmaceutical composition comprising a compound of Exemplary Embodiment 49, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, orprodrug thereof, and a pharmaceutically acceptable earner.
  • Exemplary Embodiment 57 A method of treating or preventing an NLRP3 -related disease or disorder, comprising administering to the subject at least one therapeutically effective amount of the compound of Exemplary Embodiment 43, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 58 The method of Exemplary Embodiment 57, wherein the NLRP3 -related disease or drsorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3 -related disease in a subject that lias been determined to cany' a gennline or somatic non-silent mutation in NLRP3.
  • the NLRP3 -related disease or drsorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an
  • Exemplary Embodiment 59 The method of Exemplary’ Embodiment 58, wherein the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-l- yljphenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 60 The method of Exemplary Embodiment 58, wherein the compound is 5-(difluorometbyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4- d]pyridazin-l-yl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 61 The method of Exemplary Embodiment 58, wherein the compound is (R)-5 -chloro-2-(4-((3 ,3 -dimethy Itetrahy dro-2H-pyran-4-y l)amino)py rido [3,4- d]pyridazin-l-yl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 62 Exemplary Embodiment 62.
  • 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-l-yl)-5- methylphenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 64 The method of Exemplary Embodiment 58, wherein the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyI)amino)pyrido[3,4-d]pyridazin-l-yl)-5- (trifhioromethvl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrag thereof.
  • Exemplary Embodiment 65 A method of treating or preventing an NLRP3-related disease or disorder selected from Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache/pain, and traumatic brain injury, said method comprising administe ring to the subject at least one therapeutically effective amount of the compound of Exemplaiy Embodiment 43, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 66 The method of Exemplary' Embodiment 65, wherein the compound is (R)-5 -chloro-2-(4-((4,4-dimethyltetrahydrofuran-3 -yl)amino)pyrido [3 ,4-d]py ridazin- 1 - yljphenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 67 The method of Exemplary Embodiment 65, wherein the compound is 5-(difluoromethyI)-2-(4-((2-(methoxy-d3)-2-metliylpropyl)amiiio)pyrido[3,4- d]pyridazin-l-yl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically’ labeled compound, or prodrag thereof.
  • the compound is 5-(difluoromethyI)-2-(4-((2-(methoxy-d3)-2-metliylpropyl)amiiio)pyrido[3,4- d]pyridazin-l-yl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically’ labeled compound, or prodrag thereof.
  • Exemplary Embodiment 68 The method of Exemplary Embodiment 65, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4- d]pyridazin-l-yl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrag thereof.
  • Exemplary Embodiment 69 The method of Exemplary Embodiment 65, wherein the compound is (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amiBo)pyrido[3,4’ d]pyridazin-l-yl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • 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 ⁇ l-yl) ⁇ 5- methylphenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrug thereof.
  • Exemplary Embodiment 71 The method of Exemplary’ Embodiment 65, wherein the compound is (S)-2-(4-(((4-niethyltnorpholin-2-yl)methyl)amiBo)pyrido[3 s 4-d]pyridazin-l-yl)-5- (trifluorometbyl jpheuol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotopically labeled compound, or prodrag thereof.
  • Exemplary Embodiment 72 A method of treating or preventing an NLRP3 -related disease or disorder selected from Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache/pain, and traumatic brain injury', said method comprising administering to the subject at least one therapeutically effective amount of the pharmaceutical composition of Exemplary' Embodiment 50.
  • Exemplary Embodiment A3 The compound of Exemplary' Embodiment A 1, wherein the compound is 5-(difluoromethylj-2-(4-((2-(methoxy-d3j-2-methyipropyljaminojpyrido[3,4- d]py ridazin- 1 -yljphenol .
  • Exemplary Embodiment A4 The compound of Exemplary' Embodiment A 1 , wherein the compound is (R)-5-chloro-2.-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yljaminojpyrido[3,4- d]py ridazin- 1 -yljphenol.
  • Exemplary Embodiment AS The compound of Exemplary Embodiment Al, wherein the compound is (Sj-5-c perennialo-2-(4-((2,2-dimetiiyltetraiiydro-2H-pyran-4-yl)amino)pyrido[3,4- d]py ridazin- 1 -y Ijphenol.
  • Exemplary Embodiment A7 The compound of Exemplary Embodiment A 1 , wherein the compound is (S)-2-(4-(((4-metiiylmorpho]in-2.-yl)methyl)amino)pyrido[3,4-d]pyridazin-l -yl)-5- (trifluorometbyi)phenol.
  • Exemplary Embodiment A8 A pharmaceutical composition comprising a compound of Exemplar ⁇ ' Embodiment Al, and a pharmaceutically acceptable carrier.
  • Exemplary Embodiment A9 A pharmaceutical composition comprising a compound of Exemplar,' Embodiment A2, and a pharmaceutically acceptable carrier.
  • Exemplary Embodiment Alt A pharmaceutical composition comprising a compound of Exemplary Embodiment A3, and a pharmaceutically acceptable earner.
  • a pharmaceutical composition comprising a compound of Exemplary Embodiment A4, and a pharmaceutically acceptable earner.
  • Exemplary Embodiment A12 A pharmaceutical composition comprising a compound of Exemplaiy Embodiment A5, and a pharmaceutically acceptable carrier.
  • Exemplary Embodiment A13 A pharmaceutical composition comprising a compound of Exemplaiy Embodiment A6, and a pharmaceutically acceptable carrier.
  • Exemplary Embodiment A14 A pharmaceutical composition comprising a compound of Exemplaiy 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 the subject at least one therapeutically effective amount of tiie compound of Exemplary Embodiment Al.
  • Exemplary Embodiment A16 The method of Exemplary Embodiment Al, wherein the NLRP3 -related disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3 -related disease in a subject that lias been determined to cany a gennline or somatic non-silent mutation in NLRP3.
  • the NLRP3 -related disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease,
  • Exemplary Embodiment Al 7 The method of Exemplaiy Embodiment A16, wherein the compound is (R)-5-cMoro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-l- yljphenol.
  • Exemplary Embodiment Al 8. The method of Exemplaiy Embodiment A16, wherein the compound is 5-(difluorometiiyl)-2-(4-((2-(methoxy -d3)-2-methylpropyl)amino)pyrido[3 ,4- d]py ridazin- 1 -y Ijphenol.
  • Exemplary Embodiment A19 The method of Exemplary Embodiment Al 6, wherein the compound is (R)-5-chloro-2-(4-((3,3-dimethyItetrahydro-2H-pyran-4-yl)amino)pyrido[3,4- d]pyridazin-l-yl)phenol.
  • Exemplary Embodiment A20 Exemplary Embodiment A20.
  • Exemplary Embodiment A22 The method of Exemplaiy Embodiment A16, wherein the compound is (S)-2-(4-(((4-methylmorpholin-2-yl)methyI)amino)pyrido[3,4-d]pyridazin-l-yl)-5- (trifluoromethyl)phenol.
  • Exemplary Embodiment A23 A method of treating or preventing an NLRP3 -related disease or disorder selected from Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache/pain, and traumatic brain injury, said method comprising administering to the subject at least one therapeutically effective amount of the compound of Exemplaiy Embodiment Al.
  • Exemplary Embodiment A24 The method of Exemplary Embodiment A23, wherein the compound is (R)-5 -chloro-2-(4-((4,4-dimethyltetrahydrofuran-3 -y l)amino)pyrido [3 ,4-d]pyridazin- 1 - yl)phenol.
  • Exemplary Embodiment A25 The method of Exemplary Embodiment A23, wherein the compound is 5-(difluorornethyl)-2-(4-((2-(rnethoxy-d3)-2-methylpropyl)amino)pyrido[3,4- d]pyridazin- 1 -yljphenol.
  • Exemplary Embodiment A26 The method of Exemplary Embodiment A2.3, wherein the compound is (R)-5 -chloro-2-(4-((3,3 -dimetiiyltetraiiydro-2H-py ran-4-y I)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-pyran-4-yl)amino)pyrido[3,4- d]py ridazin- 1 -v 1) 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-djpyridazin-l-yl)-5- metbylphenol.
  • Exemplary Embodiment A29 The method of Exemplaiy Embodiment A23, wherein the compound is (S)-2.-(4-(((4-methyhnorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-l -yl)-5- (trifluoro methyl )phe nol ,
  • Exemplary Embodiment A30 A method of treating or preventing an NLRP3 -related disease or disorder selected from Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, refractory epilepsy, stroke, ALS, headache/pain, and traumatic brain injury, said method comprising administering to the subject at least one therapeutically effective amount of the pharmaceutical composition of Exemplary' Embodiment A8.
  • neutral (free base) compounds described herein are synthesized and tested in the examples. It is understood that the neutral compounds disclosed herein may be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g. , by saponification of an ester to the carboxylic acid salt, or by hydrolyzing an amide to form a corresponding carboxylic acid and then converting the carboxylic acid to a carboxylic acid salt).
  • LC-MS chromatograms and spectra were recorded using a Sliimadzu LCMS-2020. Injection volumes were 0.7 - 8.0 ul and the flow rates were typically 0.8 or 1.2 ml/min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionization. MS range was 100 - 1000 Da. Solvents were gradients of water and acetonitrile both containing a modifier (typically 0.01 - 0.04 %) such as trifluoroacetic acid or ammonium carbonate.
  • DAD diode array
  • ELSD evaporative light scattering
  • MS range was 100 - 1000 Da.
  • Solvents were gradients of water and acetonitrile both containing a modifier (typically 0.01 - 0.04 %) such as trifluoroacetic acid or ammonium carbonate.
  • Step 1 Synthesis of 1 -chloro-N- (4, 4-dimethyloxolan-3-yl)pyrido [3, 4-d]pyridazin-4-amine and 4 ⁇ :hloro-Nf4,4-dimetiiyloxolan-3-yl)pyrido[3,4-d]pyridazin-l -amine.
  • l,4-dictdoropyrido[3,4-d]pyridazine 250 mg, 1.25 mmol, 1 equiv
  • DMF 3 mL
  • NayCOs 423.91 mg, 4 mmol, 3.2 equiv
  • the final reaction mixture was irradiated with microwave radiation for 40 min at 130°C. After the reaction was completed, the residue was purified by reverse flash chromatography with the following conditions: column, CIS silica gel; mobile phase, acetonitrile (MeCN) in water, 0% to 100% gradient in 30 min; detector, UV 254 nin. The resulting mixture was concentrated under reduced pressure.
  • Step 1 Synthesis of (lS,2S)-2-((l ⁇ (4 ⁇ cMoro-2-methoxyphenyl)pyrido
  • Step 2 Synthesis of l-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol .
  • 4-(4-chloro-2.-methoxybenzoyl)pyridine-3-carboxylic acid 5 g, 17.1 mmol, 1 equiv
  • SOCI2 50 ml
  • the crude product (4g, 90% purity) was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Sliield RP18 OBD Column, 19*250 mm, 10pm; mobile phase, water (10 imnoL'L NH4HCO3) and acetonitrile (MeCN) (hold 39% MeCN in 17 min); Detector, UV 254/220 mn. This resulted in l-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2.0 g, 40.6% yield) as an off- white solid.
  • 2#SHIMADZU HPLC-01
  • Step 3 Synthesis of 4-chloro-l-(4-chloro-2-methoxyphenyl)pyrido[3,4-dJpyridazine.
  • l-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2,5 g, 8,69 mmol, 1 equiv) and POCI3 (40 mL), and pyridine (4 mL).
  • the resulting mixture was stirred for 3h at 100°C.
  • the reaction progress was monitored by LCMS.
  • the reaction was quenched with 500 mL of sodium bicarbonate (aq.
  • Step 4 Synthesis of l-(4-chloro-2-methoxyphenyl)-N-(3,3-dimethyltetrahydro-2H-pyran-4- yl)pyrido[3,4-d]pyridazin-4-amine.
  • 4-chloro- l-(4-chloro-2- methoxyphenyl)pyrido[3,4-d]pyridazine 200 mg, 0.65 mmol, 1 equiv
  • 3,3-dimethyloxan-4-amine 101.28 mg, 7.84 mmol, 1.2 equiv
  • triethylamine 198.32.
  • Step 5 Synthesis of 5-chloro-2-(4- ⁇ [(lS,2S)-2-hydroxycyclopentyl]amino ⁇ pyrido[3,4- djpyridazin- 1 -yl) phenol) (Compound 3A), (S)-5-cMoro-2-(4-((3,3-dimethyltetrcihydro-2H-pyran-4- yl)amino)pyrtdo[3, 4-d]pyridazln-l-yl)phenol (Compound 3 *), and (R)-5-chloro-2-(4-((3,3- dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4 ⁇ l]pyridazin-]-yl) phenol (Compound 35*/ Into a 20 vial were added the reaction mixture from step 4, (ethylsulfanyl)sodium (1054.30 mg, 12.53 m
  • Tire resulting mixture was stirred for 2h at 120°C under nitrogen atmosphere. The reaction progress was monitored by I.. CMS. The resulting mixture was filtered, the filter cake was washed withMeCN (3x5 mL). The fillrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions (column, C18 gel; mobile phase, MeCN in water (lOmmol/L NH4HCO3), 0% to 100% gradient in 30 mm; detector, UV 254 nm), resulting product as an off-white solid.
  • Table A shows the protocol by which the compounds of the instant disclosure were prepared, and Table B provides the NMR data.
  • Step 1 Synthesis of l-bromo-4-(difluoromethoxy)-2-methoxybenzene.
  • 4-bromo-3 -methoxyphenol 5 g, 24.62 mmol, 1 equiv
  • acetonitrile MeCN
  • diethyl bromodifluoromethylphosphonate 13.15 g, 49.25 mmol, 2 equiv
  • KOH 2.76 g, 49.25 mmol, 2 equiv
  • H2O H2O
  • Step 3 Synthesis of 1 -chloro-N-( 5 ,5-dimethyloxolan-3-yl)pyrido [3 ,4-d]pyridazin-4-amine.
  • l,4-dichloropyrido[3,4-d]pyridazine 800 mg, 3.99 mmol, 1 equiv
  • 5,5-dimethyloxolan-3-amine 552.79 mg, 4.79 mmol, 1.2 equiv
  • NajCOs (1270.94 mg, 11.99 mmol, 3 equiv
  • dimethylformamide 10 mL.
  • the final reaction mixture was irradiated with microwave radiation for 30min at 130°C.
  • the reaction was monitored by LCMS.
  • the reaction was repeated for 5 times.
  • the combined resulting mixture was filtered, the filter cake was washed with EtOAc (3x20 mL). The filtrate was concentrated under reduced pressure.
  • Step 4 Synthesis ofi-(4-(difhic ⁇ omethox ⁇ f2-methoxyphenyl)-N-(5,5- dimethyltetrahydrofuran-3-yl)pyrido[3,4-d]pyridazin-4-amine.
  • Step 5 Synthesis of 5-(difluoromethoxy)-2-(4-((5,5-dimethylletrahydrofiiran-3- yl)amino)pyrido[3,4-d]pyridazin-l-yl)phenol.
  • Step 1 Synthesis of 4-(2-methoxy-4-methylbenzoyl)pyridine-3-carboxylic acid. Into a
  • Step 2 Synthesis of l-(2-methoxy-4-methylphenyl)pyrido[3,4-d]pyridazin-4-ol.
  • 4-(2-methoxy-4-methylbenzoyl)pyridine-3-caiboxylic acid (2g, 7.37 mmol, 1 equiv) 4-(2-methoxy-4-methylbenzoyl)pyridine-3-caiboxylic acid (2g, 7.37 mmol, 1 equiv)
  • SOCh 20 mL
  • the resulting mixture was stirred for 2h at 70°C, and tiie reaction was monitored by TLC. After tire reaction was completed, tire resulting mixture was concentrated under vacuum.
  • the crude product (2.0 g, 80% purity) was purified by Prep-HPLC ((Prep-HPLC-059): Column, CHIRAL ART Cellulose-SC, 2*25 cm, 5 um; mobile phase, Hex (0.5% 2M NH 3 -MeOH) and MeOH:DCMM:l (hold 60% MeOH:DCMM:l- in 10 mm);
  • Step 3 Synthesis of 4-(2-methoxy-4-methylbenzoyl)pyridine-3-carboxylic acid.
  • Step 4 Synthesis of N-(6, 6-dimethyloxan-3-yl)-l-(2-methoxy-4-methylphenyl)pyrido[3, 4- d]pyridazin-4-amine.
  • 4-chloro-l-(2-methoxy-4-methylphenyl)pyrido[3,4- djpyridazine 149.6 mg, 0.52.5 mmol, 1 equiv
  • DMSO 4.5 mL
  • 6,6-dimelhyloxan-3- amine 81.39 mg, 0.630 mmol, 1.2 equiv
  • TEA triethylamine
  • Step 1 Synthesis of 4-(4-chloro-2-methoxybenzoyl)pyrldine-3-carboxylic acid.
  • furo[3,4-c]pyridine-l, 3-dione 30.0 g, 201.20 mmol, 1 equiv
  • tetrahydrofuran 300 mL
  • bromo(4-chloro-2 ⁇ methoxyphenyl)magnesium 0.5M in THF
  • the resulting mixture was stirred for 2h at 25°C under nitrogen atmosphere.
  • the reaction progress was monitored by LCMS.
  • Step 2 Synthesis .
  • 4-(4-chIorO"2-methoxybenzoyl)pyridine--3-carboxylic acid 5 g, 17. 1 mmol, 1 equiv
  • SOC1? 50 mLl.
  • the resulting mixture was stirred for 2h at 70°C.
  • the reaction was monitored by TEC. After the reaction was completed, the resulting mixture was concentrated under vacuum.
  • the residue was dissolved in DCM (50 mL) and added into the solution of NH2NH2.H2O (3.43 g, 68.6 mmol, 4 equiv), MeOH (50 mL) at 0°C.
  • Step 3 Synthesis of 4-chloro-l-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine.
  • l-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol 2.5 g, 8.69 mmol, 1 equiv
  • POCI3 40 mL
  • pyridine 4 mL
  • Step; 4 Synthesis l-(4-chloro-2-methoxyphenyl)-N-(3-meth.yltetrahydro-2H-pyran-4- yl)pyrido[3,4-d]pyridazin-4-amine.
  • Step 6 Isolation of cis diastereomers: 5-chloro-2-(4-(((3R,4R)-3-methyltetrahydro-2H-pyran- 4-yl)amino)pyrido[3,4-dJpyridazin-l-yl)phenol (Compound 18*), 5-chloro-2-(4- ⁇ 3-methyloxan-4- yl]amino ⁇ pyrido[3,4-d]pyridazin-l-yl)phenol (Compound 18 ’*) and 5-chloro-2-(4-(((3S,4S)-3- methyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-dlpyridazin-l-yl) phenol (Compound I8D*).
  • Step 2 The stereoisomeric mixture from Step 1 was purified by Chiral-HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 tun; Mobile Phase A: hexanes (0.5% 2M NH3 in methanol), Mobile Phase B: isopropanol/dichloromethane (1:1); Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 14.5 min; Wave Length: 254/220 nm; RTl(min) ((R)-l-chloro-N-(5,5- dimethyltetrahydrofuran-3-yl)pyrido[3,4 ⁇ d]pyridazin-4-amine): 4.81; RT2(min): 11.33 (S)-l-chloro- N-(5,5-dimethyltetrahydrofuran-3-yl)pyrido[3,4-d]pyridazin-4-amine; Sample Solvent: methanol/
  • Step 3 Into a 20 nil. vial was added 2-bnorao-3,5-dimethylphenol (600 mg, 2.98 mmol, 1 equiv) and dioxane (6 mL), triethylamine (905.92 mg, 8.95 mmol, 3 equiv), and 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (1909.55 mg, 14.92 mmol, 5 equiv). The resulting mixture was stirred for 30 min al room temperature under mirogen atmosphere.
  • Step 4 Into a 8 mL vial were added 2-bydroxy-4,6-dimethylphenylboronic acid (2.14.37 mg, 1 .29 mmol, 3 equiv) and Intermediate A* (120 mg, 0.43 mmol, 1 equiv), water (0.2. mL), Naj.COs (138.19 mg, 1,29 mmol, 3 equiv), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)C12 CH2Q2) (94.50 mg, 0.12 mmol, 0.3 equiv), and dioxane (1 mL).
  • 2-bydroxy-4,6-dimethylphenylboronic acid (2.14.37 mg, 1 .29 mmol, 3 equiv) and Intermediate A* (120 mg, 0.43 mmol, 1 equiv), water (0.2. m
  • Step 5 Into a 8 mL vial was added 2-hydroxy-4,6-dunethylphenylboronic acid (214.37 mg, 1.29 mmol, 3 equiv), Intermediate B* (120 mg, 0.43 mmol, 1 equiv), water (0.2 mL), NaiCOj (138.19 mg, 1.29 mmol, 3 equiv), [l,r-bis(diphenylphospliino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Ch CH2CI2) (94.50 mg, 0.12 mmol, 0.3 equiv), and dioxane (1 mL).
  • Example 10 follows Protocol B.
  • Step 1 Into a 250 mL 3-necked round-bottom flask were added furo[3,4-c]pyridme-l, 3-dione (3 g, 20.12 mmol, 1 eqniv), tetrahydrofuran (THF) (30 mL), and bromo(4-chloro-2- metlioxyphenyl)magnesium (0.5 mol/L) (24.16 mL, 12.07 mmol, 0.6 eqniv) at -78°C. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction progress was monitored by LCMS.
  • Step 2 Into a 250mL round-bottom flask were added 4-(4-chloro-2- methoxybenzoyl)pyridine-3-carboxylic acid (2.5 g, 8.56 mmol, 1 eqniv) and SOCh (25 mLl.The resulting mixture was stirred for 2h at 70°C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was dissolved in dichlorometbane (DCM) (30 mL) and added into the solution of NH2NH2.H2O (80%) (2.39 g, 34.24 mmol, 4 equiv) in methanol (MeOH) (50 mL) at 0°C.
  • DCM dichlorometbane
  • MeOH methanol
  • Step 3 Into a 250mL round-bottom flask were added l-(4-chloro-2- methoxyphenyl)pyrido[3,4-d]pyridazin-4"Ol (1.2 g, 4.16 mmol, 1 equiv) and POCL (25 ml.), and pyridine (2.5 mL). The resulting mixture was stirred for 2h at 110°C. The reaction progress was monitored by LCMS. The resulting mixture was diluted with ethyl acetate (EtOAc) (20mL). The resulting mixture was poured into the mixture of EtOAc (IL) and sat. sodium bicarbonate (aq.)(lL) slowly at 0°C.
  • EtOAc ethyl acetate
  • Step 4 Into a 20 mL sealed tube were added 4-chloro-l-(4-chloro-2- methoxyphenyl)pyrido[3,4-d]pyridazine (200 mg, 0.65 mmol, 1 equiv), 2-methyloxan-4-amine (150.48 mg, 1.30 mmol, 2 equiv), triethylamine (198.32 mg, 1.95 mmol, 3 equiv) andDMSO (6 mL) at room temperature. The resulting mixture was stirred for 12 h at 80°C under air atmosphere. The reaction was monitored by LCMS.
  • Step 5 Sodium ethanethiolate (EtSNa) (654.78 mg, 7.80 mmol, 15 equiv) was added directly into the reaction solution from Step 4. The resulting mixture was stirred for Ih at 120°C under air atmosphere. The reaction was monitored by LCMS.
  • EtSNa Sodium ethanethiolate
  • the residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 15% to 18% gradient in 15 min; detector, UV 254 nm and 220 nm, to provide a mixture of cis and trans isomers of 5-cliloro-2 ⁇ 4 ⁇ [(2-methyloxan-4-yl)amino]pyrido[3,4-d]pyridazin ⁇ l -yljphenol (150 mg, 78% yield).
  • the crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5pm; Mobile Phase A: Water (0.05% trifluoroacetic acid), Mobile Phase B: methanol; Flow' rate: 20 mL/min; Gradient: 40% B to 45% B in 8 min; Wave Length: 254 nm; RTl(min): 10) to afford 5-chloro-2- ⁇ 4-[(2-metbyloxan- 4-yl)amino]pyrido[3,4-d]pyridazin-l -yljphenol as a mixture of cis and trans isomers ( 120 mg, 99% purity).
  • Step 6 The mixture of isomers of 5-chloro-2- ⁇ 4-[(2-methyloxan-4-yl)amino]pyrido[3,4- d]pyridazin-l-yl ⁇ phenol (120 mg) was purified by Prep-Chiral HPLC with the following conditions (Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: hexanes (0.2% formic acid).
  • Step 7 The mixture of Compounds 25A* and 25B* (55 mg) was purified by Prep-Chiral HPLC with the following conditions (Column: CHIRALPAK IE, 2*25 cm, 5 pm Mobile Phase A: hexanes (0.2% formic acid), Mobile Phase B: ethanol; Flow rate: 20 mL/min; Gradient: 35% B to 35% B in 16.5 min; Wave Length: 254/220 nm; RTl(min): 1.179 (Compound 25A*); RT2(min): 4.19 (Compound 25B*); Sample Solvent: methanol; Injection Volume: 0.6 mL) to afford to Compound 25A* (14,7 mg, 98% purity) and Compound 25B* (15.5 mg, 99% purity); stereochemistry arbitrarily assigned.
  • Step 2 In a 100-mL three-round bottom flask, to a solution of l-chloro-3-methoxy-5- methylbenzene (3 g, 19.16 mmol, 1 equiv) in tetrahydrofuran (THE) (5 mL) was added t-butyllithium solution (1.6 M in hexane, 20 mL, 1.7 equiv) by dropwise at -78°C under N 2 atmosphere. The reaction mixture was stirred at -78 °C for 1 h.
  • TEE tetrahydrofuran
  • Step 3 Into a 8mL vial were added 2"CldorO“6-methoxy-4-metIiylphenylboronic acid (287.60 mg, 1.40 mmol, 4 equiv), dioxane (1.5 mL), II 2 O (0.3 mL), Intermediate A* from Example 9 (100 mg, 0.36 mmol, 1 equiv), NajCOs (114.06 mg, 1.08 mmol, 3 equiv) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(Il), complex with dichloromethane (Pd(dppf) 2 Cl 2 CH2O2) (79.2 mg, 0.11 mmol, 0.3 equiv) at room temperature.
  • Pd(dppf) 2 Cl 2 CH2O2 dichloromethane
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, 10% to 40% gradient in 10 min; detector, UV 254/220 nm, to provide a erode product (70 mg, 90% purity), which was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 19*250 mm, 5pm; Mobile Phase A: Water (0.05% trifluoroacetic acid), Mobile Phase B: acetonitrile; Flow rate: 20 mL/min; Gradient: 20% B to 25% B in 8 min; Wave Length: 254 nm; RTl(min): 8 min; to provide Compound 26A* (25 mg, 25% yield).
  • Step 6 Into a 8mL vial was added l-(2-chloro-6"methoxy"4-methylphenyl)-N-[(3S)-5,5" dimethyloxolan-3-ylJpyrido [3,4-d]pyridazin-4-amine (80 mg, 0,20 mmol, 1 equiv), dimethyl formamide (DMF) (1 mL) and (ethylsulfanyl)sodium (168.69 mg, 2,01 mmol, 10 equiv) at room temperature. The resulting mixture was stirred for 2 h at 120°C. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with DMF (4rnL).
  • DMF dimethyl formamide
  • the filtrate was concentrated under reduced pressure.
  • the filtrate was purified by Prep- HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Prep Phenyl OBD Column, 19*250 mm, 5pm; mobile phase, water (10 mmoI/L NH4HCO3) and acetonitrile (30% up to 40% in 10 min); Detector, UV 220/254 nm, to provide Compound 26B* (20 mg, 20% yield).
  • Heparin lithium coated tubes were used to collect blood from volunteers. Blood samples were distributed on 96 well plates using 90 pl per well. Priming was performed by adding 5 ui of LPS (O26:B6; Sigma L-2654) at a final concentration of 1 pg/ml for 4.5 hours in a humidified incubator with 37 °C, 5 % CO2. Thirty minutes prior to NLRP3 activation, 5 pl of a 20X compound solution or vehicle (2% DMSO) was added to each well and plates were incubated on a shaker (450 rpm) in a humidified incubator with 37 °C, 5 % CO2. Activation was then performed by adding 3.3 ul of a 3 IX ATP solution per well.
  • the plates were centrifuged (800 g, 10 min, room temperature) and the plasma from each well was frozen at -80 °C.
  • IL- Ip levels in the supernatant were analyzed using a mesoscale discovery assay (MSD K151TUK) according to the manufacturers’ instructions. Human whole blood was drawn from healthy volunteers after obtaining written informed consent.
  • brain samples were homogenized with PBS by tissue weight (g) to PBS volume (mL) ratio 1 :3.
  • Plasma and brain drug levels were quantified by LC/MS/MS on a AB Sciex Triple Quad 5500-1- instrument, after separation on a HALO 160AES-C18, 2.7 pm 2.1x50mm column.
  • Quantitation was performed using a calibration curve prepared in blank plasma or blank brain homogenate.
  • the software WinNonlin (PhoenixTM) was used for pharmacokinetic analysis from the concentrations versus time date, including the AUCM and AUCi 6S t.
  • the Kp ratio total brain concentration over total plasma concentration was calculated as (AUCtot,br)/(AUC t ot,pi).
  • Kp uu is the free brain/free plasma concentration ratio (C,., Bf /C u ,pi).
  • the C u wCu, Pi ratios were obtained from in vivo total brain to plasma ratios (C tot/bi/C tot, pl) by using in vitro determined F u>b r and F u.pl .
  • Plasma protein binding and brain homogenate protein binding were measured by equilibrium dialysis in a HTDialysis plate.
  • the dialysis membranes were soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in dialysis buffer for 20 minutes.
  • the dialysis set up was assembled according to the manufacturer’s instruction.
  • Each cell received 150 pL of plasma orbrain homogenate spiked with 1 mM of compound, and dialyzed against an equal volume of dialysis buffer (PBS).
  • PBS dialysis buffer
  • the dialysis plate was sealed and incubated in an incubator at 37°C with 5% CO2 at 100 rpm for 6 hours.
  • Table D assigns each compound a code for potency in the human whole blood (hWB) NLRP3
  • Assay A or B, According to the code, zk represents an IC50 value ⁇ 1.0 pM; B represents an IC% value >1.0 pM. The corresponding raw activity data is also included.
  • A represents a value of >0.3
  • B represents a value of ⁇ 0.3.
  • the kp values were calculated by measuring whole brain drug levels over 24h (AUC) in mice dosed at 20 mpk PO, and dividing by plasma AU C. The kpu,u was then calculated upon correcting this kp value with mouse plasma protein binding and mouse brain homogenates binding.
  • a Kpu,u value >0.3 is brain penetrant
  • Kpu,u value less than or equal to 0.3 is not brain penetrant.
  • N.D. not determined.
  • the corresponding raw kp and kpu,u data is also included.
  • the compounds described in the present disclosure are useful for the treatment of NLRP3 proteins -mediated diseases and/or disorders and are structurally related to compounds previously disclosed in US Patent Application No. 17/528,928 as inhibitors of the same NLRP3 proteins.
  • the brain levels of these active pliarmaceutical ingredients were unexpected, and hence not contemplated in the US 17/528,928 application.
  • tire unanticipated ability of the instant compounds 1*, 2*, 3*, 4*, 5, and 6 to penetrate the brain blood barrier constitutes a novel invention.
  • [ 1)633] Furthermore, as shown in the above Table D, it is not obvious that inhibitors of NLPR3 proteins described in US Application No. 17/528,928 exhibit this unpredicted activity.
  • NLPR3 inhibitors of the instant disclosure were found to exhibit more potent brain-penetrant properties in a head-to-head comparison with compounds of the USSN 17/528,928 application similar in NLPR3 inhibitory activity in the blood as illustrated in Table D.
  • Compounds 1 *, 2, 3*, 4*, 5, and 6 of the present disclosure exhibit unexpected “A” brain levels compared to Compound 7* (Comparative Example 1, Compound 89 of USSN 17/528,928) and Compound 8 (Comparative Example 2, Compound 96 of USSN 17/528,928), each of which exhibit “B” brain levels and are not brain penetrant, thereby making the compounds of the instant application more available to treatment of NLPR3-mediated CNS diseases.
  • solubility of compounds of Formula (I) may be improved by replacing an R 3 halogen moiety, such as a chloro group, with an Ci-C 6 alkyl or Cs-Cs alkoxy group (wherein alkyl or alk- is independently substituted with 0, 1, 2, or 3 halogen atoms) while still maintaining a Kpu,u of greater than 0.3.
  • R 3 halogen moiety such as a chloro group
  • Ci-C 6 alkyl or Cs-Cs alkoxy group wherein alkyl or alk- is independently substituted with 0, 1, 2, or 3 halogen atoms
  • Example 3 Compounds which are not brain penetrant but with improved properties, such as solubility, may be useful in the treatment of systemic (non-CNS) NLPR3 -mediated diseases.

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Abstract

La présente invention concerne des inhibiteurs de NLRP3 de formule (I), ou un sel pharmaceutiquement acceptable, un solvate, un clathrate, un hydrate, un stéréoisomère, un tautomère, un composé marqué isotopiquement ou un promédicament de ceux-ci, le cycle A étant un hétérocycloalkyle monocyclique de 5 à 8 chaînons comprenant au moins un atome de cycle O, p étant 0 ou 1, et R1, R2, R3, R4 et X étant tels que définis dans la description, utiles dans le traitement de maladies et de troubles inhibés par ladite protéine.
PCT/US2023/064967 2022-03-25 2023-03-24 Dérivés de pyrido-[3,4-d]pyridazine-amine utiles en tant que dérivés de nlrp3 Ceased WO2023183943A1 (fr)

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CN202380037553.1A CN119137121A (zh) 2022-03-25 2023-03-24 可用作NLRP3衍生物的吡啶并-[3,4-d]哒嗪胺衍生物
IL315842A IL315842A (en) 2022-03-25 2023-03-24 Pyrido-[4,3-D]pyridazine amine derivatives are useful as NLRP3 derivatives
EP23722227.8A EP4499638A1 (fr) 2022-03-25 2023-03-24 Dérivés de pyrido-[3,4-d]pyridazine-amine utiles en tant que dérivés de nlrp3
PE2024002059A PE20250605A1 (es) 2022-03-25 2023-03-24 Derivados de pirido-[3,4-d]piridazina amina utiles como derivados de nlrp3
AU2023238121A AU2023238121A1 (en) 2022-03-25 2023-03-24 Pyrido-[3,4-d]pyridazine amine derivatives useful as nlrp3 derivatives
CA3246681A CA3246681A1 (fr) 2022-03-25 2023-03-24 Dérivés d’amine de pyrido-[3,4-d]pyridazine utiles en tant que dérivés de nlrp3
JP2025502799A JP2025510414A (ja) 2022-03-25 2023-03-24 ＮＬＲＰ３誘導体として有用なピリド－［３，４－ｄ］ピリダジンアミン誘導体
KR1020247034096A KR20250005125A (ko) 2022-03-25 2023-03-24 NLRP3 유도체로서 유용한 피리도-[3,4-d]피리다진 아민 유도체
US18/190,920 US12331048B2 (en) 2022-10-31 2023-03-27 Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US18/763,277 US12312351B2 (en) 2022-10-31 2024-07-03 Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US18/785,350 US12398136B2 (en) 2022-10-31 2024-07-26 Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US18/799,636 US20240409540A1 (en) 2022-10-31 2024-08-09 PYRIDO-[3,4-d]PYRIDAZINE AMINE DERIVATIVES USEFUL AS NLRP3 INHIBITORS
MX2024011697A MX2024011697A (es) 2022-03-25 2024-09-24 Derivados de pirido-[3,4-d]piridazina amina utiles como derivados de proteinas que contienen el dominio de pirina de la familia de los receptores similares al dominio de oligomerizacion de union a nucleotido 3 (nlrp3)
CONC2024/0013702A CO2024013702A2 (es) 2022-03-25 2024-10-10 Derivados de pirido-[3,4-d]piridazina amina útiles como derivados de nlrp3

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US20240383896A1 (en) * 2022-10-31 2024-11-21 Ventus Therapeutics U.S., Inc. PYRIDO-[3,4-d]PYRIDAZINE AMINE DERIVATIVES USEFUL AS NLRP3 INHIBITORS
US12168657B2 (en) 2022-03-25 2024-12-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
WO2025059481A1 (fr) 2023-09-13 2025-03-20 Ventus Therapeutics U.S., Inc. Formes solides d'un inhibiteur de nlrp3 et leurs utilisations
US12281112B2 (en) 2021-04-07 2025-04-22 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
WO2025153532A1 (fr) 2024-01-16 2025-07-24 NodThera Limited Polythérapies faisant intervenir des inhibiteurs de nlrp3 et des agonistes de glp-1
US12421209B2 (en) 2021-06-04 2025-09-23 Hoffmann-La Roche Inc. Compounds

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WO2023028534A1 (fr) * 2021-08-25 2023-03-02 Ptc Therapeutics, Inc. Inhibiteurs de nlrp3
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WO2022216971A1 (fr) * 2021-04-07 2022-10-13 Ventus Therapeutics U.S., Inc. Composés de pyridazine pour inhiber nlrp3
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US11618751B1 (en) * 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives

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US12351578B2 (en) 2021-04-07 2025-07-08 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US12281112B2 (en) 2021-04-07 2025-04-22 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US12441728B2 (en) 2021-04-07 2025-10-14 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting NLRP3
US12312350B2 (en) 2021-04-07 2025-05-27 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US12410167B2 (en) 2021-04-07 2025-09-09 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting NLRP3
US12421209B2 (en) 2021-06-04 2025-09-23 Hoffmann-La Roche Inc. Compounds
US12168657B2 (en) 2022-03-25 2024-12-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
US12195460B2 (en) 2022-03-25 2025-01-14 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US12331048B2 (en) 2022-10-31 2025-06-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US20240383896A1 (en) * 2022-10-31 2024-11-21 Ventus Therapeutics U.S., Inc. PYRIDO-[3,4-d]PYRIDAZINE AMINE DERIVATIVES USEFUL AS NLRP3 INHIBITORS
US12312351B2 (en) 2022-10-31 2025-05-27 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US12398136B2 (en) * 2022-10-31 2025-08-26 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
WO2024140824A1 (fr) * 2022-12-28 2024-07-04 长春金赛药业有限责任公司 Composé inhibiteur de pyridazine nlrp3, composition pharmaceutique, procédé de préparation correspondant et utilisation associée
WO2025059481A1 (fr) 2023-09-13 2025-03-20 Ventus Therapeutics U.S., Inc. Formes solides d'un inhibiteur de nlrp3 et leurs utilisations
WO2025153532A1 (fr) 2024-01-16 2025-07-24 NodThera Limited Polythérapies faisant intervenir des inhibiteurs de nlrp3 et des agonistes de glp-1

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