NLRP3 inflammasome inhibitors

Abstract

The present invention relates to compounds that inhibit NOD-like receptor protein 3 (NLRP3) inflammasome activity, the compounds being represented by formula (I): 1 , R 2 , R 3 , R 4 , and R 5 The present invention relates to novel pyridazin-3-ylphenol compounds of the formula (I), as defined herein. The present invention further relates to processes for their preparation, pharmaceutical compositions and medicaments containing them, and their use in the treatment of diseases and disorders mediated by NLRP3. [Formula 1] JPEG2025525866000053.jpg21170

Description

[Technical Field]

[0001] The present invention relates to a novel pyridazine-3-ylphenol compound useful as an inhibitor of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The present invention also relates to a process for preparing the compound, a pharmaceutical composition comprising the compound, and a method for using the compound in the treatment and diagnosis of various diseases and disorders mediated by NLRP3. [Background technology]

[0002] NOD-like receptor protein 3 (NLRP3) is a protein-coding gene. This protein belongs to the family of nucleotide-binding multimeric domain-like receptors (NLRs) and is also known as "pyrin domain-containing protein 3" (Inoue et al., Immunology, 2013, 139, 11-18). This gene encodes a protein containing a pyrin domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif. In response to sterile inflammatory danger signals, NLRP3 interacts with the adapter proteins apoptosis-associated speck-like protein (ASC) and procaspase-1 to form the NLRP3 inflammasome. NLRP3 inflammasome activation then leads to the release of inflammatory cytokines IL-1β (interleukin-1β) and IL-18 (interleukin-18), which, when dysregulated, can cause abnormalities in many disease situations.

[0003] NLRP3 inflammasome activation typically requires two steps. The first step involves the recognition of a pathogen-activating molecular pattern (PAMP) or danger-activating molecular pattern (DAMP) by a Toll-like receptor, leading to the activation of nuclear factor kappa B (NF-κB)-mediated signaling, which then accompanies a priming signal that upregulates the transcription of inflammasome-related components, including inactive NLRP3 and pro-IL-1β (prointerleukin-1β) (Bauernfeind et al J.Immunol.2009,183,787-791; Franchi et al Nat.Immunol.2012,13,325-332; Franchi et al J.Immunol.2014,193,4214-4222). The second step involves the oligomerization of NLRP3 and subsequent assembly of NLRP3, ASC, and procaspase-1 into the inflammasome complex. This triggers the conversion of procaspase-1 to caspase-1, as well as the production and secretion of mature IL-1β and IL-18 (Kim et al J.Inflamm.2015,12,41; Ozaki et al J.Inflamm.Res.2015,8,15-27; Rabeony et al.Eur.J.Immunol.2015,45,2847-2857).

[0004] NLRP3 inflammasome activation is associated with various inflammasome-related diseases / disorders, immune disorders, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases, such as autoinflammatory fever syndromes like cryopyrin-associated periodic syndromes (CAPS) (Mortimer et al Nature Immunol. 2016, 17(10), 1176-1188); sickle cell disease; systemic lupus erythematosus (SLE); and liver-related diseases / disorders such as chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease (Petrasek et al J. Clin. Invest. 2012, 122, 3476-89; Petrasek et al. Nat. Rev. Gastroenterol. Hepatol. 2015, 12, 387-400; Mridha et al J.Hepatol.2017,66,1037-46); diseases associated with inflammatory arthritis such as gout, pseudogout (chondrocalcification), osteoarthritis (Ridker et al N.Engl.J.Med.2017,377,1119-31) and rheumatoid arthritis (Mathews et al Ann.Rheum.Dis.2014,73,1202-10), acute or chronic arthropathy; hyperoxaluria (Knauf et al.Kidney Int.2013,84,895-901), lupus nephritis, hypertensive nephropathy (Krishnan et al It has been associated with inflammation associated with hemodialysis and kidney-related diseases such as diabetic nephropathy, a kidney-related complication of diabetes (type 1, type 2, and diabetes mellitus), also known as diabetic nephropathy (Shahzad et al Kidney Int. 2015, 87, 74-84).New research suggests that increased production of IL-1β and IL-18 by the NLRP3 inflammasome is involved in neuroinflammation-related disorders, e.g., brain infections, acute injuries, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases (Shao et al. Front.Pharmacol.2015,6,262); cardiovascular / metabolic disorders / diseases, e.g., reduced cardiovascular risk (CvRR), atherosclerosis, type 1 and type 2 diabetes and related complications (e.g., nephropathy, retinopathy), peripheral artery disease (PAD), acute heart failure and hypertension (Ridker et al N.Engl.J.Med.2017,377,1119-31; Vandanmasgar et al.Nat.Med.2011,17,179-88; Hu et al Proc.Natl.Acad.Sci.2015,112,11318-23; Antonopoulos et al Curr.Opin.Pharmacol.2017,39,1-8;Toldo S et al Nat.Rev.Cardiol.2018,15,203-214);wound healing and scar formation;inflammatory skin diseases, e.g., acne, sweat gland abscess (Sweeney et al Br.J.Dermatol.2015,173,1361), asthma, sarcoidosis, age-related macular degeneration;cancer-related diseases / disorders, e.g., myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis, lung cancer, colon cancer (Ridker et al Lancet 2017,390,1833-42;Derangere et al Cell.Death Differ.2014,21,1914-24,Gelfo et al Oncotarget 2016,7,72167-83,Baiorka et al Blood It has been shown that it can be a contributing factor to the onset and progression of various diseases, such as those described in 2016, 128, 2960-75; Carey et al Cell. Rep. 2017, 18, 3204-18). These diseases / disorders, which are either immune or inflammatory, are by their nature usually difficult to diagnose or treat effectively. Most treatments involve treating symptoms, slowing the progression of the disease / disorder, lifestyle changes, and surgery as a last resort (e.g., open-heart surgery for the progressive form of atherosclerosis).Recent studies have linked mitochondrial dysfunction and NLRP3 activation in neuroinflammatory diseases such as Parkinson's disease (Sarkar et al npj Parkinson's disease 2017,3:30; Zhou et al Nature,2011,469,221). One of the main problems associated with mitochondrial modifiers is their poor metabolic stability. Therefore, selective and stable inhibitors are needed in neuroinflammatory diseases of this nature (Lee et al Eur J.Org.Chem.2017,141,240).

[0005] Therefore, inhibitors of the NLRP3 inflammasome pathway are needed to provide novel and / or alternative treatments for these inflammasome-related diseases / disorders as well as others such as autoinflammatory fever syndromes, cryopyrin-associated periodic syndromes (e.g., CAPS), sickle cell disease, chronic liver disease, non-alcoholic steatohepatitis (NASH), gout, hyperoxaluria, secondary hyperoxaluria, pseudogout (chondrocalcification), type 1 / type 2 diabetes and associated complications (e.g., nephropathy, retinopathy), neuroinflammation-related disorders (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), hidradenitis suppurativa, wound healing and scarring, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0006] International Publication No. 2020 / 234715 describes pyridazine-3-ylphenol compounds as NLRP3 inflammasome inhibitors. International Publication No. 2022 / 135567 describes pyridazine-containing compounds as NLRP3 inflammasome inhibitors. International Publication No. 2022 / 166890 describes substituted pyridazinephenol derivatives as NLRP3 inflammasome inhibitors. [Overview of the Initiative] [Means for solving the problem]

[0007] The present invention provides a compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and combinations thereof, which compound inhibits the NLRP3 inflammasome pathway. The present invention further provides a method for treating, diagnosing, or preventing a disease and / or disorder associated with NLRP3, the method comprising administering to a subject in need thereof an effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0008] Various embodiments of the present invention are described herein.

[0009] In a first aspect, the present invention relates to a compound of formula (I):

Chemical formula

[0010] In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I) disclosed herein, or a partial formula or species thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is useful for the treatment of diseases and / or disorders related to NLRP3 activity.

[0011] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) disclosed herein, or a subformula or species thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is useful for the treatment of diseases and / or disorders related to NLRP3 activity.

[0012] In another aspect, the present invention provides a combination, particularly a combination of pharmaceuticals, comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof that conforms to the definition of formula (I) or a subformula or species thereof as disclosed herein, and one or more therapeutic agents.

[0013] In another aspect, the present invention provides combinations disclosed herein, particularly combinations of pharmaceuticals, for use as pharmaceuticals.

[0014] In another aspect, the present invention provides compounds of formula (I) disclosed herein, or a subformula or species thereof, or pharmaceutically acceptable salts thereof, for use in the treatment of a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of said disease or disorder.

[0015] In another aspect, the present invention provides a method for treating a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of the disease or disorder, comprising administering a therapeutically effective amount of a compound of formula (I) or a subformula or species thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein.

[0016] In another embodiment, the present invention provides a method for inhibiting NLRP3 inflammasome activity in a subject requiring such activity, comprising administering a therapeutically effective amount of a compound of formula (I) disclosed herein, a partial formula or species thereof, or a pharmaceutically acceptable salt thereof, to the subject requiring such activity.

[0017] In another aspect, the present invention relates to the use of compounds of formula (I) or a subformula thereof disclosed herein, or pharmaceutically acceptable salts thereof, as pharmaceuticals.

[0018] In another aspect, the present invention relates to compounds of formula (I) or a subformula thereof disclosed herein, or pharmaceutically acceptable salts thereof, for use as pharmaceuticals.

[0019] In another aspect, the present invention provides compounds of formula (I) or a subformula thereof disclosed herein, or pharmaceutically acceptable salts thereof, for use in the treatment of diseases or disorders selected from inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases.

[0020] In another aspect, the present invention provides compounds of formula (I) disclosed herein, or a subformula or species thereof, or pharmaceutically acceptable salts thereof, for use in the manufacture of pharmaceuticals intended for the treatment of diseases or disorders selected from inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases.

[0021] In another aspect, the present invention provides radioactive compounds of formula (I), or pharmaceutically acceptable salts thereof, preparations thereof, and the use thereof as radioactive tracers / markers for imaging techniques and diagnostic tools for diseases and / or disorders associated with NLRP3, such as those defined herein. [Modes for carrying out the invention]

[0022] The present invention therefore relates to formula (I): [ka] (In the formula, R 1 is Cl, CH3, -OCF3, or CF3; R 2 is a halo, C1-C4 alkyl, or halo-C1-C4 alkyl; R 3 is H, CN, C1-C4 alkyl, or halo-C1-C4 alkyl; R 4 is, -(CH2) n -OH, where n is 1, 2, 3, or 4; R 5 It is a monocyclic or bicyclic heterocycline that is unsubstituted or substituted with one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halo, oxo, and -CO2H; or R 5is either unsubstituted or an aryl or heteroaryl substituted with one or two substituents independently selected from halo, haloC1-C4alkyl, C1-C4alkyl, and -SO2NH2; or R 5 is either unsubstituted or a C3-C6 cycloalkyl group substituted with 1-3 substituents independently selected from C1-C4 alkyl, halo, halo-C1-C4 alkyl, and -OH; or R 5 (This is a C2-C6 alkyl group substituted with one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2.) The present invention provides compounds of the same, or pharmaceutically acceptable salts thereof.

[0023] definition For the purposes of interpreting this specification, unless otherwise specified, the following definitions shall apply, and where appropriate, a singular term shall also include its plural form, and vice versa.

[0024] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the,” as well as similar terms, used in connection with the present invention (particularly in connection with the claims), should be interpreted as encompassing both singular and plural referents unless the context clearly indicates or negates them. For example, a reference to “compound” includes a reference to one or more compounds.

[0025] As used herein, the term "C1-C4 alkyl" refers to a linear or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having 1 to 4 carbon atoms, and bonded to the rest of the molecule by single bonds. Examples of C1-C4 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), and n-butyl.

[0026] As used herein, the terms "halogen" or "halo" refer to bromo, chloro, or iodine.

[0027] As used herein, the terms “halo C1-C4 alkyl” or “halogen C1-C4 alkyl” refer to the C1-C4 alkyl radical as defined above, which is substituted with one or more halo radicals. Examples of halo C1-C4 alkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutan-2-yl.

[0028] As used herein, the term "C1-C4 alkoxy" refers to the formula -OR a It refers to the radical of R a These are C1-C4 alkyl radicals, as generally defined above. Examples of "C1-C4 alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy.

[0029] As used herein, the term “C1-C4 haloalkoxy” refers to the radical “C1-C4 alkoxy” as defined above, which is substituted by one or more halo radicals as defined above. Examples of halo-C1-C4 alkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, and trichloromethoxy.

[0030] As used herein, the term "hydroxy C1-C4 alkyl" refers to a C1-C4 alkyl radical in which one of the hydrogen atoms of the C1-C4 alkyl radical is substituted with an OH group. Examples of hydroxy C1-C4 alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, and 4-hydroxybutyl.

[0031] As used herein, the term "oxo" refers to an oxygen substituent, such as oxygen linked by a double bond (e.g., forming a ketone).

[0032] As used herein, the terms “heterocyclyl” or “heterocyclic” refer to a stable 5- or 6-membered non-aromatic monocyclic, bicyclic, or polycyclic ring radical having 3 to 24, preferably 4 to 16, most preferably 5 to 10 ring atoms, where one or more, preferably 1 to 4, particularly one or two ring atoms are heteroatoms selected from, for example, oxygen, sulfur, and nitrogen (the remaining ring atoms are therefore carbon). The term heterocyclyl excludes heteroaryls. The heterocyclic group can be attached to the rest of the molecule through heteroatoms or carbon atoms selected from, for example, oxygen, sulfur, and nitrogen. Heterocyclyls can include, for example, fused or bridging rings and spiro rings. For example, the term “heterocyclyl” can refer to a 5- to 7 monocyclic ring containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur. Examples of monoheterocyclils include dihydrofuranil, dioxolanil, dioxanil, dithianil, piperazinil, pyrrolidine, dihydropyranil, oxathiolanil, dithiolane, oxathianil, thiomorpholino, oxyranil, azilidinil, oxetanil, oxepanil, azetidinil, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidine, tetrahydropyranil, piperidinil, morpholino, piperazinil, oxapinil, oxazepanil, oxathianil, thiepanil, azepanil, dioxepanil, and diazepanil. Preferably, the monoheterocyclil is morpholino, pyrrolidine, or piperidinil. Examples of bicyclic heterocyclils include, for example, azabicyclooctanil or octahydroindolidine. In this invention, the term "heterocyclyl" substituted with an "OH" substituent also includes "heterocyclyls" in which a heteroatom, for example N or S, is oxidized to obtain, for example, heterocyclyl N-oxide, heterocyclyl S-oxide, or heterocyclyl S-dioxide. Examples of heterocyclyl N-oxides include piperidinyl N-oxide and 1-methylpyrrolidine 1-oxide.Examples of heterocyclyl S-oxides or heterocyclyl S-dioxides include tetrahydro-2H-thiopyran-1-oxide, tetrahydro-2H-thiopyran-1,1-dioxide, and tetrahydrothiophene-1-oxide.

[0033] As used herein, the term “aryl” refers to an aromatic hydrocarbon group having 6 to 20 carbon atoms in the ring portion. Typically, aryls are monocyclic, bicyclic, or tricyclic aryls having 6 to 20 carbon atoms. In preferred embodiments, the aryl is phenyl.

[0034] As used herein, the term “heteroaryl” refers to a five-membered or six-membered aromatic monocyclic ring radical containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur. Heteroaryl radicals may be bonded via carbon atoms or heteroatoms. Examples of heteroaryls include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridadinyl, pyrimidyl, or pyridyl.

[0035] As used herein, the term "C3-C6 cycloalkyl" refers to a stable monocyclic saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms and having 3 to 6 carbocyclic atoms. Examples of monocyclic C3-C6 cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferably, the "C3-C6 cycloalkyl" is cyclopropyl or cyclobutyl.

[0036] Unless otherwise specified, the term “(the) compound of the present invention” means compounds of formula (I) and its subformulas (such as the compounds of formula (II), formula (II-A), formula (III), and formula (III-A) described herein), as well as their salts, and all stereoisomers (including diastereoisomers and enantiomers), rotational isomers, tautomers, and isotopically labeled compounds (including deuterium substitutions). The terms “multiple (the) compound of the present invention” or “one (the) compound of the present invention” mean the compound as defined in any one of the embodiments described below.

[0037] Various embodiments of the present invention are described herein, and it will be recognized that features specified in each embodiment may be combined with other specific features to provide further embodiments of the present invention.

[0038] As Embodiment 1.0, the present invention is thus given by formula (I): [ka] (In the formula, R 1 is Cl, CH3, -OCF3, or CF3; R 2 is a halo, C1-C4 alkyl, or halo-C1-C4 alkyl; R 3 is H, CN, C1-C4 alkyl, or halo-C1-C4 alkyl; R 4 is, -(CH2) n -OH, where n is 1, 2, 3, or 4; R 5 It is a monocyclic or bicyclic heterocycline that is unsubstituted or substituted with one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halo, oxo, and -CO2H; or R 5is either unsubstituted or an aryl or heteroaryl substituted with one or two substituents independently selected from halo, haloC1-C4alkyl, C1-C4alkyl, and -SO2NH2; or R 5 is either unsubstituted or a C3-C6 cycloalkyl group substituted with 1-3 substituents independently selected from C1-C4 alkyl, halo, halo-C1-C4 alkyl, and -OH; or R 5 (This is a C2-C6 alkyl group substituted with one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2.) The present invention provides compounds of the same, or pharmaceutically acceptable salts thereof.

[0039] Embodiment 2.0 is provided, which is Embodiment 1.0 or a pharmaceutically acceptable salt thereof, in which, R 1 is -OCF3 or CF3; R 2 These are C1-C4 alkyl or halo-C1-C4 alkyl; R 3 is H, C1-C4 alkyl, or halo-C1-C4 alkyl; R 4 It is -CH2-OH; R 5 It is a monocyclic or bicyclic heterocycline that is unsubstituted or substituted with one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halo, oxo, and -CO2H; or R 5 is either unsubstituted or an aryl or heteroaryl substituted with one or two substituents independently selected from halo, haloC1-C4alkyl, C1-C4alkyl, and -SO2NH2; or R 5is either unsubstituted or a C3-C6 cycloalkyl group substituted with 1-3 substituents independently selected from C1-C4 alkyl, halo, halo-C1-C4 alkyl, and -OH; or R 5 This is a C2-C6 alkyl group substituted with one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2.

[0040] Embodiment 3.0 is provided, which is Embodiment 1.0 or 2.0, or a pharmaceutically acceptable salt thereof, in which, R 1 is -OCF3 or CF3; R 2 These are C1-C4 alkyl groups; R 3 H is; R 4 It is -CH2-OH; R 5 It is a monocyclic or bicyclic heterocycline that is unsubstituted or substituted with one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halo, oxo, and -CO2H; or R 5 is either unsubstituted or an aryl or heteroaryl substituted with one or two substituents independently selected from halo, haloC1-C4alkyl, C1-C4alkyl, and -SO2NH2; or R 5 is either unsubstituted or a C3-C6 cycloalkyl group substituted with 1-3 substituents independently selected from C1-C4 alkyl, halo, halo-C1-C4 alkyl, and -OH; or R 5 This is a C2-C6 alkyl group substituted with one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2.

[0041] Embodiment 4.0 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 It is a monocyclic or bicyclic heterocycline that is either unsubstituted or substituted with one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halo, oxo, and -CO2H.

[0042] Embodiment 4.1 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 The following: [ka] Selected from, R 5a R is independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H; 5b is independently selected from -OH, hydroxy C1-C4 alkyl, H, halo, oxo, halo C1-C4 alkyl, and -CO2H; X is O or CH2; m is 0 or 1, a " indicates the carbon atom bonded to the pyridazine amine.

[0043] Embodiment 4.2 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 The following: [ka] Selected from, In the formula, R 5a R is independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H; 5b is independently selected from -OH, C1-C4 alkyl, hydroxy C1-C4 alkyl, H, halo, oxo, halo C1-C4 alkyl, and -CO2H; X is O or CH2; m is 0 or 1, *" indicates the carbon atom bonded to the pyridazine amine.

[0044] Embodiment 4.3 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 The following: [ka] Selected from, In the formula, R 5a R is independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H; 5b m is independently selected from -OH, C1-C4 alkyl, hydroxy C1-C4 alkyl, H, halo, oxo, halo C1-C4 alkyl, and -CO2H; m is 0 or 1, * " indicates the carbon atom bonded to the pyridazine amine.

[0045] Embodiment 4.4 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 teeth, [ka] And, In the formula, R 5a is independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl and H; and " * " indicates the carbon atom bonded to the pyridazine amine.

[0046] Embodiment 4.5 is provided, which is a compound according to Embodiment 4.4, or a pharmaceutically acceptable salt thereof, where R 5a is methyl or H, in particular, R 5a It is methyl.

[0047] Embodiment 5.0 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5The molecule is either unsubstituted or substituted with one or two substituents independently selected from halo, haloC1-C4 alkyl, C1-C4 alkyl, and -SO2NH2, and is either an aryl or heteroaryl molecule.

[0048] Embodiment 5.1 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 Preferably, it has the following structure: [ka] Selected from, R 5c is independently selected from H, C1-C4 alkyl, and -SO2NH2; s is 0, 1, or 2.

[0049] Embodiment 5.2 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 Preferably, it has the following structure: [ka] Selected from, R 5c The group is independently selected from H, C1-C4 alkyl, and -SO2NH2.

[0050] Embodiment 5.3 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 Preferably, it has the following structure: [ka] Selected from, R 5c The element is independently selected from H and C1-C4 alkyl groups.

[0051] As Embodiment 6.0, the present invention provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R5 It is a C3-C6 cycloalkyl group that is either unsubstituted or substituted with 1-3 substituents independently selected from C1-C4 alkyl, halo, halo-C1-C4 alkyl, and -OH.

[0052] Embodiment 6.1 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 The structure is as follows: [ka] Selected from, R 5e , R 5e ', R 5d , R 5d ', and R 5f The group is independently selected from H, C1-C4 alkyl, halo, halo-C1-C4 alkyl, and -OH.

[0053] Embodiment 6.2 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 The structure is as follows: [ka] Selected from, R 5d and R 5d ' is independently selected from H, halo, halo C1-C4 alkyl, and C1-C4 alkyl.

[0054] Embodiment 6.3 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 The structure is as follows: [ka] Selected from, R 5d The group is independently selected from H, halo, haloC1-C4 alkyl, and C1-C4 alkyl.

[0055] Embodiment 7.0 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 This is a C2-C6 alkyl group substituted with one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2.

[0056] Embodiment 7.1 provides a compound according to any one of Embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, where R 5 The structure is as follows: [ka] Selected from, R 5h The group is selected from -NH2, -OH, -NH(C1~C4 alkyl), and -N(C1~C4 alkyl)2.

[0057] Embodiment 8.0 provides a compound according to any one of Embodiments 1.0 to 7.1, or a pharmaceutically acceptable salt thereof, wherein R 3 H is H.

[0058] Embodiment 9.0 is a compound according to Embodiment 1.0, wherein the compound is (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (Example 1) A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0059] Embodiment 9.1 provides a compound according to Embodiment 9.0, wherein the compound is a hippurate.

[0060] Embodiment 9.2 provides a compound according to Embodiment 9.0, wherein the compound is a hydrochloride salt.

[0061] Embodiment 9.3 provides a compound according to Embodiment 9.0, where the compound is in the form of a hydrate, particularly a hydrate crystal, and more specifically, the ratio of the compound to water molecules is 1:1.

[0062] Embodiment 10.0 provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of Embodiments 1.0 to 9.0, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0063] Embodiment 11.0 provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of Embodiments 1.0 to 9.0, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents.

[0064] Embodiment 12.0 provides a combination according to Embodiment 11.0, where one or more therapeutic agents are independently selected from farnesoid X receptor (FXR) agonists; anti-lipidergic agents; anti-fibrotic agents; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiotherapy and surgical procedures; uric acid-lowering therapy; anabolic and cartilage regeneration therapies; IL-17 blockade; complement inhibitors; Bruton's tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TLR7 / 8 inhibitors); CAR-T therapy; antihypertensive agents; cholesterol-lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; β2 agonists; anti-inflammatory agents; non-steroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acids (ASAs), including aspirin; regenerative therapy; treatment of cystic fibrosis; or treatment of atherosclerosis.

[0065] Embodiment 13.0 provides a compound according to any one of Embodiments 1.0 to 9.0, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 10.0, or a combination according to Embodiment 11.0 or 12.0, for use as a pharmaceutical.

[0066] Embodiment 14.0 provides a compound according to any one of Embodiments 1.0 to 9.0, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of the said disease or disorder.

[0067] Embodiment 15.0 provides a compound according to any one of Embodiments 1.0 to 9.0, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical product intended for the treatment of a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of the said disease or disorder.

[0068] Embodiment 16.0 provides a method for treating a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of the disease or disorder, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1.0 to 9.0.

[0069] As Embodiment 17.0, a compound for use according to Embodiment 14.0 or 15.0, or a method for treatment according to Embodiment 16.0 is provided, wherein the disease or disorder is a disease / disorder related to the inflammasome, an immune disease, an inflammatory disease, an autoimmune disease or an autoinflammatory disease, such as an autoinflammatory fever syndrome (e.g., cryopyrin-associated periodic syndrome), a disease / disorder related to the liver (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), a disease related to inflammatory arthritis (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthrosis, e.g., acute, chronic), a disease related to the kidney (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, inflammation related to hemodialysis), a disease related to neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), a cardiovascular / metabolic disease / disorder (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure), an inflammatory skin disease (e.g., hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and a disease / disorder related to cancer (e.g., colon cancer, lung cancer, myeloproliferative tumors, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).

[0070] As Embodiment 18.0, a method for inhibiting NLRP3 inflammasome activity in a subject who needs it is provided, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Embodiments 1.0 to 9.0, or a pharmaceutically acceptable salt thereof.

[0071] Surprisingly, for a compound of formula (I) wherein R 4 is -(CH2) n -OH and n is 1, 2, 3 or 4, hERG IC 4 compared to an analogue of a compound of formula (I) wherein R 50An increase was observed. This technical effect is demonstrated by the difference in hERG values ​​between Example 1, where R4 is -CH2-OH, and Reference Examples 1 and 2. hERG IC 50 A higher value is advantageous for evaluating the cardiac safety of the compound.

[0072] Surprisingly, in vivo experiments also revealed that the compound of formula (I) exhibits lower toxicity compared to its analogues.

[0073] Depending on the selection of starting materials and procedures, compounds may exist in one form of a possible stereoisomer or as a mixture thereof, for example, as a pure optical isomer or as a mixture of stereoisomers, such as a racemate and a mixture of diastereoisomers, depending on the number of chiral carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomer mixtures, and optically pure forms. Optically active (R)- and (S)- stereoisomers may be prepared using chiral synthons or chiral reagents or may be divided using the prior art. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomers are also intended to be included. The present invention is also intended to include any pseudo-chiral carbon atoms, represented herein as (r)- and (s)-, which do not change when reflected in a mirror but are reversed by swapping any two entities (PAC 1996, 68, 2193, Basic terminology of stereochemistry IUPAC recommendations 1996).

[0074] As used herein, the terms “salt” or “salts” refer to acid-addition salts or base-addition salts of the compounds of the present invention. “Salt” includes, in particular, “pharmaceutically acceptable salts.” The term “pharmaceutically acceptable salt” refers to a salt that retains the biological efficacy and properties of the compounds of the present invention and is not typically biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acid and / or base salts in the presence of an amino group and / or a carboxyl group or similar group.

[0075] Pharmacologically acceptable acid addition salts can be formed from inorganic and organic acids.

[0076] Inorganic acids that can induce salt formation include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and other similar substances.

[0077] Organic acids that can induce salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, hippuric acid, and other similar substances.

[0078] pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases.

[0079] Inorganic bases that can derive salts include, for example, ammonium salts and metals of columns I to XII of the periodic table. In some embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0080] Organic bases that can derive salts include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and other similar substances. Specific organic amines include isopropylamine, benzathine, corinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0081] In another embodiment, the present invention relates to acetate, ascorbyl, adipine, aspartate, benzoate, besilate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphor sulfonate, caprine, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, and maleate. The present invention provides compounds of any general formula (e.g., formula (I), etc.) or examples as defined herein, in the form of malonate, mandelate, mesylate, methyl sulfate, mucinate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalactulote, propionate, sebacinate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate. In particular embodiments, the present invention provides compounds of any general formula (e.g., formula (I), etc.) in the form of hippurate or hydrochloride.

[0082] In another embodiment, the present invention provides any general formula as defined herein (e.g., formula (I), etc.) or a compound of an example, in the form of sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, corinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or trometamine salt.

[0083] Any formula shown herein is also intended to represent both the unlabeled and isotopically labeled forms of a compound. An isotopically labeled compound has the structure represented by the formula shown herein, except that one or more atoms are substituted with atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen.

[0084] The compounds of the present invention, including their salts, hydrates, and solvates, can be isolated in one or more crystalline forms under suitable conditions.

[0085] The compounds of the present invention, i.e., compounds of formula (I) containing a group that can act as a hydrogen bond donor and / or acceptor, can form cocrystals with suitable cocrystal-forming agents. These cocrystals can be prepared from the compounds of formula (I) by known cocrystal-forming procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting the compounds of formula (I) with a cocrystal-forming agent in solution under crystallization conditions, and then isolating the resulting cocrystals. Suitable cocrystal-forming agents are those described in International Publication No. 2004 / 078163. Accordingly, the present invention further provides cocrystals containing compounds of formula (I).

[0086] Furthermore, the compounds of the present invention may also be obtained in the form of their salts, their hydrates, or other solvents used for their crystallization. The compounds of the present invention can form solvates with pharmaceutically acceptable solvents (including water) either intrinsically or by design; therefore, the present invention is intended to encompass both solvate and non-solvate forms. The term "solvate" refers to a molecular complex of the compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and known to be harmless to the recipient, such as water and ethanol. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0087] Furthermore, the incorporation of certain isotopes, particularly deuterium (i.e., 2 H or D), can result in certain therapeutic advantages, such as increased metabolic stability, e.g., increased half-life in vivo or decreased required dosage or improved therapeutic index or tolerance. In this regard, deuterium is understood to be considered as a substituent of the compounds of formula (I). The concentration of deuterium can be determined by the isotope enrichment factor. As used herein, the term "isotope enrichment factor" means the ratio between the isotopic abundance and the natural abundance for a particular isotope. When a substituent in a compound of the invention is shown to be deuterium, such a compound has an isotope enrichment factor of at least 3500 (52.5% incorporation of deuterium for each designated deuterium atom), at least 4000 (60% incorporation of deuterium atoms), at least 4500 (67.5% incorporation of deuterium), at least 5000 (75% incorporation of deuterium), at least 5500 (82.5% incorporation of deuterium), at least 6000 (90% incorporation of deuterium), at least 6333.3 (95% incorporation of deuterium), at least 6466.7 (97% incorporation of deuterium), at least 6600 (99% incorporation of deuterium) or at least 6633.3 (99.5% incorporation of deuterium) for each designated deuterium. It should be understood that the term "isotope enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0088] Further examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125I is an example. The present invention relates to various isotope-labeled compounds as defined herein, for example, 3 H and 14 Radioactive isotopes such as C, or 2 H and 13 It contains compounds that have non-radioactive isotopes such as 13C. Such isotope-labeled compounds are used in metabolic studies. 14 (by C) Study of reaction rates (for example, 2 H or 3 It is useful in detection or image processing techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy for patients. 18 F or 125 I-labeled compounds may be particularly desirable for PET or SPECT studies. Isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples and preparations, using appropriate isotope-labeling reagents instead of previously used unlabeled reagents.

[0089] Pharmaceutical composition As used herein, the term “pharmaceutical composition” means a compound of the present invention or a pharmaceutically acceptable salt thereof comprising together with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0090] As used herein, the term “pharmaceutically acceptable carrier” means a substance useful for the preparation or use of a pharmaceutical composition, including, for example, suitable diluents, solvents, dispersions, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption retarders, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, colorants, and combinations thereof, which would be known to those skilled in the art (e.g., Remington The Science and Practice of Pharmacy, 22 nd See Ed. Pharmaceutical Press, 2013, pp. 1049-1070.

[0091] The term “therapeutic dose” of the compound of the present invention refers to an amount of the compound that would induce a biological or medical response in a subject, such as a decrease or inhibition of the activity of an enzyme or protein, or that would alleviate symptoms, reduce a condition, slow or delay disease progression, or prevent a disease. In one non-limiting embodiment, the term “therapeutic dose” refers to an amount of the compound of the present invention that, when administered to a subject, is effective in at least partially alleviating, inhibiting, preventing, and / or alleviating a condition, disorder, or disease characterized by (i) being mediated by the NLRP3 pathway, or (ii) being related to NLRP3 activity, or (iii) being characterized by NLRP3 activity (normal or abnormal); or (2) reducing or inhibiting NLRP3 activity; or (3) reducing or inhibiting NLRP3 expression. In another, non-limiting embodiment, the term “therapeutic effective dose” of the compound of the present invention means an amount that, when administered to cells, tissues, or noncellular biomaterials or culture media, is effective in at least partially reducing or inhibiting the activity of NLRP3; or at least partially reducing or inhibiting the expression of NLRP3.

[0092] As used herein, the term “subject” refers to primates (e.g., humans, males or females), dogs, rabbits, guinea pigs, pigs, rats, and mice. In some embodiments, the subject is a primate. In yet another embodiment, the subject is a human.

[0093] As used herein, the terms “inhibit,” “inhibit,” or “to inhibit” refer to a reduction or suppression of a given condition, symptom or disorder or disease, or a significant decrease in baseline activity of a biological activity or process. More specifically, inhibition of NLRP3 or the NLRP3 inflammasome pathway includes reducing the function of NLRP3 or the NLRP3 inflammasome pathway that induces the production of IL-1 beta and / or IL-18. This can be achieved by mechanisms including, but not limited to, inactivating, destabilizing, and / or altering the distribution of NLRP3.

[0094] As used herein, the term "NLRP3" is intended to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologenous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, various species, and their active fragments.

[0095] As used herein, the terms “to treat,” “to treat,” or “to cure” any disease or disorder mean reducing or relieving the disease or disorder (i.e., delaying or suppressing the onset of the disease or at least one of its clinical symptoms); or reducing or relieving at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be identifiable to the patient.

[0096] As used herein, the terms “prevent,” “prevent,” or “prevention” with respect to any disease or disorder mean the preventive treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0097] As used herein, an object “needs” or “needs” a treatment if such object derives a biological, medical or quality of life benefit from such treatment.

[0098] All methods described herein may be performed in any suitable order unless otherwise indicated herein or the context clearly indicates otherwise. The use of any and all examples or exemplary expressions provided herein (e.g., "such as") is intended solely to further illustrate the invention and not to limit the scope of the invention as otherwise claimed.

[0099] Any chiral atom (e.g., carbon or other equivalent) of the compound of the present invention can exist in a racemic or enantiomerically rich configuration, such as (R)-, (S)-, or (R,S)-. In some embodiments, each chiral atom has an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in the (R)- or (S)- configuration.

[0100] Accordingly, as used herein, the compounds of the present invention can take one form of any possible stereoisomer, rotational isomer, atropisomer, tautomer, or mixture thereof, for example, substantially pure geometric (cis or trans) stereoisomer, diastereomer, optical isomer (antiseptic), racemate, or mixture thereof.

[0101] Mixtures resulting from any stereoisomerization can be separated, for example by chromatography and / or fractional crystallization, into pure or substantially pure geometric or optical isomers, diastereomers, or racemates, based on the physicochemical differences of their components.

[0102] Racemates resulting from any of the compounds or intermediates of the present invention can be separated into optical counterparts by known methods, for example, by separation of their diastereomer salts obtained with an optically active acid or base and liberation of the optically active acidic or basic compound. In particular, basic components can therefore be used to separate the compounds of the present invention into their optical counterparts by fractional crystallization of salts formed by optically active acids, such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-thuloyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be separated by chiral chromatography, for example, high-performance liquid chromatography (HPLC) using a chiral adsorbent.

[0103] Method for synthesizing the compound of the present invention The compounds of the present invention can be prepared according to the routes described in the scheme and / or examples below. All methods described herein can be carried out in any suitable order unless otherwise indicated herein or unless it is clearly inconsistent with the context. The use of any and all examples or exemplary expressions provided herein (e.g., "such as") is intended solely to further illustrate the present invention and not to otherwise limit the scope of the invention as described in the claims. In the general method below, R 1 , R 2 , R 3 , R 4 , R 5 , and halo are as previously defined in the embodiments above, or are limited to those specified in the scheme. Unless otherwise specified, the starting materials are commercially available or prepared by known methods.

[0104] Reaction Scheme 1 The compounds of the present invention may also be prepared by following the reaction sequence shown in Scheme 1 (below) as described herein, thereby obtaining appropriately substituted 3,6-dihalopyridazine (M1)(R 3 R is as defined herein, 6(It is methyl) is suitable amine (M2)(R) in the presence of a base, such as DIPEA, at low temperatures, typically between 0°C and room temperature. 5 The intermediate is then reacted with (as defined herein) to obtain 6-halopyridazine-3amine (M3), which is then reduced to 6-halopyridazine-4-alkyl-hydroxy-3amine (M4) using, for example, LiAIH. This intermediate is then subjected to a Suzuki cross-coupling reaction with a suitable boronate (M5) in the form of a boronic acid or boronic acid ester, such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, using a suitable palladium catalyst, such as Pd(PPh3)4 and an aqueous base, typically Na2CO3 or NaHCO3, in a miscible solvent such as DME or dioxane, to obtain the compound of formula (I) or a pharmaceutically acceptable salt thereof. [ka] Scheme 1.

[0105] The above process can be extended to prepare compounds of general formula (I) as described herein or pharmaceutically acceptable salts thereof. Methods for preparing compounds of formula (I) or pharmaceutically acceptable salts thereof will be well known to those skilled in the art, depending on the starting materials and chosen route, as described in Scheme 1. Specific variations or alternative steps are described in the following experimental sections of this specification.

[0106] The present invention further comprises any different process of the present invention, wherein an intermediate obtained at any stage thereof is used as a starting material and the remaining steps are carried out, or the starting material is formed in situ under reaction conditions, or the reaction components are used in the form of their salts or optically pure substances. The compounds and intermediates of the present invention can also be converted to each other according to methods generally known to those skilled in the art.

[0107] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration) and rectal administration. Topical administration may also relate to inhalation or intranasal application. The pharmaceutical composition of the present invention can be made in solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories) or liquid form (including, without limitation, liquids, suspensions or emulsions). Tablets may be film-coated or enteric-coated according to methods known in the art. Typically, the pharmaceutical composition is a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, further, c) Binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary, d) Disintegrants, such as starch, agar, alginic acid or its sodium salt or effervescent mixture; and e) Absorbents, colorants, flavorings, and sweeteners It is a tablet or gelatin capsule containing an active ingredient along with one or more of the above.

[0108] Method of use of the present invention There is evidence of the role of NLRP3-induced IL-1 and IL-18 in inflammatory responses associated with or resulting from a wide range of disorders (Menu et al. Clinical and Experimental Immunology, 2011, 166, 1-15; Strowig et al. Nature, 2012, 481, 278-286). NLRP3 mutations have been found to be the cause of a rare group of autoinflammatory disorders known as CAPS (Ozaki et al. J. Inflammation Research, 2015, 8, 15-27; Schroder et al. Cell, 2010, 140:821-832; Menu et al. Clinical and Experimental Immunology, 2011, 166, 1-15). CAPS is a genetic disorder characterized by relapsing fever and inflammation, and consists of three clinically contiguous autoinflammatory disorders. These diseases, in order of increasing severity, are Familial Cold Autoinflammatory Syndrome (FCAS), Mucklewells Syndrome (MWS), and Chronic Infantile Neurocutaneous Arthritis Syndrome (CINCA; also known as Neonatal Onset Multiorgan Inflammatory Disease or NOMID), all of which have been shown to be caused by gain-of-function mutations in the NLRP3 gene, which leads to increased IL-1β secretion. NLRP3 has also been associated with many autoinflammatory diseases, including suppurative arthritis, pyoderma gangrenosum and acne (PAPA), Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook et al. Eur.J.Immunol., 2010, 40, 595-653).

[0109] Many autoimmune diseases, particularly multiple sclerosis, type 1 diabetes (T1D), psoriasis, rheumatoid arthritis (RA), Behçet's disease, Schnitzler syndrome, macrophage activation syndrome (Braddock et al. Nat. Rev. Drug Disc. 2004, 3, 1-10; Inoue et al. Immunology, 2013, 139, 11-18; Coll et al. Nat. Med. 2015, 21(3), 248-55; Scott et al. Clin. Exp. Rheumatol. 2016, 34(1), 88-93), systemic lupus erythematosus and its complications such as lupus nephritis (Lu et al. J. Immunol., 2017, 198(3), 1119-29), and systemic sclerosis (Artlett et al. Arthritis). It has been shown to be related to NLRP3, including in Rheum. 2011, 63(11), 3563-74. NLRP3 has also been shown to play a role in many lung diseases, including chronic obstructive pulmonary disease (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 2014, 184:42-54; Kim et al. Am. J. Respir. Crit. Care Med, 2017, 196(3), 283-97). NLRP3 has also been suggested to play a role in many central nervous system conditions, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis (Walsh et al. Nature Reviews, 2014, 15, 84-97; and Dempsey et al. Brain. Behav. Immun. 2017, 61, 306-16), intracranial aneurysms (Zhang et al. J. Stroke and Cerebrovascular Dis., 2015, 24, 5, 972-9), and traumatic brain injury (Ismael et al. J. Neurotrauma., 2018, 35(11), 1294-1303).NRLP3 activity has also been shown to be involved in various metabolic diseases, including type 2 diabetes (T2D) and its organ-specific complications, atherosclerosis, obesity, gout, pseudogout, metabolic syndrome (Wen et al. Nature Immunology, 2012, 13, 352-357; Duewell et al. Nature, 2010, 464, 1357-1361; Strowig et al. Nature, 2014, 481, 278-286), and non-alcoholic steatohepatitis (Mridha et al. J. Hepatol. 2017, 66(5), 1037-46). The role of NLRP3 via IL-1 beta has also been suggested in atherosclerosis, myocardial infarction (van Hout et al. Eur. Heart J. 2017, 38(11), 828-36), heart failure (Sano et al. J. Am. Coll. Cardiol. 2018, 71(8), 875-66), aortic aneurysm and aortic dissection (Wu et al. Arterioscler. Thromb. Vase. Biol., 2017, 37(4), 694-706), and other cardiovascular events (Ridker et al. N. Engl. J. Med., 2017, 377(12), 1119-31).

[0110] Other diseases shown to be associated with NLRP3 include eye diseases such as both wet and dry age-related macular degeneration (Doyle et al., Nature Medicine, 2012, 18, 791-798; Tarallo et al. Cell 2012, 149(4), 847-59), diabetic retinopathy (Loukovaara et al. Acta Ophthalmol., 2017, 95(8), 803-8), non-infectious uveitis and optic nerve injury (Puyang et al. Sci.Rep. 2016, 6, 20998); liver diseases including non-alcoholic steatohepatitis (NASH) and acute alcoholic hepatitis (Henao-Meija et al. Nature, 2012, 482, 179-185); and contact hypersensitivity (such as bullous pemphigoid (Fang et al. J Dermatol). Sci.2016,83(2),116-23)), atopic dermatitis (Niebuhr et al. Allergy, 2014,69(8),1058-67), sweat gland abscess (Alikhan et al. J.Am.Acad.Dermatol., 2009,60(4),539-61), and inflammatory reactions in the lungs and skin, including sarcoidosis (Jager et al. Am.J.Respir.Crit.Care Med., 2015,191,A5816) (Primiano et al. J.Immunol.2016,197(6),2421-33); inflammatory reactions in the joints (Braddock et al. Nat.Rev.Drug Disc, 2004,3,1-10); amyotrophic lateral sclerosis (Gugliandolo et al.Int.J.Mol.Sci.,2018,19(7),E1992); cystic fibrosis (Iannitti et al.Nat.Commun.,2016,7,10791); stroke (Walsh et al.Nature Reviews,2014,15,84-97); chronic kidney disease (Granata et al.PLoS One 2015,10(3),eoi22272); and inflammatory bowel disease including ulcerative colitis and Crohn's disease (Braddock et al.Nat.Rev.DrugDisc,2004,3,1-10;Neudecker et al.J.Exp.Med.(Including Lazaridis et al. Dig.Dis.Sci. 2017, 62(9), 2348-56). The NLRP3 inflammasome was found to be activated in response to oxidative stress. NLRP3 has also been shown to be involved in inflammatory hyperalgesia (Dolunay et al. Inflammation, 2017, 40, 366-86).

[0111] Activation of the NLRP3 inflammasome has been shown to enhance several pathogenic infections, including influenza and leishmaniasis (Tate et al. Sci Rep., 2016, 10(6), 27912-20; Novias et al. PLOS Pathogens 2017, 13(2), e1006196).

[0112] NLRP3 has also been linked to the pathogenesis of many cancers (Menu et al. Clinical and Experimental Immunology, 2011, 166, 1-15). For example, several previous studies have suggested a role for IL-1 beta in cancer invasion, growth, and metastasis, and inhibition of IL-1 beta with canakinumab has been shown to reduce lung cancer incidence and overall cancer mortality in a randomized, double-blind, placebo-controlled clinical trial (Ridker et al. Lancet., 2017, 390(10105), 1833-42). Inhibition of the NLRP3 inflammasome or IL-1 beta has also been shown to inhibit the proliferation and migration of lung cancer cells in vitro (Wang et al. Oncol Rep., 2016, 35(4), 2053-64). The role of the NLRP3 inflammasome is found in myelodysplastic syndromes, myelofibrosis and other myeloproliferative neoplasms, as well as acute myeloid leukemia (AML) (Basiorka et al. Blood, 2016, 128(25), 2960-75), and further in gliomas (Li et al. Am.J. Cancer Res. 2015, 5(1), 442-9), pro-inflammatory tumors (Allen et al. J. Exp. Med. 2010, 207(5), 1045-56; Hu et al. PNAS., 2010, 107(50), 21635-40), multiple myeloma (Li et al. Hematology, 2016 21(3), 144-51), and squamous cell carcinoma of the head and neck (Huang et al. J. Exp. Clin. Cancer). It has been suggested in the carcinogenesis of various other cancers, including Res., 2017, 36(1), 116). Activation of the NLRP3 inflammasome has also been shown to mediate chemotherapy resistance of tumor cells to 5-fluorouracil (Feng et al. J. Exp. Clin. Cancer Res., 2017, 36(1), 81), and activation of the NLRP3 inflammasome in peripheral nerves contributes to chemotherapy-induced neuropathic pain (Jia et al. Mol. Pain., 2017, 13, 1-11). NLRP3 has also been shown to be required for the efficient control of viruses, bacteria, and fungi.

[0113] Activation of NLRP3 leads to cellular pyroptosis, a characteristic that plays a significant role in the emergence of clinical disease (Yan-gang et al. Cell Death and Disease, 2017, 8(2), 2579; Alexander et al. Hepatology, 2014, 59(3), 898-910; Baldwin et al. J. Med. Chem., 2016, 59(5), 1691-1710; Ozaki et al. J. Inflammation Research, 2015, 8, 15-27; Zhen et al. Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia et al. J. Med. Chem., 2014, 57(24), 10366-82; Satoh et al. Cell Death and Disease, 2013, 4, 644). Therefore, it is expected that NLRP3 inhibitors will block pyroptosis and the release of pro-inflammatory cytokines (e.g., IL-1 beta) from cells.

[0114] Compounds according to any one of the general formulas (e.g., formula (I), etc.) or any one of the embodiments described above, or compounds according to any one of the exemplary examples (e.g., Example 1 disclosed herein), in free form or in the form of a pharmaceutically acceptable salt, exhibit beneficial pharmacological properties, such as NRLP3 inhibitory properties against the NLRP3 pathway, as demonstrated, for example, by in vitro studies provided in the following section, and are therefore required for use as therapeutic or research chemicals, such as tool compounds.

[0115] The compounds of the present invention may be useful in treating symptoms selected from inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, for example, in which NLRP3 signaling contributes to abnormalities and / or symptoms and / or progression and may respond to NLRP3 inhibition, and which can be treated or prevented by compounds according to any one of Embodiments 1.0 to 18.0 or any one of the exemplary examples of the present invention (e.g., Example 1 disclosed herein) include: I. Inflammation, including inflammation resulting from, for example, autoinflammatory diseases, inflammation as a symptom of non-inflammatory disorders, inflammation resulting from infection, or inflammation associated with trauma, injury, or autoimmunity. Examples of inflammation that can be treated or prevented include inflammatory responses related to or resulting from the following: (a) Skin conditions such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (b) Joint conditions such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, crystal-induced arthropathy (e.g., pseudogout, gout), or seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, or Reiter's syndrome); (c) Muscle conditions such as polymyositis or myasthenia gravis; (d) Gastrointestinal conditions such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food allergies that may have a less significant impact on the gut (e.g., migraine, rhinitis, or eczema); (e) Respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, endogenous, exogenous, or dust-borne asthma, and especially chronic or persistent asthma such as delayed-onset asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, suppurative rhinitis, xerostomia, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis, such as hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (f) Vascular conditions such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (g) Immune conditions, such as autoimmune conditions including systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type 1 diabetes, idiopathic thrombocytopenic purpura, or Graves' disease; (h) Eye conditions such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (i) Neurological conditions such as multiple sclerosis or encephalomyelitis; (j) Infections or infection-related conditions such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infections, acute or chronic parasitic infections, acute or chronic viral infections, acute or chronic fungal infections, meningitis, hepatitis (types A, B, or C or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, mycobacterium tuberculosis, mycobacterium avium intracellulare, Pneumocystis carini pneumonia, orchitis / epididymitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (k) Renal conditions such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia, or nephritis syndrome; (l) Lymphatic conditions such as Castleman disease; (m) Immune system or related conditions such as hyper-IgE syndrome, leprosy, hemophagocytic histiocytosis, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (n) Liver conditions such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), or primary biliary cirrhosis; (o) Cancers including those listed below in this specification; (p) burns, wounds, injuries, bleeding, or stroke; (q) Radiation exposure; and / or (r) Obesity; and / or (s) Pain such as inflammatory hyperalgesia; II. Inflammatory disorders, including inflammation resulting from autoinflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS), Macklewells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multiorgan inflammatory disease (NOMID), Magid syndrome, septic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), adult-onset Still's disease (AOSD), A20 haploinsufficiency (HA20), granulomatous arthritis of children (PGA), PLCG2-associated antibody deficiency immunomodulation (PLAID), PLCG2-associated autoinflammatory antibody deficiency immunomodulation (APLAID), or sideroblastic anemia with B-cell immunodeficiency, periodic fever and growth retardation (SIFD); III. Immune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid syndrome (APS), anti-synthetic enzyme syndrome, aplastic anemia, autoimmune adrenal inflammatory disease, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular endocrine insufficiency, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, lupus erythematosus including systemic lupus erythematosus (SLE), multiple sclerosis (MS) including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS), myasthenia gravis, ocular clonus myoclonus syndrome (OMS), optic neuritis, odontic thyroiditis, and other related conditions. Smallpox, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Reiter's syndrome, Sjögren's syndrome, systemic sclerosis, systemic connective tissue disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia generalis, Believes' disease, Chagas's disease, autonomic neuropathy, endometriosis Autoimmune diseases such as hidradenitis suppurativa (HS), interstitial cystitis, neurogenic myotonic disease, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, vitiligo or vulvar pain, hemophagocytic lymphohistiocytosis (HLH), and cytokine release syndrome associated with T-cell engager therapy (CAR-T or bi- / tri-specific antibodies); IV. Lung cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), Langerhans cell histiocytosis (LCH), myeloproliferative neoplasms (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndrome (MDS), leukemia including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), promyelocytic leukemia (APML or APL), adrenal cancer, anal cancer, basal cell and squamous cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, tumors of the brain and spinal cord, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic bone marrow cancer Monocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi's sarcoma, renal cancer, laryngeal and hypopharyngeal cancer, liver cancer, pulmonary carcinoid tumors, lymphoma including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma cutaneous cancer, Merkel cell cutaneous cancer, monoclonal gammaglobulinemia of unknown significance (MGUS), smoldering type Plasma cell diseases including multiple myeloma and active multiple myeloma, multiple myeloma, nasal cavity cancer and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, mature T cell and NK cell tumors, non-Hodgkin lymphoma, mature B cell tumors such as non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymic cancer, thyroid cancer including undifferentiated thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldensian cancer Threm's macroglobulinemia, and myeloproliferative neoplasms (MPNs) including Wilms' tumor, myelofibrosis, brain tumors including primary brain tumors and brain metastases, myelodysplastic / myeloproliferative neoplasms (MDS / MPN), myeloid / lymphoid neoplasms with eosinophilia and PDGFRA, PDGFRB, or FGFR1 gene rearrangements, or with PCM1-JAK2, B lymphoblastic leukemia / lymphoma, T lymphoblastic leukemia / lymphoma, cancers including histiocytic and dendritic cell tumors, and post-transplant lymphoproliferative disorders (PTLD); V. Viral infections (e.g., influenza virus, human immunodeficiency virus (HIV), alphaviruses (chikungunya virus and Ross River virus, etc.), flaviviruses (dengue virus and Zika virus, etc.), herpesviruses (Epstein-Barr virus, cytomegalovirus, varicella-zoster virus and KSHV, etc.), poxviruses (vaccinia virus (modified vaccinia virus Ankara) and myxomavirus, etc.), adenoviruses (adenovirus 5, etc.) or papillomavirus-derived), bacterial infections (e.g., Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordetella pertussis, Burkholderia pseudomallei, Corynebacterium diphtheriae, Clostridium tetanus) tetani), Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteurella multocida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsia Legionella pneumophila, Klebsiella pneumoniae, PseudomonasInfections including those caused by bacteria such as *Propionibacterium acnes*, *Treponema pallidum*, *Chlamydia trachomatis*, *Vibrio cholerae*, *Salmonella typhimurium*, *Salmonella typhi*, *Borrelia burgdorferi*, or *Yersinia pestis*, fungal infections (e.g., those caused by *Candida* or *Aspergillus*), protozoan infections (e.g., those caused by *Plasmodium*, *Babesia*, *Gialida*, *Entomoeba*, *Leishmania*, or *Trypanosomes*), helminthic infections (e.g., those caused by *Schistosoma*, *Rhinoceros*, *Tapeworms*, or *Trepticus*), and prion infections; VI. Central nervous system disorders such as Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain injury resulting from pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis; VII. Metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout; VIII. Hypertension, ischemia, reperfusion injury including ischemia-reperfusion injury after MI, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, heart failure including congestive heart failure and heart failure with preserved ejection fraction, embolism, aneurysm including abdominal aortic aneurysm, reduced cardiovascular risk (CvRR), and pericarditis including Dressler syndrome, heart failure after myocardial infarction; cardiovascular diseases such as atrial fibrillation; IX. Respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis; X. Liver diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH), including advanced fibrosis stages F3 and F4; XI. Kidney diseases including acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcemia, glomerulonephritis, and diabetic nephropathy; XII. Eye diseases including diseases of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infections, diabetic retinopathy, optic nerve injury, dry eye, and glaucoma; XIII. Skin conditions including contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, sweat gland abscesses (HS), other cyst-induced skin diseases, and acne clusters; XIV. Lymphatic conditions such as lymphangitis and Castleman disease; XV. Depression and mental stress; mental disorders such as schizophrenia and bipolar disorder; XVI. Graft-versus-host disease; XVII. Bone diseases, including osteoporosis and osteopetrosis; XVIII. Blood disorders, including sickle cell disease; XVIX. Allodynia including mechanical allodynia; and XVX. Any disease in which an individual is determined to have a germline or somatic nonsilent mutation in NLRP3.

[0116] More specifically, the compounds of the present invention may be useful in treating conditions selected from the following: inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, e.g., autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndromes), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), inflammatory arthritis-related diseases (e.g., gout, pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute, chronic, calcium pyrophosphate crystal deposition disease (CPPD)), kidney-related diseases (e.g., hypertension Oxaluria, lupus nephritis, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, inflammation associated with hemodialysis), neuroinflammatory diseases (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland abscesses, acne), wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy), gout, pseudogout (chondrocalcification), chronic liver disease, NASH, neuroinflammatory disorders (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0117] In particular, the compounds of the present invention or pharmaceutically acceptable salts thereof may be useful in the treatment of diseases or disorders selected from autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcification), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0118] Accordingly, in a further embodiment, the present invention provides the use in therapeutics of a compound of any general formula (e.g., formula (I), etc.), or a compound according to any one of the prior embodiments (e.g., according to any of embodiments 1.0 to 18.0), or a compound according to any one of the exemplary examples (e.g., Example 1 disclosed herein), or a pharmaceutically acceptable salt thereof. In a further embodiment, the therapy is selected from diseases that can be treated by inhibition of the NLRP3 inflammasome pathway. In another embodiment, the disease is, appropriately, inflammasome-related disease / disorder, immune disease, inflammatory disease, autoimmune disease or autoinflammatory disease, e.g., autoinflammatory fever syndrome (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), inflammatory arthritis-related disease (e.g., gout, pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute, chronic), kidney-related disease (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes mellitus and The following are selected from: diseases and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, inflammation associated with hemodialysis), diseases related to neuroinflammation (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland abscesses, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and diseases / disorders related to cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcification), chronic liver disease, NASH, neuroinflammatory disorders (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0119] Accordingly, in a further embodiment, the present invention provides for use in therapy any one compound of the general formula (e.g., formula (I)), or a compound according to any one of the embodiments described above (i.e., any one of embodiments 1.0 to 18.0), or a compound according to any one of the exemplary examples (e.g., Example 1 disclosed herein), or a pharmaceutically acceptable salt thereof. In a further embodiment, the therapy is selected from diseases that can be treated by inhibition of the NLRP3 inflammasome pathway. In another embodiment, the disease is, appropriately, inflammasome-related disease / disorder, immune disease, inflammatory disease, autoimmune disease or autoinflammatory disease, e.g., autoinflammatory fever syndrome (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), inflammatory arthritis-related disease (e.g., gout, pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute, chronic), kidney-related disease (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes mellitus and The following are selected from: diseases and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, inflammation associated with hemodialysis), diseases related to neuroinflammation (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland abscesses, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and diseases / disorders related to cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcification), chronic liver disease, NASH, neuroinflammatory disorders (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0120] In another embodiment, the present invention provides a method for treating a disease treated by inhibiting NLRP3, comprising administering a therapeutically effective amount of any one compound of the general formula (e.g., formula (I)), or a compound according to any one of the embodiments described above (i.e., any one of embodiments 1.0 to 18.0), or an exemplary example (e.g., a compound according to any one of Example 1 disclosed herein or a pharmaceutically acceptable salt thereof). In further embodiments, the disease is, appropriately, inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, e.g., autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndromes), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic steatohepatitis and alcoholic steatohepatitis). Diseases related to inflammatory arthritis (e.g., gout, pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute, chronic), diseases related to the kidneys (e.g., hyperoxaluria, lupus nephritis, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, inflammation associated with hemodialysis), diseases related to neuroinflammation (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / The following are selected from metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland abscess, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcification), chronic liver disease, NASH, neuroinflammatory disorders (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0121] In further embodiments, the present invention provides any one compound of the general formula (e.g., formula (I), etc.), or a compound following any one of the embodiments described herein (i.e., any one of embodiments 1.0 to 18.0), or a compound following any one of the exemplary examples (e.g., Example 1 disclosed herein), or a pharmaceutically acceptable salt thereof, which is useful in treating diseases, disorders, or conditions substantially or completely mediated by NLRP3 inflammasome activity and / or NLRP3-induced IL-1 beta and / or NLRP3-induced IL-18, as disclosed herein. Some of the diseases, disorders, or conditions described herein arise from mutations in NLRP3, in particular resulting in increased NLRP3 activity.

[0122] Combination products and therapies of the present invention "Combination" refers to a fixed combination or combination of administrations in a single dosing unit, and the compounds of the present invention and their combination partners (e.g., other agents described below, also called "therapeutic agents" or "co-agents") may be administered simultaneously, separately, or in separate timeframes, particularly within such timeframes, so that the combination partners exhibit a cooperative, e.g., synergistic effect. A single component may be packaged in a single kit or separately. One or both of the components (e.g., powders or liquids) may be reduced or diluted to a desired dose before administration. As used herein, the terms "simultaneous administration" and "combination of administrations" or other similar terms are intended to encompass the administration of a selected combination partner to a single subject (e.g., a patient) that requires it, and are intended to include therapeutic regimens in which the active agents are not necessarily administered by the same route of administration or simultaneously. As used herein, the term "combination of pharmaceuticals" means a product resulting from a mixture or combination of two or more therapeutic agents, and includes both fixed and unfixed combinations of therapeutic agents. As used herein, the term “combination of pharmaceuticals” refers to a fixed or unfixed combination in a single dosing unit or a kit of components for a combination of administrations in which two or more therapeutic agents may be administered simultaneously or separately, or separately within a time frame, in particular, such a time frame, which may cause the combination partners to exhibit a cooperative, for example, synergistic effect. The term “fixed combination” means that the therapeutic agents, e.g., the compounds of the present invention and the combination partners, together, in the form of a single entity or dosage, are administered simultaneously to the patient. The term “unfixed combination” means that the therapeutic agents, e.g., the compounds of the present invention and the combination partners, together, as separate entities, are administered simultaneously, in parallel or sequentially, to the patient without any specific time limit, and such administration brings the two compounds to a therapeutically effective level in the patient’s body. The latter also applies to cocktail therapies, e.g., the administration of three or more therapeutic agents.

[0123] The term “combination of therapies” refers to the administration of two or more therapeutic agents for the treatment of a therapeutic condition or disorder described herein. Such administrations include the simultaneous administration of substantially simultaneous doses of these therapeutic agents, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administrations include the simultaneous administration of each active ingredient in multiple or separate containers (e.g., tablets, capsules, powders, and solutions). Powders and / or solutions may be reduced or diluted to a desired dose before administration. In addition, such administrations also include the sequential use of each type of therapeutic agent at approximately simultaneous or different times. In any case, the therapeutic regimen will have a beneficial effect on the combination of agents when treating the conditions or disorders described herein.

[0124] The compounds of the present invention may be administered simultaneously with, before, or after, one or more other therapeutic agents. The compounds of the present invention may be administered separately by the same or different routes of administration, or together in the same pharmaceutical composition as other active substances. The therapeutic agents may be, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids, which are therapeutically active or enhance therapeutic activity when administered to a patient in combination with the compounds of the present invention.

[0125] In one embodiment, the present invention provides a product comprising a compound of any general formula (e.g., formula (I), etc.) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent as a combination of preparations for simultaneous, individual, or sequential use in a therapeutic treatment. In one embodiment, the therapeutic treatment is the treatment of a disease or condition mediated by NLRP3. The product provided as a combination of preparations comprises, together in the same pharmaceutical composition, a compound of any general formula (e.g., formula (I), etc.) or a pharmaceutically acceptable salt thereof and another therapeutic agent, or comprises a composition containing, in individual forms, for example, in the form of a kit, a compound of any general formula (e.g., formula (I), etc.) or a pharmaceutically acceptable salt thereof and another therapeutic agent.

[0126] In one embodiment, the present invention provides a combination of pharmaceuticals comprising a compound of any general formula (e.g., formula (I), etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, and another therapeutic agent. Optionally, the combination of pharmaceuticals may include a pharmaceutically acceptable carrier, as described above.

[0127] In one embodiment, the present invention provides a kit comprising two or more distinct pharmaceutical compositions, at least one of which contains a compound of any of the general formulas (e.g., formula (I), etc.) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof. In one embodiment, the kit includes means for holding the compositions separately, such as a container, a partitioned bottle, or a partitioned foil pack. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules, and other similar items.

[0128] The kits of the present invention can be used, for example, to administer different dosage forms such as oral and parenteral administration, by administering separate compositions at different dosing intervals or by dosing separate compositions together. To facilitate compliance, the kits of the present invention typically include instructions for administration.

[0129] In the combination of therapies of the present invention, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention and other therapeutic agents may be (i) assembled into a single combination of therapies by the patient themselves (or under the guidance of the physician) immediately before the combination product is launched to the physician (for example, in the case of a kit containing the compounds of the present invention and other therapeutic agents); (ii) immediately before administration; or (iii) during the sequential administration of the compounds of the present invention and other therapeutic agents, for example, by the patient themselves.

[0130] Accordingly, the present invention provides a compound of any general formula (e.g., formula (I), etc.) or a pharmaceutically acceptable salt thereof for treating a disease or condition mediated by NLRP3, the pharmacopoeia being prepared for administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating a disease or condition mediated by NLRP3, the pharmacopoeia being administered together with a compound of any general formula (e.g., formula (I), etc.) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the prior embodiments or a pharmaceutically acceptable salt thereof.

[0131] The present invention also provides a compound of any general formula (e.g., formula (I), etc.) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the prior embodiments or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by NLRP3, the compound of any general formula (e.g., formula (I), etc.) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the prior embodiments or a pharmaceutically acceptable salt thereof, which is prepared for administration together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by NLRP3, the other therapeutic agent is prepared for administration together with a compound of any general formula (e.g., formula (I), etc.) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the prior embodiments or a pharmaceutically acceptable salt thereof. The present invention also provides a compound of any general formula (e.g., formula (I)) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the prior embodiments or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by NLRP3, wherein the compound of any general formula (e.g., formula (I)) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the prior embodiments or a pharmaceutically acceptable salt thereof, is administered together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by NLRP3, wherein the other therapeutic agent is administered together with a compound of any general formula (e.g., formula (I)) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the prior embodiments or a pharmaceutically acceptable salt thereof.

[0132] The present invention also provides the use of a compound of any general formula (e.g., formula (I)), or a compound according to any one of the prior embodiments (e.g., any of embodiments 1.0 to 18.7), or a compound according to any one of the exemplary examples (e.g., Example 1 disclosed herein), or a pharmaceutically acceptable salt thereof, for treating a disease or condition mediated by NLRP3, wherein the patient has been previously treated (e.g., within 24 hours) with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the NLRP3 inflammasome pathway, wherein the patient has been previously treated (e.g., within 24 hours) with a compound of any general formula (e.g., formula (I)), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the prior embodiments, or a pharmaceutically acceptable salt thereof.

[0133] In one embodiment, other therapeutic agents are useful in treating inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases, as disclosed herein.

[0134] In one embodiment, other therapeutic agents useful in a combination of therapies are selected from farnesoid X receptor (FXR) agonists; anti-lipidergic agents; anti-fibrotic agents; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiotherapy and surgical procedures; uric acid-lowering therapies; anabolic and cartilage regeneration therapies; IL-17 blockade; complement inhibitors; Bruton's tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TLR7 / 8 inhibitors); CAR-T therapy; antihypertensive agents; cholesterol-lowering agents; leukotriene A4 hydrolase (LTA4H) inhibitors; SGLT2 inhibitors; β2 agonists; anti-inflammatory agents; non-steroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acids (ASAs), including aspirin; paracetamol; regenerative therapy; treatment of cystic fibrosis; and treatment of atherosclerosis.

[0135] Suitable leukotriene A4 hydrolase (LTA4H) inhibitors for use in combination include, but are not limited to, the compounds disclosed in International Publication No. 2015 / 092740, particularly (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridine-2-yl)oxy)phenyl)-2H-tetrazole-2-yl)butanoic acid (LYS006), and the compounds disclosed in International Publication No. 2022 / 219546.

[0136] Suitable sodium-dependent glucose transporter 2 (SGLT2) inhibitors for use in combination include, but are not limited to, the compounds disclosed in U.S. Patent No. 8,163,704, International Publication No. 2011 / 048112, International Publication No. 2011 / 048148, or International Publication No. 2010 / 128152.

[0137] Suitable β2 agonists for use in combination include alformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline, ibuterol, isoetalin, isoprenaline, levosalbutamol, mabuterol, meladrine, metaprotenelol, noromilol, orciprenaline, pirbuterol, procaterol, reproterol, ritodrine, rimoterol, salbutamol, and Lumefamol, salmeterol, cibenadet, sotenerote, sulfonterol, terbutaline, tiaramide, tulobuterol, GSK-597901, GSK-159797, GSK-678007, GSK-642444, GSK-159802, HOKU-81, (-)-2-[7(S)-[2(R)-hydroxy-2-(4-hydroxyphenyl)ethylamino]-5,6,7,8-tetrahydro-2-naphthyloxy]-N,N-dimethylacetamide hydrochloride monohydrate, carmoterol, QAB-149 and 5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolon, 1-(1-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2- [4(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-Benzoxazine-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazole-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4benzoxazine-3-(4 This includes, but is not limited to, H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol, 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol, and combinations thereof, each of which may optionally be in the form of a racemate, enantiomer, diastereomer, or mixture thereof, and may optionally be in the form of a pharmacokinetically compatible acid addition salt.

[0138] Suitable cartilage regeneration therapies for use in combination include, but are not limited to, ANGPTL3 peptide mimetic drugs disclosed in International Publication No. 2014 / 138687 or chondrogenesis activators disclosed in International Publication No. 2015 / 175487.

[0139] Suitable checkpoint inhibitors for use in combination include, but are not limited to, anti-PD1 inhibitors, anti-LAG-3 inhibitors, anti-TIM-3 inhibitors, and anti-PDL1 inhibitors. Suitable anti-PD1 inhibitors include, but are not limited to, the antibody molecules disclosed in International Publication No. 2015 / 112900. Suitable anti-LAG-3 inhibitors include, but are not limited to, the antibody molecules disclosed in International Publication No. 2015 / 138920. Suitable anti-TIM-3 inhibitors include, but are not limited to, the antibody molecules disclosed in International Publication No. 2015 / 117002. Suitable anti-PDL1 inhibitors include, but are not limited to, the antibody molecules disclosed in International Publication No. 2016 / 061142.

[0140] Suitable Toll-like receptor inhibitors (TLR7 / 8 inhibitors) for use in combination include, but are not limited to, the compounds disclosed in International Publication No. 2018 / 04081.

[0141] Suitable FXR agonists for use in combination include obeticholic acid (so-called OCA, Intercept), GS9674, ellafibranol (GFT505), GW4064, UPF987, FXR-450, fexalamine, methyl cholate, methyl deoxycholate, 5β-coranoic acid, 5β-coranoic acid 7α,12α-diol, NIHS700, marcantin A, marcantin E, and MFA-1. This includes, but is not limited to, INT767 (also known as 6α-ethyl-CDCA as disclosed in International Publication No. 2014 / 085474), MET409 (Metacrine), EDP-305 (Enanta), 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazole-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid (also known as tropifexol) or its pharmaceutically acceptable salts, or compounds disclosed in International Publication No. 2012 / 087519 or compounds disclosed in International Publication No. 2015 / 069666.

[0142] Suitable JAK inhibitors for use in combination include, but are not limited to, ruxolitinib.

[0143] Suitable NSAIDs for use in combination include aceclofenac, acemetacin, acetylsalicylic acid, alclofenac, aluminoprofen, amfenac, ampiroxicam, antremetine guayl, anilolac, anthraphenine, azapropazon, benolilate, vermoprofen, vindarito, bromfenac, bucloxic acid, bucolome, bufexamac, bumadizone, butibufen, butixylate, carbasalate calcium, caprophene, choline magnesium trisalicylate, celecoxib, cinmethacin, and cinnoxylate. Cam, Clidanac, Clobuzalit, Deboxameth, Dexibprofen, Dexketoprofen, Diclofenac, Diflunisal, Droxicam, Eltenac, Enfenamic acid, Etersalat, Etodrug, Etofenamate, Etricoxib, Feclobuzon, Felbinac, Fenbufen, Fenclofenac, Fenoprofen, Fenthiazac, Feprazinol, Feprazon, Flobufen, Flobutaphenin, Flufenamic acid, Fluphenisal, Flunoxaprofen, Flurbiprofen, Flurbiprofen axetil, Flof Enac, Fluprofen, Glucamethac, Ibufenac, Ibuprofen, Indobufen, Indomethacin, Indomethacin Farnesil, Indoprofen, Isoxepac, Isoxicam, Ketoprofen, Ketrolac, Lobenzarit, Lonazolac, Lornoxicam, Loxoprofen, Lumiracoxib, Meclofenamim, Meclofen, Mefenamic acid, Meloxicam, Mesalazine, Miroprofen, Mofezolac, Nabumetone, Naproxen, Diflumic acid, Orsalazine, Oxaprozin, Oxypinac, Oxyfenbutazone, Pare Coxib, phenylbutazone, perbiprofen, pimeprofen, pyrazolac, pyriroxicam, pirprofen, pranoprofen, priferon, prinomod, proglummetacin, procazone, protidinic acid, lofecoxib, romazarit, salicylamide, salicylic acid, salmistein, sarnasedin, salsalat, sulindac, sudoxicam, suprofen, tarniflumart, tenidap, tenosal, tenoxicam, tepoxaline, tiaprofenic acid, taramide, tirnoprofen albamel, thimegazine, tinoridine, thiopinac,This includes, but is not limited to, tolfenamic acid, tolmetin, ufenamate, valdecoxib, xymoprofen, zaltoprofen, zoliprofen, and combinations thereof.

[0144] Suitable BTK inhibitors include, for example, ibrutinib, acalabrutinib (ACP-196), evobrutinib; fenebrutinib; tirabrutinib (ONO-4059, GS-4059); zanubrutinib (BGB-3111), spebratinib (CC-292, AVL-292), posertinib (HM-71224, LY3337641), becabrutinib (SN-062), BM-986142; BMS986195; PRN2246; PRN10 08, M7583, CT1530, BIIBO68, AC-0058TA, ARQ-531, TAK-020, TG1701 or International Publication No. 2015 / 079417, International Publication No. 2015 / 083008, International Publication No. 2015 / 110923, International Publication No. 2014 / 173289, International Publication No. 2012 / 021444, International Publication No. 2013 / 081016, International Publication No. 2013 / 067274, International Publication No. 2012 / 170976, International Publication No. 2011 / 162515, U.S. Patent Application Publication No. 2017 / 119766, International Publication No. 2016 / 065226, U.S. Patent No. 9,688,676, International Publication No. 2016 / 201280, International Publication No. 2017 / 059702, U.S. Patent No. 9,630,968 The specifications include those described in U.S. Patent Application Publication No. 2014 / 0256734, International Publication No. 2017 / 118277, International Publication No. 2014 / 039899, ​​International Publication No. 16 / 105531, International Publication No. 2018 / 005849, International Publication No. 2013 / 185082, or J.Med.Chem., 2016, 59(19), 9173-9200. Of particular interest is the compound of Example 31 described in International Publication No. 2014 / 039899, ​​and the compound described as compound 14f in Journal of Medicinal Chemistry, 2016, 59(19), 9173-9200, with the following structure: [ka] The compound of Example 2 described in U.S. Patent Application Publication No. 2017 / 119766, and the compound of International Publication Brochure No. 2016 / 065226, [ka] This includes the compound of Example 223, or Compound 1 described in International Publication No. 2016 / 201280, Compound 1 described in International Publication No. 2017 / 059702, or Compound 1 described in International Publication No. 2017 / 118277; or a pharmaceutically acceptable salt thereof.

[0145] Of particular interest are the compounds described in International Publication No. 2015 / 079417, such as N-(3-(5-((1-acryloylazetidine-3-yl)oxy)-6-aminopyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-((1-propioloylazetidine-3-yl)oxy)pyrimidine-4-yl N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylpropiolamamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2- Methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylbuta-2-inamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-ethylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -Fluorobenzamide; N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(buta-2-inamide)propoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)-N-(3-(6-amino-5-(2-(N-methylbut-2-ynamide)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, and N-(3-(6-amino-5-(3-(N-methylacrylamide)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof.;

Brief Description of Drawings

[0146] [Figure 1] It is the X-ray powder diffraction pattern of Form HA. [Figure 2] It shows the differential scanning calorimetry (DSC) trace of Form HA. [Figure 3] It shows the thermogravimetric analysis (TGA) trace of Form HA. [Figure 4] It shows the X-ray powder diffraction pattern of Form A. [Figure 5] It shows the differential scanning calorimetry (DSC) trace of Form A. [Figure 6] It shows the TGA trace of Form A. [Figure 7] It shows the X-ray powder diffraction pattern of Form B. [Figure 8] It shows the differential scanning calorimetry (DSC) trace of Form B. [Figure 9] It shows the TGA trace of Form B. [Figure 10] It shows the X-ray powder diffraction pattern of the hippurate (1:1) of Form Example 1. [Figure 11] It shows the differential scanning calorimetry (DSC) trace of the hippurate (1:1) of Form Example 1. [Figure 12] It shows the TGA trace of the hippurate (1:1) of Form Example 1. [Figure 13] It shows the X-ray powder diffraction pattern of the hydrochloride (1:1) of Example 1. [Figure 14] It shows the differential scanning calorimetry (DSC) trace of Form hydrochloride (1:1). [Figure 15]The TGA trace of the hydrochloride (1:1) of morphological example 1 is shown. [Examples]

[0147] Examples of the present invention This disclosure is further illustrated by the following examples and synthesis schemes, which should not be construed as limiting this disclosure in scope or spirit to the specific procedures described herein. It should be understood that examples are provided to illustrate certain embodiments, and that no limitation to the scope of this disclosure is intended therein. It should be further understood that various other embodiments, variations thereof, and equivalents that can be conspicuous to those skilled in the art may be used without departing from the spirit of this disclosure and / or the scope of the appended claims.

[0148] The compounds of this disclosure can be prepared by methods known in the art of organic synthesis. In all of these methods, it is understood that protecting groups for sensitive or reactive groups may be used as necessary in accordance with general principles of chemistry. Protecting groups are handled in accordance with standard methods of organic synthesis (TW. Green and PG. M. Tuts (2014), Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage in the synthesis of the compounds using methods readily apparent to those skilled in the art.

[0149] Unless otherwise specified, reagents and solvents were obtained and used from private suppliers.

[0150] The chemical names were generated using CambridgeSoft's ChemBioDraw Ultra v14.

[0151] The temperature is indicated in degrees Celsius. Unless otherwise stated, evaporation is usually carried out under reduced pressure, typically at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods, such as microanalysis and spectroscopic properties, e.g., MS, IR, NMR. The abbreviations used are common in the art.

[0152] Abbreviations AA Acetic acid ACN Acetonitrile CPME Cyclopentyl methyl ether DCM Dichloromethane DMSO Dimethyl sulfoxide EtOAc Ethyl acetate EtOH Ethanol FA Formic acid G Gram H Hour(s) Hz / MHz Hertz / Megahertz IC50 50% inhibitory concentration IL-1β Interleukin 1 beta IPA Isopropyl alcohol LC-MS Liquid chromatography - mass spectrometry LiAlH4 Lithium aluminum hydride(IV) M Mole MCC Microcrystalline cellulose MEK Methyl ethyl ketone MeOH Methanol min Minute mL / L Milliliter / liter Mmol Millimole MTBE Methyl tert-butyl ether NMR Nuclear magnetic resonance Ppm Parts per million Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) RP Reverse phase Rpm Revolutions per minute RPMI (Roswell Park Memorial Institute) RT Room temperature (Celsius) Rt retention time Rochelle's salt: Sodium potassium tartrate tetrahydrate TEA (Triethylamine) TEAC Tetraethylammonium Chloride TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) TNF-α Tumor necrosis factor-α UPLC (Ultra High Performance Liquid Chromatography)

[0153] Analysis details NMR: Measurements were performed with or without tetramethylsilane (TMS) as an internal standard using a Bruker Ascend® (400 MHz) spectrometer or a Bruker Ultrashield® 400 (400 MHz) or Bruker Ascend® (400 MHz) or Bruker cryo system (600 MHz) spectrometer. Chemical shifts (δ) were reported in ppm from TMS to low field, and spectral splitting patterns were shown as singlelines (s), doublelines (d), triplelines (t), quadruples (q), quintlines (quint), heptlines (sept), multilines, undissolved or overlapping signals (m), and broad signals (br). The deuterated solvents are indicated in parentheses and have chemical shifts of dimethyl sulfoxide (δ 2.50 ppm), methanol (δ 3.31 ppm), chloroform (δ 7.26 ppm), or other solvents as shown in the NMR spectral data. • ULC-MS (Method 1): System: Waters Acquity UPLC with Waters SQ detector. Column: CORTECS C18 2.7μm 2.1×50mm, Column temperature: 80℃. Gradient: 1% to 50% B in 1.4 minutes; 50% to 98% B in 0.3 minutes, A = water + 4.76% isopropanol + 0.05% FA + 3.75 mM AA, B = isopropanol + 0.05% FA, flow rate: 1.0 mL / min. UPLC-MS Basic: System: Waters Acquity UPLC with Waters SQ detector. Column: Type: XBridge(registered trademark) BEH(trademark) C18 2.5μm 2.1×50mm, Column temperature: 80℃. Gradient: 2% to 98% B in 1.4 minutes, A = water + 5mM NH4OH, B = acetonitrile + 5mM NH4OH, Flow rate: 1.0 mL / min. • UPLC-MS (Method 2): System: Waters Acquity UPLC with Waters SQ detector. Column: Waters Acquity UPLC BEH C18, Column temperature: 40°C. Gradient: 5% to 95% B over 8 minutes; hold 95% B for 2 minutes, A = 95% water + 5% acetonitrile + 0.05% TFA, B = 5% water + 95% acetonitrile + 0.05% TFA, flow rate: 0.5 mL / min.

[0154] Mass spectrometry results are reported as the mass-to-charge ratio.

[0155] Preparative separation method • Flash column chromatography system: System 1: Teledyne ISCO, CombiFlash Rf. Column: Pre-packed RediSep RF cartridge. The samples were typically adsorbed onto isolute. System 2: Isolera One Biotage Chromatography System Column: Pre-packed Biotage SNAP cartridge

[0156] All starting materials, constituent units, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are commercially available or can be produced by organic synthesis methods well known to those skilled in the art.

[0157] Synthesis of intermediates Intermediate 1: (R)-6-chloro-3-((1-methylpiperidine-3-yl)amino)pyridazine-4-carboxylate methyl [ka] To a solution of methyl 3,6-dichloropyridazine-4-carboxylate (3.0 g, 14.49 mmol) in dry THF (20 mL), triethylamine (3.03 mL, 21.74 mmol) and (R)-1-methylpiperidine-3-amine (1.99 g, 17.39 mmol) were added by RT. The mixture was heated to 60°C and stirred for 6 days. The reaction mixture was diluted with ELISA, and brine was added. The phases were separated, the aqueous layer was extracted with ELISA, and the combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by column chromatography on silica gel using DCM and MeOH (0-10%) to obtain the title compound as an orange solid. UPLC / MS (method 1): Rt=0.28min;MS m / z 285.2[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ(ppm)7.85(s,1H),4.43-4.26(m,1H),3.88(s,3H),3.18- 2.99(m,2H),2.41-2.29(m,2H),2.21(s,3H),1.72-1.56(m,3H),1.57-1.46(m,1H).

[0158] Intermediate 2: (R)-6-chloro-3-((1-methylpiperidine-3-yl)amino)pyridazin-4-yl)methanol [ka] LiAlH4 (1 M in THF, 1.84 mL, 1.84 mmol) was added to a solution of intermediate 1 (0.5 g, 1.76 mmol) in dry THF (10 mL) under a nitrogen atmosphere at -10°C. The mixture was stirred at -10°C for 40 minutes, then quenched by dropwise addition of a saturated solution of Rochelle salt, stirred at RT for 15 minutes, and then pharmaceutically acceptable (siRNA) was added. The phases were separated, and the aqueous layer was extracted with siRNA (twice). The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain the oil. The crude product was purified by column chromatography on silica gel using DCM and 0%-20% MeOH (5% aq. NH4OH) to obtain the title compound. UPLC / MS Basic Method: Rt=0.58min; MS m / z 257.3[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.30(s,1H),6.03(d,1H),5.68-5.59(m,1H),4.41-4.32(m,2H),4.22-4.09(m,1H),2.85-2.75(m,1H) ),2.56-2.50(m,1H),2.16(s,3H),2.06-1.88(m,2H),1.83-1.74(m,1H),1.71-1.62(m,1H),1.57-1.46(m,1H),1.45-1.32(m,1H).

[0159] Intermediate 3: 2-iodo-3-methyl-5-(trifluoromethyl)phenol (can be prepared as described in International Publication No. 2020 / 234715, Int B007) [ka] To an ice-cold solution of 3-methyl-5-(trifluoromethyl)phenol (13.03 g, 74 mmol) in 370 mL of toluene, NaH (60% dispersion in mineral oil, 5.92 g, 148 mmol) was added. The suspension was stirred at 0°C for 30 minutes, then iodine (18.77 g, 74 mmol) was added in small amounts, and stirring was continued for 3 hours. The mixture was diluted with water, acidified to pH=5 with 2 M HCl, and extracted with siRNA. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and evaporated. The crude product was purified by column chromatography on silica gel (220 g) using cyclohexane and siRNA (5%~100%) to obtain the title compound as a yellow oil. 1 H NMR(400MHz,CDCl3)δ(ppm)7.08-7.04(m,2H),5.74(s,1H),2.50(s,3H).

[0160] Intermediate 4: 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (can be prepared as described in International Publication No. 2020 / 234715, Int B010) [ka] (1) 1-(ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl)benzene [ka] (Chloromethoxy)ethane (3.35 g, 35.50 mmol) was added dropwise to a white suspension of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (intermediate 3, 8.50 g, 28.10 mmol) and Cs2CO3 (9.17 g, 28.10 mmol) in 30 mL of dry DMF. The reaction mixture was stirred at RT for 2 hours and then evaporated to dryness. The crude product was purified by column chromatography on silica gel using cyclohexane and RINKAN (0%~5%) to obtain the title compound.

[0161] (2) 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] A solution of 1-(ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl)benzene (10 g, 27.80 mmol), 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (20.15 mL, 139 mmol), and NEt3 (28.6 mL, 205 mmol) in 60 mL of 1,4-dioxane was purged with nitrogen. Pd(OAc)2 (0.81 g, 3.61 mmol) and biphenyl-2-yl-dicyclohexylphosphane (2.33 g, 6.66 mmol) were added, and the mixture was stirred at 80°C for 18 hours. Next, it was cooled to RT, diluted with ethyl acetate, and washed with saturated NH4Cl, water, and brine. The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography on silica gel using cyclohexane and CH2Cl2 (0%~20%) to obtain the title compound.

[0162] (3) 3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol TFA (44.9 mL, 583 mmol) was slowly added at 0°C to a solution of 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.00 g, 19.43 mmol) in 250 mL of CH2Cl2. The reaction mixture was stirred at 0°C for 20 minutes and then evaporated. The resulting oil was purified by column chromatography on silica gel using cyclohexane and CH2Cl2 (0%~100%) to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.80(s,1H),6.92(s,1H),6.82(s,1H),2.30(s,3H),1.30(s,12H).

[0163] Synthesis of the Examples Example 1: (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol [ka] (R)-(6-chloro-3-((1-methylpiperidine-3-yl)amino)pyridazin-4-yl)methanol (intermediate 2, 0.25 g, 0.83 mmol), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (intermediate 4, 0.3 g, 0.99 mmol) and a 2 M aqueous solution of Na2CO3 (1.2 mL) were suspended in dioxane (7 mL), and the mixture was purged with nitrogen for 5 minutes. Pd(PPh3)4 (47.8 mg, 0.041 mmol) was added, and the mixture was stirred at 120°C for 1 hour under microwave irradiation. The reaction mixture was diluted with DCM and brine, and the phases were separated. The aqueous layer was extracted with DCM, and the combined organic layers were dried / filtered using an isolute phase separator and evaporated to dryness. The residue was purified by column chromatography on silica gel using DCM and 0%-20% MeOH (5% aq. NH4OH) to obtain a pale yellow solid. This solid was dissolved in MeOH at 60°C, the volume was reduced, and the solution was cooled to RT overnight. The MeOH supernatant was removed, and the resulting crystals were dried under high vacuum to obtain the title compound. UPLC / MS (method 1): Rt=0.61 min; MS m / z 397.4 M+H] + . 1¹H NMR (400MHz, DMSO-d6) δ(ppm) 10.18 (br s, 1H), 7.22 (s, 1H), 7.13-7.02 (m, 2H), 5.98-5.87 (m, 1H), 5.61-5.49 (m, 1H), 4.47-4.37 (m, 2H), 4.34-4.23 (m, 1H), 2.89-2.79 (m, 1H), 2.57-2.43 (m was not observed due to DMSO, 1H), 2.19 (s, 3H), 2.12 (s, 3H), 2.09-1.94 (m, 2H), 1.86-1.77 (m, 1H), 1.75-1.65 (m, 1H), 1.62-1.39 (m, 2H).

[0164] Alternative synthesis of Example 1: Example 1 can be prepared according to the following scheme. [ka]

[0165] Step 1: [ka] Compound 1 (41.2 g, 571.3 mmol, 1.2 eq.), pyridine (37.7 g, 476.6 mmol, 1 eq.), and DCM (60 g) were packed into reactor 1. Reactor 1 was stirred for 1 hour at a temperature of 20-30°C. Compound 2 (100 g, 476.1 mmol, 1 eq.) and DCM (600 g) were packed into reactor 2. Reactor 2 was cooled to a temperature of -10-0°C. The mixture from reactor 1 was added dropwise to reactor 2, reactor 1 was rinsed with MTBE (150 g), and the whole was stirred at a temperature of -10-0°C for 1-3 hours. Next, reactor 2 was adjusted to 20-30°C and the whole was stirred for 17-20 hours. 200 g of 0.1 N hydrochloric acid (aqueous solution) was added dropwise to reactor 2 at a temperature of 20-30°C. The aqueous layer and the organic layer were separated, and the organic layer was recovered in reactor 2. 200 g of 7% NaHCO3 (aqueous solution) was added to reactor 2, and the pH was adjusted to 6-7 at a temperature of 20-30°C. The organic layer was recovered, washed with water (200 g), and then concentrated under vacuum at a temperature below 40°C to obtain crude compound 3 as oil. 1H NMR(300MHz,CDCl3)δ 5.67(s,1H),3.78(s,3H),2.40(s,3H).

[0166] Step 2 [ka] Compound 3 (100 g, 594.8 mmol, 1.0 eq.), TEA (60.2 g, 594.9 mmol, 1 eq.), and 4 (297.8 g, 2.974 mol, 5 eq.) were packed into reactor 1. Reactor 1 was stirred for 20 hours at a temperature range of 90-100°C. After the reaction was complete, the mixture was cooled to a temperature range of 15-25°C. Water (200 g) and toluene (450 g) were added to the reaction mixture. 10% citric acid (aq.) was added dropwise to reactor 1, and the pH was adjusted to 6-7 at a temperature range of 20-30°C. The aqueous layer and the organic layer were separated, and the organic layer was washed twice with 10% NaCl (aq.) (200 g). The organic layer was collected and concentrated under vacuum below 70°C to obtain the crude product as oil. 1 H NMR(300MHz,CDCl3)δ 11.91(s,1H),7.11(s,1H),6.98(s,1H),2.71(s,3H),2.66(s,3H). LCMS(m / z,ESI) calculated value C 10 H 10 F3O2 + [M+H] + :219.0

[0167] Step 3: [ka] Compound 5 (100 g, 458.3 mmol, 1.0 eq.) and 2M KOH (aq.) (800 g) were packed into reactor 1, and the reaction mixture was stirred for 1 hour at a temperature range of 20-30°C. Compound 6 (212.1 g, 2.86 mol, 6.2 eq.) and water (410 g) were packed into reactor 2. 733 g of 2M KOH (aq.) was added to reactor 1 at a temperature range of -5-0°C, and the mixture was stirred for 1 hour. The aqueous layer from reactor 1 was slowly added to reactor 2 at a temperature range of -5-0°C. The reaction mixture was stirred for a further 20 hours at a temperature range of -5-0°C. The pH was adjusted to 9-10 using acetic acid at a temperature range of -5-5°C. DCM (768 g) was packed into reactor 2, and the organic layer was separated and collected. The pH was further adjusted to 4-5 using acetic acid. Next, the pH was adjusted to 8-9 with NH3.H2O at a temperature range of 10-20°C. N2H4.H2O (80% w / w, 71.7g) was added to the mixture at a temperature range of 10-20°C. Subsequently, the temperature of the mixture was adjusted to 90-100°C and the whole mixture was stirred for 20 hours. The mixture was cooled to a temperature range of 30-40°C and the pH was adjusted to 6-7 with acetic acid. 2-MeTHF (800g) was added to the mixture, the organic layer was collected, and filtered through a silica gel pad. After concentrating the solution to 600-700g, heptane (680g) was added dropwise at a temperature of 40-50°C. The mixture was cooled to 15-25°C over 5 hours, stirred for a further 3 hours at 15-25°C, and then filtered. The wet cake was slurryed with MeOH (600g) and water (800g) at a temperature of 40-50°C, and the mixture was cooled to a temperature of 15-25°C over 5 hours, after which it was stirred for a further 3 hours. The wet cake was dried at a temperature of 40-50°C for 20 hours to obtain product 7 (42.1g) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 13.21(br s,1H),10.38(br s,1H),7.41(d,J=9.7Hz,1H),7.10(d,J=13.1Hz,2H),6.94(d,J=9.7Hz,1H),2.19(s,1H). LCMS(m / z,ESI)UPLC-MS(Method 2) Calculated value C 12 H 10 F3N2O2 + [M+H] + 271.1

[0168] Step 4 [ka] Compound 7 (17.4g, 64.5 mmol, 1.0 eq.), TEAC (21.4g, 129.1 mmol, 2 eq.), POCl3 (14.8g, 96.8 mmol, 1.5 eq.), and ACN (70g) were packed into reactor 1. The mixture was stirred at a temperature of 15-25°C for 17 hours. After the reaction was complete, water (280g) was packed into reactor 2, and the whole was heated to 50°C. The mixture was slowly transferred from reactor 1 to reactor 2 at a temperature of 45-55°C. The reaction mixture was stirred at a temperature of 45-55°C for 16 hours, then the mixture was filtered, and the wet cake was washed with water (40mL). The wet cake was packed into reactor 2, water (140g) was added, and the pH was adjusted to 7-8 with 2% aqueous ammonia solution (14g). The reaction mixture was filtered, and the resulting wet cake was washed twice with water (25g*2). The wet cake was dried at 60°C, yielding 14.6 g of the product as a white solid. 1 H NMR (400MHz, DMSO-d6): δ 10.23(s,1H),7.78(d,J=8.8Hz,1H),7.61(d,J=9.0Hz,1H),6.95(s,1H),6.89(s,1H),1.89(s,3H). HRMS (high resolution mass spectrometry) m / z, ESI) calculated value C 12 H9ClF3N2O + [M+H] + :289.0284

[0169] Step 5 [ka] Compound 8 (17.2 g, 1.0 eq.), ACN (172 mL), and Cs2CO3 (23.3 g, 1.2 eq.; 200 mesh) were packed into a reactor at a temperature of 20–30°C. The mixture was stirred at 50°C for 2 hours. Then, BnCl (8.3 g, 1.1 eq.) was added dropwise to the reactor. The mixture was stirred at 50°C for 10 hours. The mixture was cooled to room temperature, and water (51 g) was added to the mixture. After stirring for 30 minutes, the organic layer was collected, and H2O (330 g) was added dropwise to the organic layer at a temperature of 20–30°C, followed by stirring for 3 hours. The reaction mixture was filtered, and the cake was washed with water (51 g). The wet cake was vacuum-dried at 55°C to obtain 21.1 g of product as a light brown solid. 1 H NMR(400MHz,DMSO-d6)δ 7.80(d,J=8.8Hz,1H),7.69(d,J=9.0Hz,1H),7.17(d,J=12.1Hz,2H),7.12-6.97(m,5H),4.96(s,2H),1.90(s,3H). HRMS (high resolution mass spectrometry) (m / z, ESI) calculated value C 19 H 15 ClF3N2O + [M+H] + :379.1378.

[0170] Step 6 [ka] Compounds 9 (20 g, 52.8 mmol, 1 eq.), 10 (13.8 g, 73.9 mmol, 1.4 eq.), t-BuOLi (25.4 g, 316.8 mmol, 6 eq.), and CPME (260 mL) were packed into the reactor. Next, the reactor was placed under an N2 atmosphere. Then, Pd(dppf)Cl2 (3.1 g, 4.22 mmol, 0.08 eq.) was added to the reactor under an N2 atmosphere, and the mixture was stirred at a temperature of 60-70°C for 16 hours. After the reaction was complete, the mixture was cooled to a temperature of 20-30°C. 4% HCl (aq.) (310 g) was added to the mixture to adjust the pH to 1-2. The aqueous layer was collected and further extracted twice with isopropyl acetate (150 mL x 2). The pH of the aqueous layer was adjusted to 8-9 with 20% NaOH (aq.), and extracted twice with isopropyl acetate (200 mL x 2). The combined organic layer was concentrated to approximately 260 g, and n-heptane (320 g) was added dropwise to the mixture at 50°C. After cooling the mixture to 0°C, it was filtered to obtain a wet cake. After drying at 50°C for 16 hours, 16.9 g of the dried product was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.11-6.99(m,7H),6.66(d,J=9.3Hz,1H),6.56(d,J=7.8Hz,1H),4.93(s,2H),3.92-3.80(m,1H),2.64(d,J=9.0Hz,1H),2.34-2.28(m,1H),1 .96(s,3H),1.92(s,3H),1.86-1.76(m,1H),1.77-1.66(m,1H),1.66- 1.55(m,1H),1.54-1.43(m,1H),1.40-1.25(m,1H),1.16-1.02(m,1H). HRMS (high resolution mass spectrometry) (m / z, ESI) calculated value C 25 H 28 F3N4O + [M+H] + :457.2232.

[0171] Step 7 [ka] Compound 11 (54 g, 118.3 mmol, 1 eq.), 8% H2O2 (aq.) (7.23 g, 212.9 mmol, 1.8 eq.), TFA (26.97 g, 236.6 mmol, 2 eq.), 1,1'-bis(diphenylphosphin)ferrocenedioxide (dppfO2) (0.69 g, 1.18 mmol, 0.01 eq.), and MeOH (504 mL) were packed into the reactor. The reaction mixture was pumped via a blue light reactor (450 nm) at a flow rate of 30°C. After completion, the mixture was quenched with 10% Na2SO3 (aq.). The pH of the mixture was adjusted to 8-9 with 10% Na2SO3 (aq.). The mixture was extracted twice with isopropyl acetate (600 mL x 2). Next, the combined organic layers were concentrated under vacuum at 40-50°C, and the crude product was purified by column chromatography. 46 g of the product was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.37-7.23(m,8H),5.98(d,J=7.8Hz,1H),5.61(t,J=5.2Hz,1H),5.18(s,2H),4.48-4.38(m,2H),4.35-4.25(m,1H),2.91-2.80( m,1H),2.19(s,3H),2.16(s,3H),2.10-1.98(m,2H),1.87-1.79(m,1H),1.76-1.66(m,1H),1.61-1.51(m,1H),1.49-1.40(m,1H). HRMS (high resolution mass spectrometry) (m / z, ESI) calculated value C 26 H 30 F3N 4 O 2+ [M+H] + :487.2321.

[0172] Step 8 [ka] Compound 12 (25.3 g, 52.08 mmol, 1 eq.), 20% Pd(OH)2 / C (50% wet, 7.3 g), and MeOH (860 mL) were packed into the reactor. The mixture was stirred at 25°C for 17 hours under an H2 pressure of 1 bar. After the reaction was complete, the mixture was filtered through an MCC pad. The filtrate was concentrated, and acetonitrile (approximately 150 g) was added at a temperature of 40–50°C. The mixture was cooled to 10–20°C and filtered. Next, the wet cake was washed with acetonitrile (100 mL) and MeOH (10 mL) at 50°C for 2 hours, and the mixture was cooled to a temperature of 20–30°C. The wet cake was dried at 50°C to obtain 14.4 g of product. 1 H NMR(400MHz,DMSO-d6)δ 10.12(br s,1H),7.22(s,1H),7.11(s,1H),7.06(s,1H),5.95(d,J=7.9Hz,1H),5.58(br s,1H),4.42(s,2H),4.35-4.18(m,1H),2.84(d,J=10.4Hz,1H),2.19(s,3H),2.12(s,3H),2. 09-1.96(m,2H),1.88-1.76(m,1H),1.75-1.64(m,1H),1.61-1.50(m,1H),1.50-1.37(m,1H). HRMS (high resolution mass spectrometry) (m / z, ESI) calculated value C 19 H 24 F3N4O2 + [M+H] + :397.1160.

[0173] Crystal morphology of Example 1: 1. Preparation of crystal morphology: 1.1:Form H A Preparation: Example (A): (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol form A (Example 1, 30 mg, see below for preparation) in 1 mL of acetonitrile / water (94.35 / 4.11, v / v, a w(=0.6) was added, and the suspension was stirred with RT. After 3 days, the suspension was filtered, and the wet cake was air-dried for 4 hours to obtain (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol hydrate H A I obtained it.

[0174] Example (B): (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (Example 1, 2.0 g) was dissolved in 34 g of IPA / water (80 / 20, w / w) at 70°C with a stirring speed of 250 rpm. The temperature was cooled to 45°C in 30 minutes, and then a small amount of H prepared in Example (A) was added. A (10 mg) was added. After holding for 3 hours, 5 g of water was added dropwise over 20 minutes and held for 4 hours. The temperature was cooled to 0°C over 7 hours, the suspension was filtered, and the wet cake was washed with IPA / water (70 / 30, w / w). The wet cake was vacuum dried at 45°C for 4 hours and then at 50°C for 3 hours.

[0175] 1.2: Preparation of Morphology A Example (A): Water (19.7 kg), intermediate 2 (1.25 kg, 4.87 mol, 1.0 equivalent), 2-methyltetrahydrofuran (21.4 kg), intermediate 4 (1.76 kg, 5.83 mol, 1.2 equivalents), NaOtBu (1.40 kg, 14.57 mol, 3 equivalents), and 1,1'-bis(diisopropylphosphin)ferrocenepalladium dichloride (0.175 kg, 0.29 mol, 0.06 equivalents) were packed into a reactor under nitrogen. The resulting solution was stirred at 70°C for 16 hours, and the reaction mixture was extracted twice with aqueous HCl. The resulting aqueous phases were combined and extracted with 2-methyltetrahydrofuran. The organic phase was collected, and the Pd residue was removed by applying N-acetyl-cysteine ​​and SiliaMetS® thiol (Si-THU), respectively. Subsequently, the organic phase was concentrated to dryness (solvent removal), and crystallization was carried out with MeOH and water. The resulting wet product was recrystallized with EtOH and n-heptane. After drying, compound 7a was finally obtained as an off-white solid in 23% yield (402 g, 1.01 mol). (400MHz,DMSO-d6):δ:10.12(s,1H,ArOH),7.23(s,1H,ArH),7.08(dd,2H,ArH),5.95(d ,1H,NH),5.59(s,1H,CH2OH),4.43(s,2H,CH2OH),4.30(tp,1H,CH),3.40(s,1H,CHCH2N ),2.85(m,1H,CHCH2N),2.19(s,3H,Me),2.12(s,3H,Me),2.08(s,2H,CH2CH2N),1.81(m ,1H,CHCH2CH2),1.70(qd,1H,CHCH2CH2),1.55(qd,1H,CH2CH2N),1.46(t,1H,CH2CH2N). 13 C NMR(100MHz,DMSO-d6):δ:155.8,155.1,149.1,139.4,129.6,128.8,126.6,125.6,125.5 ,122.8(CF3),117.1,109.4,109.4,60.5,58.9(CH2OH),55.4,46.7,46.2,23.3,20.0(2C). 19 F NMR(376MHz,DMSO-d6):δ:-61.4. LCMS(m / z,ESI+)UPLC-MS(Method 2):C 19 H 23 Calculated value of F3N4O2: 396.18. Detected [M+H]+: 397.1818.

[0176] Example (B): (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (Example 1, 2.0 g) was dissolved in 32 g of ethanol and 0.8 g of water at 70°C with a stirring speed of 250 rpm. The temperature was cooled to 40°C over 30 minutes, and 80 mg of Mod A seed was added. After holding for 3 hours, 20 mL of n-heptane was added dropwise over 1 hour, and stirring was continued at 40°C for 12 hours. The temperature was cooled to 30°C over 2 hours, and then held for 4 hours. After that, the temperature was cooled to 20°C over 2 hours, and held for 4 hours. Finally, the temperature was cooled to 0°C over 7 hours, and the remaining wet cake was washed with n-heptane. After filtration and washing, the obtained wet cake was vacuum dried at 40°C.

[0177] 1.3: Preparation of Form B: (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 mg) was dissolved in 6 mL of MeOH at 70°C, and the solution was filtered through a 22 μm membrane. The solution / suspension was reheated to 70°C to obtain a clear solution, and then the temperature was cooled to 55°C over 2 hours. After letting the solution stand for 2 hours, the temperature was cooled to 5°C over 10 hours and held overnight. The suspension was filtered, and the wet cake was vacuum-dried at 50°C for 2 hours to obtain (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol form B.

[0178] 1.4: Example 1: Preparation of hippurate (1:1): (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (1.5 g) and 711.9 mg of hippuric acid were added to 30 mL of MEK and stirred at approximately 250 rpm at 50°C. After 4 hours, the temperature was cooled to 25°C over 2 hours and held overnight. The suspension was filtered, the wet cake was washed with MEK, and then vacuum-dried at 50°C for 4 hours to obtain the hippuric acid (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (1:1) salt.

[0179] 1.5: Preparation of Hydrochloride (1:1) in Example 1: Example (A): (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (60 mg) and 11.6 μL of aqueous HCl acid (12 mol / L) were added to 1 mL of methyl ethyl ketone by RT to obtain a suspension. The temperature was raised to 50°C and maintained for 4 hours. After 4 hours, the temperature was cooled to 25°C and maintained over the weekend. The suspension was filtered, the wet cake was washed with MEK, and then vacuum-dried at 50°C for 4 hours to obtain the hydrochloric acid (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (1:1) salt.

[0180] Example (B): (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (100 mg) and 22.08 μL of aqueous HCl acid (12 mol / L) were added to 0.7 mL of MeOH by RT to obtain a clear solution. After adding 1.4 mL of MTBE, a small amount of the HCl salt prepared in Example (A) was added. After curing for 2 hours, 1.4 mL of MTBE was added over 30 minutes and held for 4 hours. The temperature was cooled to 5°C and held overnight. The suspension was filtered and the wet cake was vacuum dried at 50°C for 2 hours.

[0181] 2. Characterization of crystal morphology 2.1 Analyzer 2.1.1 Powder X-ray diffraction method Powder X-ray diffraction (XRPD) patterns were obtained using a Bruker Advance D8 in reflection configuration. The powder was analyzed using a zero-background Si flat sample holder. Cu Kα (λ=1.5418 Å) radiation was used. Patterns were measured in the 2-θ range from 2° to 40°. The error limit for the 2-θ angle is ±0.2°.

[0182] Sample size: 5-10 mg Sample holder: Zero background Si flat sample holder

[0183] [Table 1]

[0184] The most characteristic peaks in the XRPD patterns of each morphology were recorded as A (strong), B (moderate), C (moderate), and D (moderate).

[0185] 2.1.2 Differential Scanning Calorimetry (DSC) Method DSC traces were recorded using a TA Discovery DSC with an aluminum pan (TA, Tzero pan, 901683.901): heating rate 10K / min, temperature range: 0~300℃.

[0186] 2.1.3 Thermogravimetric analysis (TGA) method A TGA trace was recorded using a TA Discovery TGA (TA) with an aluminum pan; heating rate 10K / min, temperature range: room temperature to 300°C.

[0187] 2.2: Crystalline form H A Characterization; 2.2.1 Form H A XRPD data Form H A The XRPD data is shown in Table 1.

[0188] [Table 2]

[0189] 2.2.2 Form H A Differential scanning calorimetry (DSC) data Figure 2 shows morphology H A The DSC trace is shown. The melting onset temperature at the first endothermic peak is 109.1°C (first endothermic peak: 124.5°C), and the melting onset temperature at the second endothermic peak is 235.8°C (second endothermic peak: 236.9°C).

[0190] 2.2.3 Thermogravimetric analysis (TGA) Figure 3 shows morphology H A The TGA trace is shown.

[0191] 2.3: Characterization of Crystal Form A 2.3.1 XRPD data of form A: Table 2 shows the XRPD data for morphology A.

[0192] [Table 3]

[0193] 2.3.2. Differential Scanning Calorimetry (DSC) Data for Form A Figure 5 shows the DSC trace of morphology A. The melting onset temperature at the endothermic peak is 233.6°C (endothermic peak: 234.4°C).

[0194] 2.3.3 Thermogravimetric analysis (TGA) Figure 6 shows the TGA trace of morphology A.

[0195] 2.4: Characterization of Crystal Form B 2.4.1 XRPD data for form B: Table 3 shows the XRPD data for form B.

[0196] [Table 4]

[0197] 2.4.2. Differential Scanning Calorimetry (DSC) Data for Form B Figure 8 shows the DSC trace for morphology B. The melting onset temperature at the endothermic peak is 220.1°C (endothermic peak: 223.4°C).

[0198] 2.4.3 Thermogravimetric Analysis (TGA) of Morphology B Figure 9 shows the TGA trace of morphology B.

[0199] 2.5: Crystal Form Example 1: Characterization of Hippurate (1:1): 2.5.1 Morphological Example 1: XRPD data of hippurate (1:1): Table 4 shows the XRPD data for example 1, hippurate (1:1).

[0200] [Table 5]

[0201] 2.5.2. Morphological Example 1: Differential Scanning Calorimetry (DSC) Data of Hippurate (1:1) Figure 11 shows the DSC trace of Example 1 hippurate (1:1). The melting onset temperature at the endothermic peak is 215.9°C (endothermic peak: 217.1°C).

[0202] 2.5.3 Example 1: Thermogravimetric analysis (TGA) of hippurate (1:1) Figure 12 shows the TGA trace of morphological example 1, hippurate (1:1).

[0203] 2.6: Crystal Form Example 1: Characterization of Hydrochloride Salt (1:1): 2.6.1 XRPD data for Form Example 1 hydrochloride (1:1): Table 5 shows the XRPD data for morphological example 1: hydrochloride (1:1).

[0204] [Table 6]

[0205] 2.6.2. Example 1: Differential scanning calorimetry (DSC) data of hydrochloride (1:1) Figure 14 shows the DSC trace of Example 1 hydrochloride (1:1). The melting onset temperature of the first endothermic peak is 68.3°C (endothermic peak: 91.7°C), and the melting onset temperature of the second endothermic peak is 243.0°C (endothermic peak: 246.8°C).

[0206] 2.6.3 Example 1: Thermogravimetric analysis (TGA) of hydrochloride (1:1) Figure 15 shows the TGA trace of morphological example 1 hydrochloride (1:1).

[0207] Reference Example 1: (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol [ka] This compound can be prepared as described in Example Ex 005 of International Publication No. 2020 / 234715.

[0208] Reference Example 2: (R)-3-methyl-2-(6-((1-methylpiperidine-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol [ka] This compound can be prepared as described in Example Ex 064 of International Publication No. 2020 / 234715.

[0209] Reference example 3: 3-methyl-2-(4-(((R)-1-methylpiperidine-3-yl)amino)-5,7-dihydrofluoro[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [ka] This compound can be prepared as described in Example Ex 42 of International Publication No. 2022 / 135567.

[0210] Biological assays and data The activity of compounds according to the present invention can be evaluated by the in vitro methods described below. Compounds of formula (I) or pharmaceutically acceptable salts thereof exhibit beneficial pharmacological properties, such as the ability to inhibit NLRP3 activity, as shown in the tests provided in the following section, and are therefore indicated for therapies related to NLRP3 inflammasome activity.

[0211] IL-1β secretion assay: Monocyte-derived THP-1 cells (ATCC:TIB-202) were maintained in RPMI medium (RPMI / Hepes + 10% fetal bovine serum + sodium pyruvate + 0.05 mM beta-mercaptoethanol (1000x raw material) + Pen-Strep) according to the supplier's instructions. The cells were differentiated in large quantities for 3 hours with 0.5 μM 13-12-myristate phorbol 13-acetic acid (PMA; Sigma #P8139), the medium was changed, and the cells were cultured in 384-well flat-bottom cell culture plates (Greiner, #781986) at a rate of 50,000 cells per well and differentiated overnight. Compounds in a serial dilution series of 1:3.16 in DMSO were added to the cells at a ratio of 1:100 and incubated for 1 hour. The NLRP3 inflammasome was activated by adding 15 μM (final concentration) of nigericin (Enzo Life Sciences, #BML-CA421-0005), and the cells were incubated for 3 hours. 10 μL of supernatant was removed, and IL-1β levels were monitored using an HTRF (Homogeneous Time-Resolved Fluorescence) assay (CisBio, #62IL1PEC) according to the manufacturer's instructions. Cell viability and pyroptosis were monitored by directly adding PrestoBlue cell viability reagent (Life Technologies, #A13261) to the cell culture plate.

[0212] TNF-α secretion assay: Monocytic THP-1 cells were maintained in RPMI medium according to the supplier's instructions as described above. Undifferentiated cells were cultured in 384-well flat-bottom cell culture plates (Greiner, #781986) at a rate of 50,000 cells per well and rested overnight. Experimental compounds were prepared and added as described above. TNF-α secretion was induced experimentally by adding 1 μg / mL LPS (Sigma, #L4391) or 100 ng / mL Pam3CSK4 (Invivogen, #tlrl-pms), and cells were incubated for 3 hours. 10 μL of supernatant was taken out, and TNF-α levels were monitored using an HTRF assay (CisBio, #62TNFPEC) according to the manufacturer's instructions. Viability was monitored as described above.

[0213] Data interpretation: I C 50 The values ​​were calculated from the plot of percentage inhibition versus inhibitor concentration by logistic fitting according to the following: y = A2 + (A1 - A2) / (1 + (x / IC) 50 )^p) y is the inhibitor concentration, or the percentage of inhibition at x. A1 is the lowest inhibition value, i.e., 0%, and A2 is the highest inhibition value, i.e., 100%. The exponent, p, is the Hill coefficient. Curve fitting was performed using an in-house developed software suite.

[0214] NLRP3-dependent IL-1β secretion was stimulated in PMA-differentiated THP-1 cells by the addition of nigericin, and cytokine levels were measured in serum after 3 hours. As discussed above, activation of the NLRP3 inflammasome requires both an NF-κB-dependent priming step and the addition of an NLRP3 activator. To ensure that the inhibitor does not interfere with the priming step, Pam3CSK4-stimulated NF-κB-dependent TNF-α secretion was monitored as a counterscreen. The inhibitory effect of the compounds of the present invention (IC) for both assays was assessed. 50The data for ) are shown in the table below. IL-1β secretion data were calculated as the arithmetic mean of at least three individual experiments, and TNF-α secretion data were consistent across at least two individual replicates.

[0215] [Table 7]

[0216] hERG channel testing using QPatch technology 4 CHO cells (AVIVA Biosciences Corp, San Diego, CA) stably expressing hERG channels were patched using a single-pore QPatch-HT automated patch-clamp instrument (Sophion Bioscience A / S, Valerup, Denmark). The intracellular solution consisted of 120 mM KCl, 5 mM CaCl2, 2 mM MgCl2, 10 mM ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), 10 mM (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES)), and 4 mM adenosine-5'-tripotassium phosphate (ATP-K2), and the pH was adjusted to 7.2 using KOH. The extracellular solution consisted of 145 mM NaCl, 4 mM KCl, 2 CaCl2, 1 mM MgCl2, 10 mM HEPES, and 0.3% dimethyl sulfoxide (DMSO), adjusted to pH 7.4 with NaOH. All measurements were performed at room temperature, with the blocking agent pre-incubated for 4 minutes. Cells were voltage-clamped at -90 mV, and the hERG current was activated using a voltage step up to +20 mV over 4 seconds. The hERG tail current was measured by dropping to -50 mV over 4 seconds and then returning to -90 mV. This protocol was repeated every 20 seconds. Peak hERG currents were automatically corrected by subtracting the leakage current, which was estimated by measuring the average current between the resting membrane potential and a short depolarization step from -50 mV immediately before the long depolarization step up to +20 mV at the start of the voltage protocol. Test materials were diluted with DMSO stock solution and extracellular solution. The final concentration of vehicle DMS0 did not exceed 0.3%. The effect of the test substance on the hERG tail current was evaluated, and 1, 10, and 30 μM of the test substance and a positive control (amitriptyline, 1, 3, and μM) were added to each plate. If the inhibitory activity was >50% at the maximum test concentration, the data point was fitted to the standard Hill equation, and the IC50 value was determined using a fixed minimum current of 0% and a maximum current of 100% (residual current (%) = MaxI + ((MinI - MaxI) / (1 + ((Conc. / IC50)). 50)^Hill)))(In the formula, MaxI=100MinI=0). If the hERG activity was less than 50% at the maximum test concentration, hERG IC 50 The value is estimated to be greater than this (e.g., >30uM). 4) Robert A Pearlstein, K Andrew MacCannell, Guel Erdemli, Sarita Yeola, Gabriel Helmlinger, Qi-Ying Hu, Ramy Farid, William Egan, Steven Whitebread, Clayton Springer, Jeremy Beck, Hao-Ran Wang, Mateusz Maciejewski, Laszlo Urban, Jose S Duca Current Topics in Medicinal Chemistry (2016), 16:1792-1818.

[0217] [Table 8]

[0218] hERG electrophysiological inhibition assay using Qube technology Using a commercially available T-Rex® system (Invitrogen), we created a Chinese hamster ovary (CHO) cell line that overexpresses the α subunit of the hERG channel under the control of a tetracycline-regulated promoter. CHO(T-REx®)hERG cells were maintained in Ham's F-12 nutrient medium (Life Tech) supplemented with 10% fetal bovine serum (HyClone), 1% penicillin-streptomycin, 10 μg / mL blasticidin, and 50 μg / mL zeocin (all from Life Technologies and Thermo Fisher Scientific). To induce hERG expression, 1 μg / mL tetracycline (Sigma-Aldrich) was added to the growth medium 24 hours before current recording. To prepare the cell suspension for the Qube experiment, cells were removed from the culture flask by incubation in Detachin (Genlantis) at 37°C for approximately 5 minutes, and then resuspended in serum-free CHO medium (CHO-SFM II, Life Technologies) at a cell density of 2-3 million cells / mL.

[0219] Patch clamp experiments were performed at 35°C using a Qube APC (Automated Patch Clamp) platform (Sophion Bioscience A / S, Valerup, Denmark) with a 384×10-hole chip. The intracellular KF-Ringer solution consisted of 120KF, 20KCl, 2⁻¹⁰ ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 10(4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), with pH adjusted to 7.2 with KOH. The extracellular solution consisted of 145NaCl, 4KCl, 2CaCl₂, 1MgCl₂, 1⁻¹⁰HEPES, 1⁻¹⁰ glucose, and 0.3% dimethyl sulfoxide (DMSO), with pH adjusted to 7.4 with NaOH. The following voltage protocol was applied to hERG Current induction was performed by holding the cells at a resting membrane potential of -90mV for 100ms, then clamping them at -50mV for 100ms for leak estimation, depolarizing to +20mV over 4 seconds (peak current measurement), and finally repolarizing to -50mV over 4 seconds (tail current recording), before returning to the holding potential of -90mV. Data were sampled at 10kHz, cutoff at 2kHz, and filtered with a Bessel filter. The protocol was repeated 30 times before and after compound application every 15 seconds.

[0220] All compounds were prepared as 10 mM stocks in 100% DMSO, and then serially diluted 1:3 in Labcyte 384-well Echo Qualified LDV (low diamond volume) microplates. Qube assay plates were prepared by transferring 0.15–0.3 μL of compounds from serially diluted plates to 384-well Greiner plates using a Labcyte Echo 650 liquid handler (Beckman). Immediately before the experiment, the compounds in each well were further diluted with extracellular solution using a Biomek i7 liquid handler (Beckman) to form final concentrations of 0.37, 1.1, 3.3, 10, 15, and 30 μM (the 1:33 dilution maintained a final DMSO concentration of ≤0.3% for all samples). Amitriptyline hydrochloride (positive control) and DMSO (0.3%, vehicle control) were added to each plate.

[0221] The results were first examined using Qube-specific Sophion Analyzer software (Sophion Bioscience), and then analyzed using the Data Analysis and Visualization in Discovery (DAVID) software package (Novartis AG). The effect of the compound on hERG current inhibition (normalized inhibition rate (%)) was given by %Inh=(I 化合物 -I ビヒクル ) / I ビヒクル *Calculate using -100, and in the formula, I 化合物 and I ビヒクル These are the average values ​​of the last three leakage-corrected tail hERG currents before and after compound application, respectively. For the compound concentration response, a custom four-parameter fit to the Hill equation was used to derive the IC50 value (with a fixed minimum current of 0% and a maximum current of 100%): I(C) = I b +(( I f -I b )*C n ) / I C 50 +C n Here, C is the input concentration, I(C) is the residual current after inhibition by the test compound, and Ib This is the maximum current before compound application, I f This is a fixed minimum current. All data and assay-specific information are stored in the company's internal database for biochemical assays (Pharon).

[0222] [Table 9]

[0223] Activity in hERG channels is known to cause QTc prolongation in clinical settings, which is undesirable. Such QTc prolongation means that the myocardium takes longer than normal to recharge between heartbeats, which can negatively impact safety. Therefore, in vitro hERG assays are used to evaluate drug molecule-channel interactions and to assist medicinal chemists in identifying drug candidates that do not cause such serious toxicity in clinical settings. hERG IC 50 A higher value is advantageous for evaluating the cardiac safety of the compound.

[0224] Reference examples 1 and 2 are hERG QPatch IC 50 These are 13.1 and 3.9 respectively, and hERG Qube IC 50 These were found to be 4.71 and 5.62, respectively. Surprisingly, Example 1 is hERG QPatch IC 50 and hERG Qube close 50 It was found that this increased considerably, resulting in compounds with an improved drug safety profile. Therefore, the general structure [ka] In a compound of formula (I) having -(CH2) n- OH is OH, where n is 1, 2, 3 or 4, R 4 The introduction of this technology unexpectedly resulted in compounds with improved drug safety profiles. The present specification includes the following embodiments. Section 1. Equation (I): [ka] (In the formula, R 1 Cl, CH3, -OCF 3、 or CF3; R 2 is a halo, C1-C4 alkyl, or halo-C1-C4 alkyl; R 3 is H, CN, C1-C4 alkyl, or halo-C1-C4 alkyl; R 4 is, -(CH2) n -OH, where n is 1, 2, 3, or 4; R 5 It is a monocyclic or bicyclic heterocycline that is unsubstituted or substituted with one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halo, oxo, and -CO2H; or R 5 is either unsubstituted or an aryl or heteroaryl substituted with one or two substituents independently selected from halo, haloC1-C4alkyl, C1-C4alkyl, and -SO2NH2; or R 5 is either unsubstituted or a C3-C6 cycloalkyl group substituted with 1-3 substituents independently selected from C1-C4 alkyl, halo, halo-C1-C4 alkyl, and -OH; or R 5 (This is a C2-C6 alkyl group substituted with one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2.) Compounds thereof, or pharmaceutically acceptable salts thereof. Section 2. R 1 is -OCF3 or CF3; R 2These are C1-C4 alkyl or halo-C1-C4 alkyl; R 3 is H, C1-C4 alkyl, or halo-C1-C4 alkyl; R 4 It is -CH2-OH; R 5 It is a monocyclic or bicyclic heterocycline that is unsubstituted or substituted with one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halo, oxo, and -CO2H; or R 5 is either unsubstituted or an aryl or heteroaryl substituted with one or two substituents independently selected from halo, haloC1-C4alkyl, C1-C4alkyl, and -SO2NH2; or R 5 is either unsubstituted or a C3-C6 cycloalkyl group substituted with 1-3 substituents independently selected from C1-C4 alkyl, halo, halo-C1-C4 alkyl, and -OH; or R 5 This is a C2-C6 alkyl group substituted with one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2. The compounds listed in item 1, or their pharmaceutically acceptable salts. Section 3. R 1 is -OCF3 or CF3; R 2 These are C1-C4 alkyl groups; R 3 H is; R 4 It is -CH2-OH; R 5It is a monocyclic or bicyclic heterocycline that is unsubstituted or substituted with one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halo, oxo, and -CO2H; or R 5 is either unsubstituted or an aryl or heteroaryl substituted with one or two substituents independently selected from halo, haloC1-C4alkyl, C1-C4alkyl, and -SO2NH2; or R 5 is either unsubstituted or a C3-C6 cycloalkyl group substituted with 1-3 substituents independently selected from C1-C4 alkyl, halo, halo-C1-C4 alkyl, and -OH; or R 5 This is a C2-C6 alkyl group substituted with one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2. A compound as described in item 1 or 2, or a pharmaceutically acceptable salt thereof. Section 4. R 5 The compound described in any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, is a monocyclic or bicyclic heterocycline that is either unsubstituted or substituted with one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halo, oxo, and -CO2H. Section 5. R 5 The following: [ka] Selected from, R 5a R is independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H; 5bis independently selected from -OH, hydroxy C1-C4 alkyl, H, halo, oxo, halo C1-C4 alkyl and -CO2H; X is O or CH2; m is 0 or 1, a " is a compound described in any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, which represents a carbon atom bonded to a pyridazine amine. Section 6. R 5 The following: [ka] Selected from, In the formula, R 5a R is independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H; 5b is independently selected from -OH, C1-C4 alkyl, hydroxy C1-C4 alkyl, H, halo, oxo, halo C1-C4 alkyl, and -CO2H; X is O or CH2; m is 0 or 1, * " is a compound described in any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, which represents a carbon atom bonded to a pyridazine amine. Section 7. R 5 The following: [ka] Selected from, In the formula, R 5a R is independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H; 5b m is independently selected from -OH, C1-C4 alkyl, hydroxy C1-C4 alkyl, H, halo, oxo, halo C1-C4 alkyl, and -CO2H; m is 0 or 1, * " is a compound described in any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, which represents a carbon atom bonded to a pyridazine amine. Section 8. R 5 teeth, [ka] And, In the formula, R 5a is independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H; * " is a compound described in any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, which represents a carbon atom bonded to a pyridazine amine. Section 9. R 5a is methyl or H, and in particular, R 5a The compound described in item 8, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl. Section 10. The aforementioned compound, The compound described in item 1, which is (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (Example 1), or a pharmaceutically acceptable salt thereof. Section 11. A pharmaceutical composition comprising a therapeutically effective amount of a compound described in any one of items 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. Section 12. A combination comprising a therapeutically effective amount of any one of the compounds described in items 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents. Section 13. A compound described in any one of items 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 11, or a combination described in item 12, for use as a pharmaceutical. Section 14. A compound described in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of the disease or disorder. Section 15. A method for treating a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of the disease or disorder, comprising administering a therapeutically effective amount of a compound described in any one of items 1 to 10, or a pharmaceutically acceptable salt thereof. Section 16. The aforementioned diseases or disorders include inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as autoinflammatory fever syndrome, cryopyrin-associated periodic syndromes, liver-related diseases / disorders, chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, and alcoholic liver disease, diseases related to inflammatory arthritis, gout, calcium pyrophosphate deposition disease, osteoarthritis, rheumatoid arthritis, arthropathy, kidney-related diseases, hyperoxaluria, lupus nephritis, type 1 / 2 diabetes and related complications, nephropathy, retinopathy, hypertensive nephropathy, inflammation related to hemodialysis, and inflammation related to neuroinflammation. Compounds for use as described in item 14, or methods of treatment as described in item 15, selected from diseases, multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease, cardiovascular / metabolic diseases / disorders, reduced cardiovascular risk, hypertension, atherosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease, acute heart failure, inflammatory skin diseases, hidradenitis suppurativa, acne, wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and diseases / disorders related to cancer, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes, myelofibrosis, chronic obstructive pulmonary disease, chronic myelomonocytic leukemia, and post-myocardial infarction heart failure. Section 17. A method for inhibiting the NLRP3 inflammasome activity in a subject requiring such activity, comprising administering a therapeutically effective amount of a compound described in any one of items 1 to 10, or a pharmaceutically acceptable salt thereof, to the subject requiring such activity.

Claims

1. A compound having the following structure, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

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