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 novel pyridazin-3-ylphenol compounds useful as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The present invention also relates to processes for the preparation of the compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds 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 nucleotide-binding multimer domain-like receptor (NLR) family 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 adaptor proteins apoptosis-associated speck-like protein (ASC) and procaspase-1 to form the NLRP3 inflammasome. NLRP3 inflammasome activation then leads to the release of the proinflammatory cytokines IL-1β (interleukin-1β) and IL-18 (interleukin-18), which, when dysregulated, can cause abnormalities in many disease conditions.

[0003] NLRP3 inflammasome activation typically involves two steps. The first step involves the recognition of pathogen-activating molecular patterns (PAMPs) or danger-activating molecular patterns (DAMPs) by Toll-like receptors, resulting in the activation of nuclear factor kappa B (NF-κB)-mediated signaling, which then upregulates the transcription of inflammasome-associated components, including inactive NLRP3 and pro-IL-1β (pro-interleukin-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 the subsequent assembly of NLRP3, ASC, and pro-caspase-1 into the inflammasome complex. This triggers the conversion of procaspase-1 to caspase-1 and 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 a key player in a variety of inflammasome-related diseases / disorders, including immune, inflammatory, autoimmune, and autoinflammatory diseases, such as autoinflammatory fever syndromes (e.g., 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, nonalcoholic 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 related to inflammatory arthritis such as gout, pseudogout (chondrocalcinosis), 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 Br. J. Pharmacol. 2016, 173, 752-65), hemodialysis-associated inflammation, and kidney-related diseases such as diabetic nephropathy, a kidney-related complication of diabetes (type 1, type 2, and diabetes mellitus), also called diabetic kidney disease (Shahzad et al Kidney Int. 2015, 87, 74-84).Emerging studies have implicated increased production of IL-1β and IL-18 by the NLRP3 inflammasome in neuroinflammation-related disorders, such as brain infections, acute injuries, multiple sclerosis, Alzheimer's disease, and neurodegenerative diseases (Shao et al. Front.Pharmacol. 2015,6,262); cardiovascular / metabolic disorders / diseases, such as cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes and associated complications (e.g., nephropathy, retinopathy), peripheral arterial 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 such as acne, hidradenitis suppurativa (Sweeney et al Br. J. Dermatol. 2015, 173, 1361), asthma, sarcoidosis, age-related macular degeneration; cancer-related diseases / disorders such as myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (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 inflammatory bowel disease can contribute to the onset and progression of various diseases, such as inflammatory bowel disease (e.g., inflammatory bowel disease ...Recent studies have linked mitochondrial dysfunction and NLRP3 activation to neuroinflammation-related 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 neuroinflammation 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 new and / or alternative treatments for these inflammasome-related diseases / disorders as well as others such as autoinflammatory fever syndrome, cryopyrin-associated periodic syndromes (e.g., CAPS), sickle cell disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, hyperoxaluria, secondary hyperoxaluria, pseudogout (chondrocalcinosis), type I / II diabetes and related complications (e.g., nephropathy, retinopathy), disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis), etc.

[0006] WO 2020 / 234715 describes pyridazin-3-ylphenol compounds as NLRP3 inflammasome inhibitors. WO 2022 / 135567 describes pyridazine-containing compounds as NLRP3 inflammasome inhibitors. WO 2022 / 166890 describes substituted pyridazine phenol derivatives as NLRP3 inflammasome inhibitors. Summary of the Invention [Means for solving the problem]

[0007] The present invention provides a compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and a combination 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, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

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

[0009] In a first aspect, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 are Cl, CH3, -OCF 3、 or CF3; R 2 is halo, C1-C4 alkyl, or haloC1-C4 alkyl; R 3 is H, CN, C1-C4 alkyl, or haloC1-C4 alkyl; R 4 is -(CH2) n -OH, where n is 1, 2, 3, or 4; R 5 is a monocyclic or bicyclic heterocyclyl that is unsubstituted or substituted with 1 to 2 substituents independently selected from C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, halo, oxo, and —CO2H; or R 5 is aryl or heteroaryl that is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, haloC1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or R 5is a C3-C6 cycloalkyl that is unsubstituted or substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, halo, haloC1-C4 alkyl, and —OH; or R 5 is C2-C6 alkyl substituted by one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2. or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound according to Formula (I), or a subformula or species thereof, as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical compositions are useful for treating diseases and / or disorders associated with NLRP3 activity.

[0011] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula (I), or a subformula or species thereof, as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, the pharmaceutical compositions being useful for treating diseases and / or disorders associated with NLRP3 activity.

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

[0013] In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, as disclosed herein for use as a medicine.

[0014] In another aspect, the present invention provides a compound of formula (I) as disclosed herein, or a subformula or species thereof, 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 said disease or disorder.

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

[0016] In another aspect, the present invention provides a method of inhibiting NLRP3 inflammasome activity in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), its subformula or species, as disclosed herein, or a pharmaceutically acceptable salt thereof.

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

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

[0019] In another aspect, the present invention provides a compound of formula (I) or a subformula thereof as disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from an inflammasome-associated disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease.

[0020] In another aspect, the present invention provides a compound of formula (I), or a subformula or species thereof, as disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder selected from an inflammasome-associated disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease.

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

[0022] The present invention therefore provides a compound of formula (I): [ka] (In the formula, R 1 is Cl, CH3, -OCF3, or CF3; R 2 is halo, C1-C4 alkyl, or haloC1-C4 alkyl; R 3 is H, CN, C1-C4 alkyl, or haloC1-C4 alkyl; R 4 is -(CH2) n -OH, where n is 1, 2, 3, or 4; R 5 is a monocyclic or bicyclic heterocyclyl that is unsubstituted or substituted with 1 to 2 substituents independently selected from C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, halo, oxo, and —CO2H; or R 5is aryl or heteroaryl that is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, haloC1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or R 5 is a C3-C6 cycloalkyl that is unsubstituted or substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, halo, haloC1-C4 alkyl, and —OH; or R 5 is C2-C6 alkyl substituted by one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2. or a pharmaceutically acceptable salt thereof.

[0023] definition For the purposes of interpreting this specification, the following definitions shall apply unless otherwise indicated, and where appropriate, terms used in the singular shall also include the plural and vice versa.

[0024] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the," and similar terms used in connection with the present invention (especially in connection with the claims), should be construed to include both singular and plural referents unless the context clearly dictates otherwise or is clearly contradicted by the context. Thus, for example, reference to "a compound" includes reference to one or more compounds, and so forth.

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

[0026] As used herein, the term "halogen" or "halo" refers to bromo, chloro, or iodo.

[0027] As used herein, the terms "halo C1-C4 alkyl" or "halogen C1-C4 alkyl" refer to a C1-C4 alkyl radical, as defined above, substituted by one or more halo radicals, as defined above. 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 a group of the formula -OR a refers to the radical of R a is a C1-C4 alkyl radical, 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, substituted by one or more halo radicals, as defined above. Examples of haloC1-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 has been replaced by OH. Examples of hydroxy C1-C4 alkyl include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 4-hydroxy-butyl.

[0031] As used herein, the term "oxo" refers to an oxygen substituent, for example, an oxygen linked by a double bond (eg, to form a ketone).

[0032] As used herein, the term "heterocyclyl" or "heterocyclic" refers to a stable, 5- or 6-membered, non-aromatic monocyclic, bicyclic, or polycyclic ring radical having 3 to 24, preferably 4 to 16, and most preferably 5 to 10 ring atoms, in which one or more, preferably 1 to 4, and especially 1 or 2, ring atoms are heteroatoms selected from, for example, oxygen, sulfur, and nitrogen (the remaining ring atoms are therefore carbon). The term heterocyclyl excludes heteroaryl. A heterocyclic group can be attached to the rest of the molecule through a heteroatom or a carbon atom selected from, for example, oxygen, sulfur, or nitrogen. Heterocyclyls can include, for example, fused or bridged rings and spirocyclic rings. For example, the term "heterocyclyl" can refer to a 5- to 7-membered monocyclic ring containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur. Examples of monoheterocyclyl include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolane, oxathianyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, oxapinyl, oxazepanyl, oxathianyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl. Preferably, the monoheterocyclyl is morpholino, pyrrolidine, or piperidinyl. Examples of bicyclic heterocyclyl include, for example, azabicyclooctanyl or octahydroindolizinyl. In the present invention, the term "heterocyclyl" substituted by an "OH" substituent also includes "heterocyclyl" in which a heteroatom, such as N or S, is oxidized to give, for example, a heterocyclyl N-oxide, heterocyclyl S-oxide, or heterocyclyl S-dioxide. Examples of heterocyclyl N-oxides include piperidinyl-N-oxide. 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, the aryl is a monocyclic, bicyclic, or tricyclic aryl having 6 to 20 carbon atoms. In a preferred embodiment, the aryl is phenyl.

[0034] As used herein, the term "heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring radical containing 1, 2, 3, or 4 heteroatoms individually selected from nitrogen, oxygen, and sulfur. The heteroaryl radical may be bonded via a carbon atom or a heteroatom. Examples of heteroaryl include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, 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 carbon ring atoms. Examples of monocyclic C3-C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferably, "C3-C6 cycloalkyl" is cyclopropyl or cyclobutyl.

[0036] Unless otherwise specified, the term "compounds of the invention" refers to compounds of Formula (I) and subformulas thereof (such as compounds of Formula (II), Formula (II-A), Formula (III), Formula (III-A) as described herein), and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitution). The terms "compounds of the invention" or "a compound of the invention" refer to a compound as defined in any one of the embodiments described below.

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

[0038] In embodiment 1.0, the present invention therefore provides a compound of formula (I): [ka] (In the formula, R 1 is Cl, CH3, -OCF3, or CF3; R 2 is halo, C1-C4 alkyl, or haloC1-C4 alkyl; R 3 is H, CN, C1-C4 alkyl, or haloC1-C4 alkyl; R 4 is -(CH2) n -OH, where n is 1, 2, 3, or 4; R 5 is a monocyclic or bicyclic heterocyclyl that is unsubstituted or substituted with 1 to 2 substituents independently selected from C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, halo, oxo, and —CO2H; or R 5is aryl or heteroaryl that is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, haloC1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or R 5 is a C3-C6 cycloalkyl that is unsubstituted or substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, halo, haloC1-C4 alkyl, and —OH; or R 5 is C2-C6 alkyl substituted by one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2. or a pharmaceutically acceptable salt thereof.

[0039] As embodiment 2.0, there is provided embodiment 1.0, or a pharmaceutically acceptable salt thereof, wherein: R 1 is -OCF3 or CF3; R 2 is C1-C4 alkyl or haloC1-C4 alkyl; R 3 is H, C1-C4 alkyl or haloC1-C4 alkyl; R 4 is -CH2-OH; R 5 is a monocyclic or bicyclic heterocyclyl that is unsubstituted or substituted with 1 to 2 substituents independently selected from C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, halo, oxo, and —CO2H; or R 5 is aryl or heteroaryl that is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, haloC1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or R 5is a C3-C6 cycloalkyl that is unsubstituted or substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, halo, haloC1-C4 alkyl, and —OH; or R 5 is C2-C6 alkyl substituted by one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2.

[0040] As embodiment 3.0, there is provided embodiment 1.0 or 2.0, or a pharmaceutically acceptable salt thereof, wherein: R 1 is -OCF3 or CF3; R 2 is C1-C4 alkyl; R 3 is H; R 4 is -CH2-OH; R 5 is a monocyclic or bicyclic heterocyclyl that is unsubstituted or substituted with 1 to 2 substituents independently selected from C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, halo, oxo, and —CO2H; or R 5 is aryl or heteroaryl that is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, haloC1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or R 5 is a C3-C6 cycloalkyl that is unsubstituted or substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, halo, haloC1-C4 alkyl, and —OH; or R 5 is C2-C6 alkyl substituted by one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2.

[0041] As embodiment 4.0, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 is a monocyclic or bicyclic heterocyclyl that is unsubstituted or substituted with 1 to 2 substituents independently selected from C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, halo, oxo, and —CO2H.

[0042] As embodiment 4.1, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 is the following: [ka] is selected from R 5a is independently selected from C1-C4 alkyl, hydroxyC1-C4 alkyl, and H; R 5b is independently selected from —OH, hydroxyC1-C4 alkyl, H, halo, oxo, haloC1-C4 alkyl, and —CO2H; X is O or CH2; m is 0 or 1, and a " indicates the carbon attached to the pyridazine-amine.

[0043] As embodiment 4.2, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 is the following: [ka] is selected from In the formula, R 5a is independently selected from C1-C4 alkyl, hydroxyC1-C4 alkyl, and H; R 5b is independently selected from —OH, C1-C4 alkyl, hydroxyC1-C4 alkyl, H, halo, oxo, haloC1-C4 alkyl, and —CO2H; X is O or CH2; m is 0 or 1, and *" indicates the carbon atom attached to the pyridazine-amine.

[0044] As embodiment 4.3, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 is the following: [ka] is selected from In the formula, R 5a is independently selected from C1-C4 alkyl, hydroxyC1-C4 alkyl, and H; R 5b is independently selected from —OH, C1-C4 alkyl, hydroxyC1-C4 alkyl, H, halo, oxo, haloC1-C4 alkyl, and —CO2H; m is 0 or 1; * " indicates the carbon atom attached to the pyridazine-amine.

[0045] As embodiment 4.4, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 teeth, [ka] and In the formula, R 5a are independently selected from C1-C4 alkyl, hydroxyC1-C4 alkyl, and H; and * " indicates the carbon atom attached to the pyridazine-amine.

[0046] As embodiment 4.5, there is provided a compound according to embodiment 4.4, or a pharmaceutically acceptable salt thereof, wherein R 5a is methyl or H, in particular, R 5a is methyl.

[0047] As embodiment 5.0, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5is aryl or heteroaryl that is unsubstituted or substituted with 1 to 2 substituents independently selected from halo, haloC1-C4 alkyl, C1-C4 alkyl, and -SO2NH2.

[0048] As embodiment 5.1, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 preferably has the following structure: [ka] is selected from R 5c is independently selected from H, C1-C4 alkyl, and -SO2NH2; and s is 0, 1, or 2.

[0049] As embodiment 5.2, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 preferably has the following structure: [ka] is selected from R 5c are independently selected from H, C1-C4 alkyl, and -SO2NH2.

[0050] As embodiment 5.3, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 preferably has the following structure: [ka] is selected from R 5c are independently selected from H and C1-C4 alkyl.

[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 is a C3-C6 cycloalkyl that is unsubstituted or substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, halo, haloC1-C4 alkyl, and —OH.

[0052] As embodiment 6.1, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 has the following structure: [ka] is selected from R 5e , R 5e ', R 5d , R 5d ', and R 5f are independently selected from H, C1-C4 alkyl, halo, haloC1-C4 alkyl, and —OH.

[0053] As embodiment 6.2, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 has the following structure: [ka] is selected from R 5d and R 5d ' is independently selected from H, halo, haloC1-C4 alkyl, and C1-C4 alkyl.

[0054] As embodiment 6.3, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 has the following structure: [ka] is selected from R 5d are independently selected from H, halo, haloC1-C4 alkyl, and C1-C4 alkyl.

[0055] As embodiment 7.0, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 is C2-C6 alkyl 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] As embodiment 7.1, there is provided a compound according to any one of embodiments 1.0 to 3.0, or a pharmaceutically acceptable salt thereof, wherein R 5 has the following structure: [ka] is selected from R 5h is selected from -NH2, -OH, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2.

[0057] As embodiment 8.0, there is provided a compound according to any one of embodiments 1.0 to 7.1, or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

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

[0059] As embodiment 9.1, there is provided a compound according to embodiment 9.0, wherein said compound is hippurate.

[0060] As embodiment 9.2, there is provided a compound according to embodiment 9.0, wherein said compound is a hydrochloride salt.

[0061] As embodiment 9.3, there is provided a compound according to embodiment 9.0, wherein the compound is a hydrate, particularly a hydrate crystalline form, more particularly, the ratio of compound to water molecules is 1:1.

[0062] As embodiment 10.0, there is provided 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] As embodiment 11.0, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1.0-9.0, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents.

[0064] As embodiment 12.0, there is provided a combination according to embodiment 11.0, wherein the one or more therapeutic agents are independently selected from farnesoid X receptor (FXR) agonists; antilipidogenic agents; antifibrotic agents; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiation therapy, and surgery; urate-lowering therapy; anabolic and cartilage regenerative therapy; 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; beta-2 agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acid drugs (ASA), including aspirin; regenerative therapy treatment; treatment of cystic fibrosis; or treatment of atherosclerosis.

[0065] As embodiment 13.0, there is provided 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 medicament.

[0066] As embodiment 14.0, there is provided a compound according to any one of embodiments 1.0 to 9.0, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of the disease or disorder.

[0067] As embodiment 15.0, there is provided 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 medicament for 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.

[0068] As embodiment 16.0, there is provided a method of 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 according to any one of embodiments 1.0 to 9.0, or a pharmaceutically acceptable salt thereof.

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

[0070] As embodiment 18.0, there is provided a method of inhibiting NLRP3 inflammasome activity in a subject in need thereof, the method comprising administering to a subject in need thereof 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, R 4 But -(CH2) n For compounds of formula (I) where n is 1, 2, 3 or 4, R 4 is C1-C4 alkyl or C1-C4 haloalkyl, 50An increase in hERG IC 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. 50 The higher the value, the more favorable it is for cardiac safety evaluation of the compound.

[0072] It has also been surprisingly found in in vivo experiments that compounds of formula (I) exhibit reduced toxicity compared to analogues of compounds of formula (I).

[0073] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible stereoisomers or as a mixture thereof, e.g., as pure optical isomers or, depending on the number of asymmetric carbon atoms, as stereoisomeric mixtures, such as racemic and diastereoisomeric mixtures. The present invention is intended to encompass all such possible stereoisomers, including racemic mixtures, diastereoisomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included. The present invention is also intended to encompass any pseudo-asymmetric carbon atoms, designated herein as (r)- and (s)-, which are unchanged by mirror reflection but are reversed by interchanging any two entities (PAC 1996, 68, 2193, Basic terminology of stereochemistry IUPAC recommandations 1996).

[0074] As used herein, the term "salt" or "salts" refers to acid addition or base addition salts of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and that are not typically biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0075] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0076] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0077] Organic acids from which salts can be derived 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 the like.

[0078] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0079] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain 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 from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0081] In another aspect, the present invention provides an anti-inflammatory agent, comprising an anti-inflammatory agent, selected from the group consisting of acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate

[0023] The present invention provides a compound of any of the general formulas (e.g., Formula (I), etc.) or examples defined herein in the form of a salt of malonate, mandelate, mesylate, methyl sulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate. In certain aspects, the present invention provides a compound of any of the general formulas (e.g., Formula (I), etc.) in the form of a hippurate or hydrochloride salt.

[0082] In another aspect, the present invention provides a compound of any of the general formulae (e.g., Formula (I)) or Examples defined herein in the form of a sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine salt.

[0083] Any formula shown herein is also intended to represent the unlabeled form of the compound as well as the isotopically labeled form.Isotopically labeled compounds have the structure shown by the formula shown herein, except that one or more atoms are replaced with atoms having selected atomic mass or mass number.The isotope that can be incorporated into the compound of the present invention includes, for example, hydrogen isotopes.

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

[0085] The compounds of the present invention, i.e., compounds of formula (I) containing groups capable of acting as hydrogen bond donors and / or acceptors, can form co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting a compound of formula (I) with a co-crystal former in solution under crystallization conditions and isolating the co-crystal formed thereby. Suitable co-crystal formers include those described in WO 2004 / 078163. Accordingly, the present invention further provides co-crystals comprising compounds of formula (I).

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

[0087] Furthermore, certain isotopes, particularly deuterium (i.e. 2 Incorporation of hydrogen atoms (H or D) may result in certain therapeutic advantages due to better metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, or improved therapeutic index or tolerability. In this context, it is understood that deuterium is considered a substituent of the compounds of formula (I). The concentration of deuterium can be determined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the present invention is designated as deuterium, such compounds have an isotopic enrichment factor for each designated deuterium of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic 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 compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125The present invention includes various isotopically labeled compounds as defined herein, such as 3 H and 14 Radioactive isotopes such as C, or 2 H and 13 These include compounds in which non-radioactive isotopes such as C exist. Such isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction rate studies (e.g., 2 H or 3 H), are useful in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation treatment of patients. 18 F or 125 I-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically 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, substituting the appropriate isotopically labeled reagent for the previously used unlabeled reagent.

[0089] Pharmaceutical Composition As used herein, the term "pharmaceutical composition" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof, 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" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, dyes, and combinations thereof, which would be known to those skilled in the art (see, e.g., Remington: The Science and Practice of Pharmacy, 22 nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0091] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and / or ameliorate a condition, disorder, or disease that is (i) mediated by the NLRP3 pathway, or (ii) associated with NLRP3 activity, or (iii) characterized by NLRP3 activity (normal or abnormal); or (2) reduce or inhibit the activity of NLRP3; or (3) reduce or inhibit the expression of NLRP3. In another non-limiting embodiment, the term "therapeutically effective amount" of a compound of the present invention refers to an amount that, when administered to a cell, or tissue, or noncellular biological material or medium, is effective to at least partially reduce or inhibit the activity of NLRP3; or at least partially reduce or inhibit the expression of NLRP3.

[0092] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In some embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0093] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, disorder, or disease, or a significant decrease in baseline activity of a biological activity or process. Specifically, inhibition of NLRP3 or inhibition of the NLRP3 inflammasome pathway includes reducing the function of NLRP3 or the NLRP3 inflammasome pathway in inducing 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 strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, various species, and active fragments thereof.

[0095] As used herein, the terms "treat," "treating," or "treatment" in reference to any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or suppressing the onset of the disease or at least one of its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible to the patient.

[0096] As used herein, the terms "prevent," "preventing," or "prevention," in reference to any disease or disorder, refers to the prophylactic treatment of the disease or disorder; or the delay in the onset or progression of the disease or disorder.

[0097] As used herein, a subject is "in need of" or "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

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

[0099] Any asymmetric atom (e.g., carbon or other similar) of the compounds of the invention can be present in racemic or enantiomerically enriched, e.g., (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom is in the (R)- or (S)-configuration in at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0100] Thus, as used herein, the compounds of the present invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example they may exist as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0101] Any resulting mixtures of stereoisomers can be separated on the basis of the physical chemical differences of the components into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0102] The resulting racemates of the compounds of the present invention or of any intermediates can be resolved into their optical antipodes by known methods, for example, by separation of their diastereomeric salts obtained with optically active acids or bases and liberating the optically active acidic or basic compounds. In particular, basic components can thus be used to resolve the compounds of the present invention into their optical antipodes, for example, by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, for example, high-performance liquid chromatography (HPLC) using a chiral adsorbent.

[0103] Methods of synthesizing compounds of the present invention The compounds of the present invention can be prepared according to the routes illustrated in the following schemes and / or examples. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to further clarify the invention and does not otherwise limit the scope of the invention as set forth in the claims. In the general methods below, R 1 , R 2 , R 3 , R 4 , R 5 and halo are as previously defined in the above embodiments or limited as specified in the schemes. Unless otherwise noted, starting materials are commercially available or prepared by known methods.

[0104] Reaction Scheme 1 Compounds of the present invention may be prepared as described herein by the reaction sequence shown in Scheme 1 (below), whereby appropriately substituted 3,6-dihalopyridazines (M1) (R 3 is as defined herein, and R 6is methyl) can be reacted with the appropriate amine (M2) (R 5 (as defined herein) to give 6-halopyridazine-3-amine (M3), which is then reduced to 6-halopyridazine-4-alkyl-hydroxy-3-amine (M4), for example, using LiAIH. This intermediate then undergoes a Suzuki cross-coupling reaction with an appropriate boronate (M5), in the form of a boronic acid or ester, such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, using a suitable palladium catalyst, for example Pd(PPh3)4, and aqueous base, typically Na2CO3 or NaHCO3, in a miscible solvent such as DME or dioxane, to give a compound of formula (I), or a pharmaceutically acceptable salt thereof. [ka] Scheme 1.

[0105] The above steps can be extended to prepare the compounds of general formula (I) or pharmaceutically acceptable salts thereof described herein. Depending on the starting materials and selected route as described in Scheme 1, those skilled in the art will know how to prepare the compounds of formula (I) or pharmaceutically acceptable salts thereof. Specific variations or alternative steps are described in the experimental section below.

[0106] The present invention further includes any of the different inventive processes, in which intermediate products obtained at any stage thereof are used as starting materials to carry out the remaining steps, or in which starting materials are formed in situ under the reaction conditions, or in which 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 into each other according to methods generally known to those skilled in the art.

[0107] In another aspect, 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 a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for a specific route of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also involve 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, solutions, suspensions, or emulsions). Tablets can be film-coated or enteric-coated according to methods known in the art. Typically, the pharmaceutical composition comprises: 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, additionally c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired, d) disintegrants, such as starch, agar, alginic acid or its sodium salt or effervescent mixtures; and e) Absorbents, colorants, flavors and sweeteners It is a tablet or gelatin capsule containing the active ingredient together with one or more of the following.

[0108] Methods of using the present invention There is evidence for a role for NLRP3-induced IL-1 and IL-18 in the inflammatory response associated with or resulting from many different 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 responsible for a group of rare 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 comprises three autoinflammatory disorders that are linked on a clinical continuum. These diseases, in order of increasing severity, are familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurological, cutaneous, and articular syndrome (CINCA; also known as neonatal-onset multisystem inflammatory disease, NOMID), all of which have been shown to be caused by gain-of-function mutations in the NLRP3 gene, which result in increased secretion of IL-1β. NLRP3 has also been implicated in many autoinflammatory diseases, including septic 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, especially 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 Rheum. 2011,63(11),3563-74) and has been shown to associate with NLRP3. NLRP3 has also been shown to play a role in many lung diseases, including chronic obstructive pulmonary disorder (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 have 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 implicated 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 nonalcoholic steatohepatitis (Mridha et al. J. Hepatol. 2017, 66(5), 1037-46). A role for NLRP3 through IL-1beta 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 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 damage (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); contact hypersensitivity (bullous pemphigoid) and other conditions (Fang et al. J Dermatol. Sci. 2016,83(2),116-23)), atopic dermatitis (Niebuhr et al. Allergy, 2014,69(8),1058-67), hidradenitis suppurativa (Alikhan et al. J. Am. Acad. Dermatol., 2009,60(4),539-61) and sarcoidosis (Jager et al. Am. J. Respir. Crit. Care Med., 2015,191,A5816) in inflammatory reactions in the lungs and skin (Primiano et al. J. Immunol. 2016,197(6),2421-33); in inflammatory reactions in the joints (Braddock et al. Nat. Rev. Drug Disc, 2004,3,1-10); amyotrophic lateral sclerosis (Gugliandolo et al. 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 diseases, including ulcerative colitis and Crohn's disease (Braddock et al. Nat. Rev. Drug Disc, 2004, 3, 1-10; Neudecker et al. J. Exp. Med.2017,214(6),1737-52; 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, such as 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 implicated in 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 the incidence of lung cancer and all-cause 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). A role for the NLRP3 inflammasome has been demonstrated 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 also in gliomas (Li et al. Am. J. Cancer Res. 2015, 5(1), 442-9), inflammation-induced 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. Res., 2017, 36(1), 116). NLRP3 inflammasome activation has also been shown to mediate tumor cell chemoresistance 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 efficient viral, bacterial, and fungal control.

[0113] NLRP3 activation leads to cell pyroptosis, a hallmark of the disease that plays a key role in the development 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 predicted that inhibitors of NLRP3 would block pyroptosis and the release of pro-inflammatory cytokines (e.g., IL-1beta) from cells.

[0114] Compounds according to any one of the general formulas (e.g., Formula (I), etc.), or any one of the foregoing embodiments, or any one of the exemplified 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 the in vitro tests provided in the next section, and are therefore indicated for use as therapeutic or research chemicals, e.g., tool compounds.

[0115] The compounds of the present invention may be useful in treating an indication selected from an inflammasome-associated disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, e.g., a disease, disorder, or condition in which NLRP3 signaling contributes to the abnormalities and / or symptoms and / or progression and which may respond to NLRP3 inhibition, and which may be treated or prevented according to a compound according to any one of embodiments 1.0-18.0 or any one of the exemplified examples of the invention (e.g., Example 1 disclosed herein), include: I. Inflammation, including inflammatory disorders, such as inflammation resulting from autoinflammatory diseases, inflammation occurring 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 associated with or resulting from: (a) skin conditions such as contact sensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (b) a joint condition 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-related allergies that may have effects less related to the gut (e.g., migraine, rhinitis, or eczema); (e) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including chronic or persistent asthma such as bronchial, allergic, intrinsic, extrinsic or dust asthma and especially late-onset asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, suppurative rhinitis, rhinitis sicca, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis, e.g. 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, Behcet's disease, vasculitis, or Wegener's granulomatosis; (g) immune conditions, e.g., autoimmune conditions such as 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) an infection or condition related to an infection, such as acquired immune deficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (hepatitis A, B, or C or other viral), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, mycobacterium tuberculosis, mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis / epidymitis, Legionnaires' disease, 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 nephritic syndrome; (l) lymphatic conditions such as Castleman's disease; (m) conditions of or related to the immune system, such as hyper-IgE syndrome, lepromatous leprosy, hemophagocytic histiocytosis, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (n) a liver condition such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcohol-induced hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), or primary biliary cirrhosis; (o) Cancer, including those listed herein below; (p) burns, wounds, trauma, hemorrhage 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), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multisystem inflammatory disease (NOMID), Majeed syndrome, septic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), adult-onset Still's disease (AOSD), A20 haploinsufficiency (HA20), childhood granulomatous arthritis (PGA), PLCG2-associated antibody deficiency immunoregulation dysregulation (PLAID), PLCG2-associated autoinflammatory antibody deficiency immunoregulation dysregulation (APLAID) or B-cell immunodeficiency, periodic fever, and sideroblastic anemia with growth retardation (SIFD); III. Immune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid syndrome (APS), antisynthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyendocrine deficiency, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture's 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, opsoclonus-myoclonus syndrome (OMS), optic neuritis, ordinal thyroiditis, thyroiditis, and thyroiditis. 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, Sjogren's syndrome, systemic sclerosis, systemic connective tissue disorders, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Beliefs' disease, Chagas' disease, autonomic neuropathy, endometriosis autoimmune diseases such as hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, vitiligo or vulvodynia, hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome of T-cell engager therapy (CAR-T or bi / trispecific antibody); IV. Lung cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), Langerhans cell histiocytosis (LCH), myeloproliferative neoplasms (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndromes (MDS), acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML), leukemia including promyelocytic leukemia (APML or APL), adrenal gland cancer, anal cancer, basal cell and squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelogenous leukemia (CML), and leukemias including leukemias of the genital lining (GI). Monocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing's family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, renal cancer, laryngeal and hypopharyngeal cancer, liver cancer, pulmonary carcinoid tumors, lymphomas including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, monoclonal gammopathy of undetermined significance (MGUS), smoldering Plasma cell dyscrasias including multiple myeloma and active multiple myeloma, multiple myeloma, cancer of the nasal cavity and paranasal sinuses, nasopharyngeal carcinoma, neuroblastoma, mature T-cell and NK-cell tumors, non-Hodgkin's lymphoma, mature B-cell tumors such as non-Hodgkin's 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 anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's disease Myeloproliferative neoplasms (MPN) 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, cancers including B lymphoblastic leukemia / lymphoma, T lymphoblastic leukemia / lymphoma, histiocytic and dendritic cell neoplasms, post-transplant lymphoproliferative disorders (PTLD); V. Viral infections (e.g., influenza virus, human immunodeficiency virus (HIV), alphaviruses (such as chikungunya virus and Ross River virus), flaviviruses (such as dengue virus and Zika virus), herpesviruses (such as Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxviruses (such as vaccinia virus (modified vaccinia virus Ankara) and myxoma virus), adenoviruses (such as adenovirus 5) or papillomaviruses), bacterial infections (e.g., Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordetella pertussis, Burkholderia pseudomallei, Corynebacterium diphtheriae, Clostridium tetani, tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Haemophilus influenzae, Pasteurella multocida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosainfectious diseases, 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., from Candida species or Aspergillus species), protozoal infections (e.g., from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosoma), helminth infections (e.g., from Schistosoma, Ascaris, Tapeworms or Flukes) and prion infections; VI. Central nervous system diseases such as Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain damage 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. Cardiovascular diseases such as 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, aneurysms, including abdominal aortic aneurysms, cardiovascular risk reduction (CvRR), and pericarditis, including Dressler syndrome, heart failure after myocardial infarction; atrial fibrillation; IX. Respiratory diseases including chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis and idiopathic pulmonary fibrosis; X. Liver disease, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), including advanced fibrosis stages F3 and F4, alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH); XI. Kidney disease, including acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, 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 damage, dry eye, and glaucoma; XIII. Skin diseases including dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cystic skin diseases, and acne conglobata; XIV. Lymphatic conditions such as lymphangitis and Castleman's disease; XV. Depression and mental stress; psychiatric 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 non-silent mutation in NLRP3.

[0116] More particularly, the compounds of the present invention may be useful in the treatment of an indication selected from the following: inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as 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, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), inflammatory arthritis-related diseases (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute, chronic, calcium pyrophosphate crystal deposition disease (CPPD)), kidney-related diseases (e.g., hypertension, hyperlipidemia, rheumatoid arthritis ... oxaluria, lupus nephritis, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, inflammation associated with hemodialysis), diseases associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (e.g., hidradenitis suppurativa, 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 syndromes (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and associated complications (e.g., nephropathy, retinopathy), gout, pseudogout (cartilage calcification), chronic liver disease, NASH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, 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 a disease or disorder preferably 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 (cartilage calcification), chronic liver disease, NASH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0118] Thus, in a further aspect, the present invention provides the use of a compound of any general formula (e.g., Formula (I), etc.), or according to any one of the preceding embodiments (e.g., according to any of Embodiments 1.0-18.0), or according to any one of the exemplified Examples (e.g., Example 1 disclosed herein), or a pharmaceutically acceptable salt thereof, in a method of therapy. 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 one of those listed above, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease or an autoinflammatory disease, such as autoinflammatory fever syndrome (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), a liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), a disease associated with inflammatory arthritis (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute, chronic), a kidney-related disease (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes and and associated complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, inflammation associated with hemodialysis), diseases associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and associated complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g., hidradenitis suppurativa, 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 syndromes (MDS), myelofibrosis).In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and associated complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (cartilage calcification), chronic liver disease, NASH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0119] Thus, in a further aspect, the present invention provides a compound of any one of the general formulas (e.g., Formula (I)), or according to any one of the foregoing embodiments (i.e., according to any one of Embodiments 1.0-18.0), or according to any one of the exemplified examples (e.g., Example 1 disclosed herein), or a pharmaceutically acceptable salt thereof, for use in therapy. 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 one of those listed above, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease or an autoinflammatory disease, such as autoinflammatory fever syndrome (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), a liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), a disease associated with inflammatory arthritis (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute, chronic), a kidney-related disease (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes and and associated complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, inflammation associated with hemodialysis), diseases associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and associated complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g., hidradenitis suppurativa, 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 syndromes (MDS), myelofibrosis).In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and associated complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (cartilage calcification), chronic liver disease, NASH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0120] In another aspect, the present invention provides a method of treating a disease treated by inhibiting NLRP3, comprising administering a therapeutically effective amount of a compound of any one of the general formulas (e.g., Formula (I)), or a compound according to any one of the foregoing embodiments (i.e., according to any one of Embodiments 1.0 to 18.0), or a compound according to any one of the exemplified Examples (e.g., a compound according to any one of Example 1 disclosed herein), or a pharmaceutically acceptable salt thereof. In a further embodiment, the disease is selected from the list above, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, such as autoinflammatory fever syndrome (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), a liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcohol-associated steatohepatitis). liver disease), inflammatory arthritis-related diseases (e.g., gout, pseudogout (cartilage calcification), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute and chronic), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammation-related diseases (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular / The therapeutic agent is selected from metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (e.g., hidradenitis suppurativa, 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 syndromes (MDS), myelofibrosis).In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and associated complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (cartilage calcification), chronic liver disease, NASH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0121] In a further aspect, the present invention provides compounds of any one of the general formulas (e.g., Formula (I)), or according to any one of the foregoing embodiments (i.e., according to any one of Embodiments 1.0-18.0), or according to any one of the exemplified Examples (e.g., Example 1 disclosed herein), or a pharmaceutically acceptable salt thereof, useful in the treatment of 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 due to mutations in NLRP3, resulting in, in particular, increased NLRP3 activity.

[0122] Combination Products and Therapeutic Combinations of the Invention "Combination" refers to a fixed combination or administration combination in a single dosage unit form, wherein a compound of the present invention and a combination partner (e.g., another agent described below, also referred to as a "therapeutic agent" or "coagent") can be administered separately at the same time or within a time frame, particularly where the combination partners exhibit a synergistic, e.g., synergistic, effect. The single components can be packaged in a single kit or separately. One or both components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose before administration. As used herein, the terms "co-administration" and "administration combination" or the like are intended to encompass the administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include therapeutic regimens in which the agents are not necessarily administered by the same route of administration or at the same time. As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining of two or more therapeutic agents, including both fixed and loosely combined therapeutic agents. The term "pharmaceutical combination" as used herein refers to a fixed or non-fixed combination in a single dosage unit form or a kit of parts for administration combination, in which two or more therapeutic agents can be administered separately at the same time or within a time frame, particularly where the combination partners exhibit a cooperative, e.g., synergistic, effect. The term "fixed combination" means that the therapeutic agents, e.g., a compound of the present invention and a combination partner, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the therapeutic agents, e.g., a compound of the present invention and a combination partner, are administered to a patient simultaneously, in parallel, or sequentially as separate entities without any specific time limit, such administration resulting in therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more therapeutic agents.

[0123] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents substantially simultaneously, such as in a single capsule with a fixed ratio of active ingredients. Alternatively, such administration includes co-administration in multiple or separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. The powders and / or liquids may be reconstituted or diluted to the desired dose before administration. In addition, such administration also includes the use of each type of therapeutic agent at approximately the same time or sequentially at different times. In either case, the treatment regimen will provide a beneficial effect of the drug combination in treating the condition or disorder described herein.

[0124] The compounds of the present invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention can be administered separately by the same or different routes of administration, or together in the same pharmaceutical composition with other agents. The therapeutic agent can be, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid, which is therapeutically active or which enhances therapeutic activity when administered to a patient in combination with a compound of the present invention.

[0125] In one embodiment, the present invention provides a product comprising a compound of any of the general formulas (e.g., Formula (I), etc.), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in a therapeutic method. In one embodiment, the therapeutic method is treatment of a disease or condition mediated by NLRP3. A product provided as a combined preparation may comprise a compound of any of the general formulas (e.g., Formula (I), etc.), or a pharmaceutically acceptable salt thereof, and the other therapeutic agent together in the same pharmaceutical composition, or may comprise a composition containing a compound of any of the general formulas (e.g., Formula (I), etc.), or a pharmaceutically acceptable salt thereof, and the other therapeutic agent in separate forms, e.g., in the form of a kit.

[0126] In one embodiment, the present invention provides a pharmaceutical combination comprising 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 preceding embodiments, or a pharmaceutically acceptable salt thereof, and another therapeutic agent. Optionally, the pharmaceutical combination may include a pharmaceutically acceptable carrier, as described above.

[0127] In one embodiment, the present invention provides a kit comprising two or more separate 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 comprises means for keeping the compositions separate, such as containers, divided bottles, or divided foil packets. An example of such a kit is a blister pack commonly used for packaging tablets, capsules, and the like.

[0128] The kits of the invention can be used to administer different dosage forms, e.g., oral and parenteral, to administer the separate compositions at different dosage intervals, or to titrate the separate compositions relative to one another. To facilitate compliance, the kits of the invention typically include instructions for administration.

[0129] In the therapeutic combination of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Moreover, the compound of the present invention and the other therapeutic agent may be combined into a single therapeutic combination (i) before the combined product is released to the physician (e.g., in the case of a kit containing the compound of the present invention and the other therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; or (iii) by the patient themselves, for example, during sequential administration of the compound of the present invention and the other therapeutic agent.

[0130] Thus, 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, wherein the medicament is 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, wherein the medicament is 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 preceding 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 preceding 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), etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, is prepared for administration together with another therapeutic agent. The present invention also provides a further therapeutic agent for use in a method of treating a disease or condition mediated by NLRP3, wherein the further therapeutic agent is prepared for administration together with 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 preceding embodiments, or a pharmaceutically acceptable salt thereof. 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 preceding 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), etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, is administered together with another therapeutic agent. The present invention also provides a method of treating a disease or condition mediated by NLRP3, wherein the other therapeutic agent is administered together with 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 preceding 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), etc.), or a compound according to any one of the preceding embodiments (e.g., according to any of Embodiments 1.0-18.7), or a compound according to any one of the exemplified 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 previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides the use of 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 preceding embodiments, or a pharmaceutically acceptable salt thereof, for treating a disease or condition mediated by the NLRP3 inflammasome pathway, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent.

[0133] In one embodiment, the other therapeutic agent is a therapeutic agent useful in the treatment of an inflammasome-associated disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, as disclosed herein.

[0134] In one embodiment, other therapeutic agents useful in the combination therapy are selected from farnesoid X receptor (FXR) agonists; antilipidogenic agents; antifibrotic agents; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiation therapy, and surgery; uric acid-lowering therapy; anabolic and cartilage regenerative therapy; 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; beta-2 agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acid drugs (ASA), including aspirin; paracetamol; regenerative therapy treatments; treatments for cystic fibrosis; and treatments for atherosclerosis.

[0135] Suitable leukotriene A4 hydrolase (LTA4H) inhibitors for use in combination include, but are not limited to, the compounds disclosed in WO 2015 / 092740, in particular (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid (LYS006), and the compounds disclosed in WO 2022 / 219546.

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

[0137] Suitable beta-2 agonists for use in combination include arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meladrine, metaprotenol, noromilol, orciprenaline, pirbuterol, procaterol, reproterol, ritodrine, rimoterol, salbutamol, salivarium ... Lumefamol, salmeterol, cibenadet, sotenerot, 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 and 5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolone, 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-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4benzoxazin-3-(4 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 optionally is in the form of a racemate, enantiomer, diastereomer, or mixture thereof, and optionally in the form of a pharmacologically compatible acid addition salt.

[0138] Suitable cartilage regeneration therapies for use in combination include, but are not limited to, the ANGPTL3 peptidomimetics disclosed in WO 2014 / 138687 or the chondrogenic activators disclosed in WO 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 WO 2015 / 112900. Suitable anti-LAG-3 inhibitors include, but are not limited to, the antibody molecules disclosed in WO 2015 / 138920. Suitable anti-TIM-3 inhibitors include, but are not limited to, the antibody molecules disclosed in WO 2015 / 117002. Suitable anti-TIM-3 inhibitors include, but are not limited to, the antibody molecules disclosed in WO 2015 / 117002. Suitable anti-PDL1 inhibitors include, but are not limited to, the antibody molecules disclosed in WO 2016 / 061142.

[0140] Suitable Toll-like receptor inhibitors (TLR7 / 8 inhibitors) for use in the combination include, but are not limited to, compounds disclosed in WO 2018 / 04081.

[0141] Suitable FXR agonists for use in combination include obeticholic acid (also known as OCA, Intercept), GS9674, elafibranor (GFT505), GW4064, UPF987, FXR-450, fexaramine, methyl cholate, methyl deoxycholate, 5β-cholanic acid, 5β-cholanic acid 7α,12α-diol, NIHS700, marcantin A, marcantin E, MFA-1 These compounds include, but are not limited to, INT767 (also known as 6α-ethyl-CDCA disclosed in WO 2014 / 085474), MET409 (Metacrine), EDP-305 (Enanta), 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid (also known as tropifexor) or a pharmaceutically acceptable salt thereof, or a compound disclosed in WO 2012 / 087519 or a compound disclosed in WO 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, alminoprofen, amfenac, ampiroxicam, antormetin guacil, anilolac, antrafenine, azapropazone, benorylate, bermoprofen, bindarit, bromfenac, bucloxic acid, bucolome, bufexamac, bumadizone, butibufen, butixylate, carbasalate calcium, carprofen, choline magnesium trisalicylate, celecoxib, cinmetacin, cinnoxic Cam, clidanac, clobuzarit, devoxamethasone, dexibuprofen, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, enfenamic acid, etersalate, etodolac, etofenamate, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, fenoprofen, fentiazac, feprazinol, feprazone, flobufen, floctafenine, flufenamic acid, flufenisal, flunoxaprofen, flurbiprofen, flurbiprofen axetil, furofuran phenac, fluprofen, glucamethasone, ibufenac, ibuprofen, indobufen, indomethacin, indomethacin farnesyl, indoprofen, isoxepac, isoxicam, ketoprofen, ketorolac, lobenzarit, lonazolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamime, meclofen, mefenamic acid, meloxicam, mesalazine, miroprofen, mofezolac, nabumetone, naproxen, niflumic acid, olsalazine, oxaprozin, oxypinac, oxyphenbutazone, parfum Coxib, phenylbutazone, perbiprofen, pimeprofen, pyrazolac, piriloxicam, pirprofen, pranoprofen, priferon, prinomod, proglumetacin, proquazone, protidinic acid, rofecoxib, romazarit, salicylamide, salicylic acid, salmisteine, salnacedin, salsalate, sulindac, sudoxicam, suprofen, talniflumate, tenidap, tenosal, tenoxicam, tepoxalin, tiaprofenic acid, talamide, tirnoprofen albamel, timegadine, tinoridine, tiopinac,Including, but 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), spebrutinib (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, WO 2013 / 067274, WO 2012 / 170976, WO 2011 / 162515, U.S. Patent Application Publication No. 2017 / 119766, WO 2016 / 065226, U.S. Patent No. 9,688,676, WO 2016 / 201280, WO 2017 / 059702, U.S. Patent No. 9,630,968 No. 2014 / 0256734, WO 2017 / 118277, WO 2014 / 039899, WO 16 / 105531, WO 2018 / 005849, WO 2013 / 185082, or J. Med. Chem., 2016, 59(19), 9173-9200. Of particular interest, the BTK inhibitor includes the compound of Example 31 described in WO 2014 / 039899, the compound described as compound 14f in Journal of Medicinal Chemistry, 2016, 59(19), 9173-9200, which has the following structure: [ka] the compound of Example 2 described in U.S. Patent Application Publication No. 2017 / 119766; the compound of Example 2 described in WO 2016 / 065226; [ka] or Compound 1 described in WO 2016 / 201280, Compound 1 described in WO 2017 / 059702, or Compound 1 described in WO 2017 / 118277; or a pharmaceutically acceptable salt thereof.

[0145] Other BTK inhibitors of particular interest include compounds described in WO 2015 / 079417, such as N-(3-(5-((1-acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (remibrutinib); N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2- N-(3-(6-amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide -fluorobenzamide; N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, and N-(3-(6-amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof; [Brief explanation of the drawings]

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

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

[0148] The compounds of the present disclosure can be prepared by methods known in the art of organic synthesis. It is understood that in all of the methods, protecting groups for sensitive or reactive groups can be utilized as needed in accordance with general principles of chemistry. Protecting groups are handled according to standard methods of organic synthesis (T.W. Green and P.G. Mughuts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that will be readily apparent to those skilled in the art.

[0149] Unless otherwise noted, reagents and solvents were used as obtained from commercial suppliers.

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

[0151] Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations are carried out under reduced pressure, typically at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structure of final products, intermediates, and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

[0152] Abbreviation 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 time (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 mL / L milliliters / liters Mmol millimolar 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 on 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 with or without tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are reported in ppm downfield from TMS, and spectral splitting patterns are indicated as singlets (s), doublets (d), triplets (t), quartets (q), quintets (quint), septets (sept), multiplets, unresolved or overlapping signals (m), or broad signals (br). Deuterated solvents are indicated in parentheses and have chemical shifts of dimethylsulfoxide (δ 2.50 ppm), methanol (δ 3.31 ppm), chloroform (δ 7.26 ppm), or other solvents as indicated in the NMR spectral data. UPLC-MS (Method 1): System: Waters Acquity UPLC equipped with a Waters SQ detector. Column: CORTECS C18 2.7 μm 2.1 × 50 mm. Column temperature: 80 °C. Gradient: 1% to 50% B in 1.4 min; 50% to 98% B in 0.3 min, 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® BEH™ C18 2.5 μm 2.1 x 50 mm, Column Temperature: 80°C. Gradient: 2% to 98% B in 1.4 min, A = water + 5 mM NH4OH, B = acetonitrile + 5 mM 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 in 8 min; hold 95% B for 2 min, 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 mass-to-charge ratios.

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

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

[0157] Synthesis of intermediates Intermediate 1: (R)-6-chloro-3-((1-methylpiperidin-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) was added triethylamine (3.03 mL, 21.74 mmol) and (R)-1-methylpiperidin-3-amine (1.99 g, 17.39 mmol) at RT. The mixture was warmed to 60 °C and stirred for 6 days. The reaction mixture was diluted with EtOAc and brine was added. The phases were separated, the aqueous layer was extracted with EtOAc, 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 give 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-methylpiperidin-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) at -10 °C under a nitrogen atmosphere. The mixture was stirred at -10 °C for 40 min, then quenched by the dropwise addition of a saturated solution of Rochelle's salt and stirred at RT for 15 min, after which EtOAc was added. The phases were separated, and the aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give an oil. The crude product was purified by column chromatography on silica gel using DCM and 0% to 20% MeOH (5% aq. NH4OH) to give the title compound. UPLC / MS Basic Method: Rt = 0.58 min; 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 WO 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 was added NaH (60% dispersion in mineral oil, 5.92 g, 148 mmol). After stirring the suspension at 0 °C for 30 min, iodine (18.77 g, 74 mmol) was added portionwise and stirring was continued for 3 h. The mixture was diluted with water, acidified to pH = 5 with 2 M HCl, and extracted with EtOAc. 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) with cyclohexane and EtOAc (5% to 100%) to give 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 WO 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 CsCO (9.17 g, 28.10 mmol) in 30 mL of dry DMF. The reaction mixture was stirred at RT for 2 h and then evaporated to dryness. The crude product was purified by column chromatography on silica gel with cyclohexane and EtOAc (0% to 5%) to give 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 NEt (28.6 mL, 205 mmol) in 60 mL of 1,4-dioxane was purged with nitrogen. Pd(OAc) (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 h. It was then cooled to RT, diluted with EtOAc, and washed with saturated NH Cl, water, and brine. The organic layer was dried over Na SO , filtered, and evaporated. The crude product was purified by column chromatography on silica gel with cyclohexane and CH2Cl2 (0% to 20%) to give 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 added slowly 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 CHCl at 0° C. The reaction mixture was stirred at 0° C. for 20 min and then evaporated. The resulting oil was purified by column chromatography on silica gel using cyclohexane and CHCl (0% to 100%) to give 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 Examples Example 1: (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol [ka] (R)-(6-chloro-3-((1-methylpiperidin-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 2 M aqueous NaCO (1.2 mL) were suspended in dioxane (7 mL), and the mixture was purged with nitrogen for 5 min. Pd(PPh) (47.8 mg, 0.041 mmol) was added, and the mixture was stirred at 120 °C under microwave irradiation for 1 h. 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 through an Isolute phase separator and evaporated to dryness. The residue was purified by column chromatography on silica gel using DCM and 0% to 20% MeOH (5% aq. NH4OH) to give 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 give the title compound. UPLC / MS (method 1): Rt=0.61 min; MS m / z 397.4 M+H] + . 1H NMR (400 MHz, 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 not observed in 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 charged into reactor 1. Reactor 1 was stirred at a temperature range of 20 to 30 °C for 1 hour. Compound 2 (100 g, 476.1 mmol, 1 eq.) and DCM (600 g) were charged into reactor 2. Reactor 2 was cooled to a temperature range of -10 to 0 °C. The mixture from reactor 1 was added dropwise to reactor 2, and reactor 1 was rinsed with MTBE (150 g). The whole mixture was stirred at a temperature of -10 to 0 °C for 1 to 3 hours. Next, reactor 2 was adjusted to 20 to 30 °C, and the whole mixture was stirred for 17 to 20 hours. 200 g of 0.1 N hydrochloric acid (aqueous) was added dropwise to reactor 2 at a temperature range of 20 to 30 °C. The aqueous and organic layers were separated, and the organic layer was collected in reactor 2. 200 g of 7% NaHCO3 (aqueous) was added to reactor 2 to adjust the pH to 6-7 at a temperature of 20-30 °C. The organic layer was collected and washed with water (200 g), then concentrated under vacuum below 40 °C to obtain crude compound 3 as an 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 charged into reactor 1. Reactor 1 was stirred for 20 hours at a temperature range of 90-100 °C. After the reaction was completed, 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 and organic layers were separated, and the organic layer was washed twice with 10% NaCl (aq.) (200 g). The organic layer was collected and concentrated under vacuum at less than 70 °C to obtain the crude product as an 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 2 M KOH (aq.) (800 g) were charged to reactor 1, and the reaction mixture was stirred for 1 h at a temperature range of 20 to 30 °C. Compound 6 (212.1 g, 2.86 mol, 6.2 eq.) and water (410 g) were charged to reactor 2. 733 g of 2 M KOH (aq.) was added to reactor 1 at a temperature range of -5 to 0 °C and stirred for 1 h. The aqueous layer from reactor 1 was slowly added to reactor 2 at a temperature range of -5 to 0 °C. The reaction mixture was stirred for an additional 20 h at a temperature range of -5 to 0 °C. The pH was adjusted to 9 to 10 with acetic acid at a temperature range of -5 to 5 °C. DCM (768 g) was charged to reactor 2, and the organic layer was separated and collected. The pH was further adjusted to 4 to 5 with 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, 71.7 g) was added to the mixture at a temperature range of 10-20°C. The temperature of the mixture was then adjusted to 90-100°C, and the whole 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 (800 g) was added to the mixture, and the organic layer was collected and filtered through a silica gel pad. The solution was concentrated to 600-700 g, and then heptane (680 g) was added dropwise at a temperature of 40-50°C. The mixture was cooled to 15-25°C over 5 hours, stirred at 15-25°C for an additional 3 hours, and then filtered. The wet cake was slurried with MeOH (600 g) and water (800 g) at 40-50° C., and the mixture was cooled to 15-25° C. over 5 hours and then stirred for an additional 3 hours. The wet cake was dried at 40-50° C. for 20 hours to give product 7 (42.1 g) 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 (17.4 g, 64.5 mmol, 1.0 eq.), TEAC (21.4 g, 129.1 mmol, 2 eq.), POCl3 (14.8 g, 96.8 mmol, 1.5 eq.), and ACN (70 g) were charged to reactor 1. The mixture was stirred at 15-25 °C for 17 h. After the reaction was completed, water (280 g) was charged to reactor 2, and the whole was heated to 50 °C. The mixture was slowly transferred from reactor 1 to reactor 2 at 45-55 °C. After stirring the reaction mixture at 45-55 °C for 16 h, the mixture was filtered, and the wet cake was washed with water (40 mL). The wet cake was charged to reactor 2, water (140 g) was added, and the pH was adjusted to 7-8 with 2% aqueous ammonia (14 g). The reaction mixture was filtered, and the resulting wet cake was washed twice with water (25 g * 2). The wet cake was dried at 60° C. to give 14.6 g of 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 charged into a reactor at a temperature range 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 then HO (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 dried under vacuum at 55°C to obtain 21.1 g of the 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] Compound 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 charged into a reactor. The reactor was then placed under a N2 atmosphere. Pd(dppf)Cl2 (3.1 g, 4.22 mmol, 0.08 eq.) was then added to the reactor under a N2 atmosphere, and the mixture was stirred at 60–70 °C for 16 h. After completion of the reaction, the mixture was cooled to 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 × 2). The pH of the aqueous layer was adjusted to 8-9 with 20% NaOH (aq.) and extracted twice with isopropyl acetate (200 mL * 2). The combined organic layers were concentrated to approximately 260 g, and n-heptane (320 g) was added dropwise to the mixture at 50 °C. The mixture was cooled to 0 °C and 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% HO (aq.) (7.23 g, 212.9 mmol, 1.8 eq.), TFA (26.97 g, 236.6 mmol, 2 eq.), 1,1'-bis(diphenylphosphino)ferrocenedioxide (dppfO) (0.69 g, 1.18 mmol, 0.01 eq.), and MeOH (504 mL) were charged into a reactor. The reaction mixture was pumped through a blue light reactor (450 nm) at 30 °C. After completion, the mixture was quenched with 10% NaSO (aq.). The pH of the mixture was adjusted to 8–9 with 10% NaSO (aq.). The mixture was extracted twice with isopropyl acetate (600 mL). The combined organic layers were then concentrated under vacuum at 40-50°C and the crude product was purified by column chromatography to give 46g of the product 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) / C (50% wet, 7.3 g), and MeOH (860 mL) were charged to a reactor. The mixture was stirred at 25 °C for 17 h under 1 bar H pressure. After the reaction was complete, the mixture was filtered through a pad of MCC. The filtrate was concentrated, and then acetonitrile (approximately 150 g) was added at a temperature range of 40–50 °C. The mixture was cooled to a temperature of 10–20 °C and filtered. The wet cake was then washed with acetonitrile (100 mL) and MeOH (10 mL) at 50 °C for 2 h, and the mixture was cooled to a temperature range of 20–30 °C. The wet cake was then dried at 50 °C to give 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] Crystalline Form of Example 1: 1. Preparation of crystalline forms: 1.1:Form H A Preparation of: Example (A): (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Form A (Example 1, 30 mg, preparation see below) was dissolved in 1 mL of acetonitrile / water (94.35 / 4.11, v / v, a w=0.6) and the suspension was stirred at RT. After 3 days, the suspension was filtered and the wet cake was air-dried for 4 hours to give (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol hydrate H A obtained.

[0174] Example (B): (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-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 O 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 at 50°C for 3 hours.

[0175] 1.2: Preparation of Form A Example (A): Water (19.7 kg), Intermediate 2 (1.25 kg, 4.87 mol, 1.0 eq.), 2-methyltetrahydrofuran (21.4 kg), Intermediate 4 (1.76 kg, 5.83 mol, 1.2 eq.), NaOtBu (1.40 kg, 14.57 mol, 3 eq.), and 1,1'-bis(diisopropylphosphino)ferrocene palladium dichloride (0.175 kg, 0.29 mol, 0.06 eq.) were charged to a reactor under nitrogen. The resulting solution was stirred at 70°C for 16 hours, after which the reaction mixture was extracted twice with aqueous HCl. The resulting aqueous phases were combined and extracted with 2-methyltetrahydrofuran. The organic phases were collected, and N-acetyl-cysteine and SiliaMetS® thiol (Si-THU) were applied to remove Pd residues, respectively. The organic phase was then concentrated to dryness (solvent removal) and crystallized from MeOH and water. The resulting wet product was recrystallized from 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 for F3N4O2: 396.18. Found [M+H]+: 397.1818.

[0176] Example (B): (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-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. using a stirring speed of 250 rpm. The temperature was cooled to 40° C. over 30 minutes, and 80 mg of Mod A seeds were 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. The temperature was then cooled to 20° C. over 2 hours and then 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 resulting wet cake was dried under vacuum at 40° C.

[0177] 1.3: Preparation of Form B: (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 mg) was dissolved in 6 mL of MeOH at 70° C. and then the solution was filtered through a 22 μm membrane. The solution / suspension was reheated to 70° C. to obtain a clear solution, after which the temperature was cooled to 55° C. in 2 hours. The solution was allowed to stand for 2 hours, after which the temperature was cooled to 5° C. over 10 hours and held overnight. The suspension was filtered and the wet cake was dried under vacuum at 50° C. for 2 hours to obtain (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-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-methylpiperidin-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 50°C at a stirring speed of approximately 250 rpm. After 4 hours, the temperature was cooled to 25°C over 2 hours and maintained overnight. The suspension was filtered, and the wet cake was washed with MEK and then vacuum dried at 50°C for 4 hours to obtain hippuric acid (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (1:1) salt.

[0179] 1.5: Preparation of Example 1 Hydrochloride (1:1): Example (A): (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-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 at RT to give a suspension. The temperature was raised to 50° C. and held for 4 hours. After 4 hours, the temperature was cooled to 25° C. and held over the weekend. The suspension was filtered, and the wet cake was washed with MEK and then dried under vacuum at 50° C. for 4 hours to give (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol hydrochloride (1:1) salt.

[0180] Example (B): (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-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 at RT to give a clear solution. 1.4 mL of MTBE was added, followed by a small amount of the HCl salt prepared in Example (A). After aging 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 dried under vacuum at 50°C for 2 hours.

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

[0182] Sample amount: 5 to 10 mg Sample holder: Zero background Si flat sample holder

[0183] [Table 1]

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

[0185] 2.1.2 Differential scanning calorimetry (DSC) method DSC traces were recorded on a TA Discovery DSC (TA, Tzero pan, 901683.901) with an aluminum pan: heating rate 10 K / min, temperature range: 0–300 °C.

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

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

[0188] [Table 2]

[0189] 2.2.2 Form H A Differential scanning calorimetry (DSC) data Figure 2 shows Form H A 1 shows a DSC trace of the compound of formula (I). The melting onset temperature of the first endothermic peak is 109.1°C (first endothermic peak: 124.5°C), and the melting onset temperature of the second endothermic peak is 235.8°C (second endothermic peak: 236.9°C).

[0190] 2.2.3 Thermogravimetric analysis (TGA) Figure 3 shows Form H A 1 shows the TGA trace of

[0191] 2.3: Characterization of Crystalline Form A 2.3.1 XRPD Data for Form A: XRPD data for Form A is shown in Table 2.

[0192] [Table 3]

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

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

[0195] 2.4: Characterization of Crystalline Form B 2.4.1 XRPD Data for Form B: XRPD data for Form B is shown in Table 3.

[0196] [Table 4]

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

[0198] 2.4.3 Thermogravimetric Analysis (TGA) of Form B FIG. 9 shows the TGA trace of Form B.

[0199] 2.5: Characterization of Crystalline Form Example 1 Hippurate (1:1): 2.5.1 XRPD data for Form Example 1 Hippurate (1:1): The XRPD data of Form Example 1 Hippurate (1:1) is shown in Table 4.

[0200] [Table 5]

[0201] 2.5.2. Example 1: Differential Scanning Calorimetry (DSC) Data for Hippurate (1:1) Figure 11 shows the DSC trace of Example 1 Hippurate (1:1). The melting onset temperature of 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) FIG. 12 is a TGA trace of Form Example 1 Hippurate (1:1).

[0203] 2.6: Characterization of Crystalline Form Example 1 Hydrochloride (1:1): 2.6.1 XRPD Data for Form Example 1 Hydrochloride Salt (1:1): XRPD data for Form Example 1 Hydrochloride (1:1) is shown in Table 5.

[0204] [Table 6]

[0205] 2.6.2. Differential Scanning Calorimetry (DSC) Data for Form Example 1 Hydrochloride (1:1) Figure 14 shows the DSC trace of the hydrochloride salt (1:1) of Example 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 Thermogravimetric Analysis (TGA) of Example 1 Hydrochloride (1:1) FIG. 15 shows the TGA trace of Form Example 1 Hydrochloride (1:1).

[0207] Reference Example 1: (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol [ka] This compound can be prepared as described in Example Ex 005 of WO 2020 / 234715.

[0208] Reference Example 2: (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol [ka] This compound can be prepared as described in Example Ex 064 of WO 2020 / 234715.

[0209] Reference Example 3: 3-methyl-2-(4-(((R)-1-methylpiperidin-3-yl)amino)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [ka] This compound can be prepared as described in Example Ex 42 of WO 2022 / 135567.

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

[0211] IL-1β secretion assay: Monocytic 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 stock) + Pen-Strep) according to the supplier's instructions. Cells were extensively differentiated with 0.5 μM phorbol 12-myristate 13-acetate (PMA; Sigma #P8139) for 3 h, the medium was replaced, and cells were plated at 50,000 cells per well in 384-well flat-bottom cell culture plates (Greiner, #781986) and allowed to differentiate overnight. A 1:3.16 serial dilution of compounds in DMSO was added to the cells at 1:100 and incubated for 1 h. The NLRP3 inflammasome was activated by adding 15 μM (final concentration) nigericin (Enzo Life Sciences, #BML-CA421-0005), and the cells were incubated for 3 h. 10 μL of the supernatant was removed, and IL-1β levels were monitored using a Homogeneous Time-Resolved Fluorescence (HTRF) assay (CisBio, #62IL1PEC) according to the manufacturer's instructions. PrestoBlue cell viability reagent (Life Technologies, #A13261) was added directly to the cell culture plate to monitor viability and pyroptosis.

[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 plated at 50,000 cells per well in 384-well flat-bottom cell culture plates (Greiner, #781986) and allowed to rest overnight. Experimental compounds were prepared and added as described above. TNF-α secretion was induced by adding 1 μg / mL LPS (Sigma, #L4391) or 100 ng / mL Pam3CSK4 (Invivogen, #tlrl-pms), depending on the experiment, and cells were incubated for 3 h. 10 μL of supernatant was removed, 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] Interpretation of the data: I C 50 Values were calculated from a plot of percentage inhibition versus inhibitor concentration by logistic fit according to the following: y=A2+(A1-A2) / (1+(x / IC 50 )^p) y is the % inhibition at inhibitor concentration, 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 with 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 cytokines were measured in serum 3 h later. As discussed above, activation of the NLRP3 inflammasome requires both an NF-kB-dependent priming step and the addition of an NLRP3 activator. To ensure that inhibitors do not interfere with the priming step, Pam3CSK4-stimulated NF-kB-dependent TNF-α secretion was monitored as a control screen. The inhibitory effects (IC) of compounds of the present invention for both assays were compared. 50) are shown in the table below. Data for IL-1β secretion were calculated as the arithmetic mean of at least three independent experiments, and data for TNF-α secretion were consistent across at least two independent repeats.

[0215] [Table 7]

[0216] hERG Channel Testing with QPatch Technology 4 CHO cells (AVIVA Biosciences Corp, San Diego, CA) stably expressing hERG channels were patched using a QPatch-HT automated patch clamp instrument (Sophion Bioscience A / S, Valerup, Denmark) in single-hole mode. The intracellular solution consisted of 120 mM KCl, 5 mM CaCl, 2 mM MgCl, 10 mM ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), and 4 mM adenosine-5'-triphosphate dipotassium (ATP-K), pH adjusted to 7.2 with KOH. The extracellular solution consisted of 145 mM NaCl, 4 mM KCl, 2 mM CaCl, 1 mM MgCl, 10 mM HEPES, and 0.3% dimethyl sulfoxide (DMSO), adjusted to pH 7.4 with NaOH. All measurements were performed at room temperature, with blockers preincubated for 4 min. Cells were voltage-clamped at -90 mV, and hERG currents were activated using a 4-second voltage step to +20 mV. hERG tail currents were measured by stepping down to -50 mV over 4 seconds and then back to -90 mV. This protocol was repeated every 20 seconds. Peak hERG currents were automatically corrected by subtracting leak current, which was estimated by measuring the mean current during a short depolarizing step from the resting membrane potential to -50 mV immediately before the long depolarizing step to +20 mV at the beginning of the voltage protocol. Test substances were diluted using DMSO stock solutions and extracellular solution. The final concentration of vehicle DMS0 did not exceed 0.3%. The effect of test substances on hERG tail currents was assessed by adding 1, 10, and 30 μM and a positive control (amitriptyline, 1, 3, and μM) to each plate. If the highest test concentration had inhibitory activity >50%, data points were fitted to the standard Hill equation to determine IC50 values using a fixed minimum current of 0% and a maximum current of 100% (Residual Current (%) = MaxI + ((MinI - MaxI) / (1 + ((Conc. / IC 50)^Hill))) (where MaxI = 100 MinI = 0). If hERG activity was less than 50% at the highest test concentration, the hERG IC 50 Values are estimated to be higher than this (eg, >30 uM). 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 A Chinese hamster ovary (CHO) cell line overexpressing the α subunit of the hERG channel under the control of a tetracycline-regulated promoter was generated using the commercially available T-Rex™ system (Invitrogen). CHO (T-REx™) hERG cells were maintained in Ham's F-12 nutrient medium (Life Technologies) supplemented with 10% fetal bovine serum (HyClone), 1% penicillin-streptomycin, 10 μg / mL blasticidin, and 50 μg / mL Zeocin (all from Life Technologies, Thermo Fisher Scientific). To induce hERG expression, 1 μg / mL tetracycline (Sigma-Aldrich) was added to the growth medium 24 h before current recording. To prepare cell suspensions for Qube experiments, cells were removed from culture flasks by incubation in Detachin (Genlantis) at 37°C for approximately 5 min and resuspended in CHO serum-free 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 on a Qube APC (automated patch clamp) platform (Sophion Bioscience A / S, Ballerup, Denmark) using a 384 × 10-well tip. The intracellular KF-Ringer solution consisted of 120 KF, 20 KCl, 2 10 ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), 10 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH adjusted to 7.2 with KOH. The extracellular solution consisted of 145 NaCl, 4 KCl, 2 CaCl2, 1 MgCl2, 10 HEPES, 10 glucose, and 0.3% dimethyl sulfoxide (DMSO), pH adjusted to 7.4 with NaOH. The following voltage protocol was applied to measure the hERG activity: Currents were elicited by holding cells at a resting membrane potential of -90 mV for 100 ms, then clamping them at -50 mV for 100 ms for leak estimation, depolarizing to +20 mV for 4 s (peak current measurement), and finally repolarizing to -50 mV for 4 s (tail current recording) before returning to a holding potential of -90 mV. Data were sampled at 10 kHz, cut off at 2 kHz, and filtered with a Bessel filter. The protocol was repeated 30 times every 15 s, before and after compound application.

[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 compound from the serial dilution plate to a 384-well Greiner plate using a Labcyte Echo 650 liquid handler (Beckman). Immediately prior to the experiment, 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 (1:333 dilution, maintaining 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] 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 compounds on hERG current inhibition (normalized % inhibition) was calculated as %Inh = (I 化合物 -I ビヒクル ) / I ビヒクル * Calculated as -100, where I 化合物 and I ビヒクル where I(C) is the average of the last three leak-corrected tail hERG currents before and after compound application, respectively. For compound concentration responses, a custom four-parameter fit to the Hill equation was used to derive IC50 values, with a fixed minimum current at 0% and a maximum current at 100%: I(C) = I b +((I f -I b )*C n ) / I C 50 +C n , where C is the input concentration, I(C) is the residual current after inhibition by the test compound, Ib is the maximum current before compound application, I f is the fixed minimum current. All data and assay specific information is stored in an in-house database for biochemical assays (Pharon).

[0222] [Table 9]

[0223] Activity at the hERG channel is known to cause QTc prolongation in clinical practice, which is undesirable. Such QTc prolongation means that the heart muscle takes longer than normal to recharge between beats, which can have adverse safety implications. Therefore, in vitro hERG assays are used to evaluate the interaction of drug molecules with the channel and to assist medicinal chemists in finding drug candidates that do not cause such serious toxicity in clinical practice. hERG IC 50 The higher the value, the more favorable it is for cardiac safety evaluation of the compound.

[0224] Reference Examples 1 and 2 are hERG QPatch IC 50 were 13.1 and 3.9, respectively, and the hERG Qube IC 50 were found to be 4.71 and 5.62, respectively. Surprisingly, Example 1 showed that hERG QPatch IC 50 and hERG Qube IC 50 It has been found that the .alpha.-hydroxybenzoates of the general structure [ka] In compounds of formula (I) having -(CH2) n- OH, where n is 1, 2, 3 or 4; R 4 The introduction of has unexpectedly resulted in compounds with improved drug safety profiles.

Claims

1. Formula (I): 【Chemical 1】 (In the formula, R １ is Cl, CH ３ , -OCF ３、 or CF ３ and R ２ Ha, Halo, C １ ~C ４ Alkyl or haloC １ ~C ４ is alkyl; R ３ are H, CN, and C １ ~C ４ Alkyl or haloC １ ~C ４ is alkyl; R ４ is -(CH ２ ) ｎ -OH, where n is 1, 2, 3, or 4; R ５ is unsubstituted or C １ ~C ４ Alkyl, haloC １ ~C ４ Alkyl, hydroxy C １ ~C ４ Alkyl, —OH, halo, oxo, and —CO ２ a monocyclic or bicyclic heterocyclyl substituted by 1 to 2 substituents independently selected from H; or R ５ is unsubstituted or halo, haloC １ ~C ４ Alkyl, C １ ~C ４ Alkyl, and —SO ２ NH ２ or an aryl or heteroaryl substituted with 1 to 2 substituents independently selected from R ５ is unsubstituted or C １ ~C ４ Alkyl, halo, haloC １ ~C ４ C substituted by 1 to 3 substituents independently selected from alkyl and —OH ３ ~C ６ is cycloalkyl; or R ５ is -OH, C １ ~C ４ Alkoxy, halo, -NH ２ , —NH(C １ ~C ４ alkyl), and —N(C １ ~C ４ alkyl) ２ C substituted by one or more substituents independently selected from ２ ~C ６ alkyl) or a pharmaceutically acceptable salt thereof.

2. R １ is -OCF ３ or CF ３ and R ２ is C １ ~C ４ Alkyl or haloC １ ~C ４ is alkyl; R ３ is H, C １ ~C ４ Alkyl or haloC １ ~C ４ is alkyl; R ４ is -CH ２ -OH; R ５ is unsubstituted or C １ ~C ４ Alkyl, haloC １ ~C ４ Alkyl, hydroxy C １ ~C ４ Alkyl, —OH, halo, oxo, and —CO ２ a monocyclic or bicyclic heterocyclyl substituted by 1 to 2 substituents independently selected from H; or R ５ is unsubstituted or halo, haloC １ ~C ４ Alkyl, C １ ~C ４ Alkyl, and —SO ２ NH ２ or an aryl or heteroaryl substituted with 1 to 2 substituents independently selected from R ５ is unsubstituted or C １ ~C ４ Alkyl, halo, haloC １ ~C ４ C substituted by 1 to 3 substituents independently selected from alkyl and —OH ３ ~C ６ is cycloalkyl; or R ５ is -OH, C １ ~C ４ Alkoxy, halo, -NH ２ , —NH(C １ ~C ４ alkyl), and —N(C １ ~C ４ alkyl) ２ C substituted by one or more substituents independently selected from ２ ~C ６ is alkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ is -OCF ３ or CF ３ and R ２ is C １ ~C ４ is alkyl; R ３ is H; R ４ is -CH ２ -OH; R ５ is unsubstituted or C １ ~C ４ Alkyl, haloC １ ~C ４ Alkyl, hydroxy C １ ~C ４ Alkyl, —OH, halo, oxo, and —CO ２ a monocyclic or bicyclic heterocyclyl substituted by 1 to 2 substituents independently selected from H; or R ５ is unsubstituted or halo, haloC １ ~C ４ Alkyl, C １ ~C ４ Alkyl, and —SO ２ NH ２ or an aryl or heteroaryl substituted with 1 to 2 substituents independently selected from R ５ is unsubstituted or C １ ~C ４ Alkyl, halo, haloC １ ~C ４ C substituted by 1 to 3 substituents independently selected from alkyl and —OH ３ ~C ６ is cycloalkyl; or R ５ is -OH, C １ ~C ４ Alkoxy, halo, -NH ２ , —NH(C １ ~C ４ alkyl), and —N(C １ ~C ４ alkyl) ２ C substituted by one or more substituents independently selected from ２ ~C ６ is alkyl, 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R ５ is unsubstituted or C １ ~C ４ Alkyl, haloC １ ~C ４ Alkyl, hydroxy C １ ~C ４ Alkyl, —OH, halo, oxo and —CO ２ The compound according to any one of claims 1 to 3, which is a monocyclic or bicyclic heterocyclyl substituted by 1 to 2 substituents independently selected from H, or a pharmaceutically acceptable salt thereof.

5. R ５ Below: 【Chemistry 2】 is selected from R ５ａ is C １ ~C ４ Alkyl, hydroxy C １ ~C ４ alkyl, and H; R ５ｂ is -OH, hydroxy C １ ~C ４ Alkyl, H, halo, oxo, haloC １ ~C ４ Alkyl and —CO ２ H; X is independently selected from O or CH ２ m is 0 or 1, and ａ 4. The compound of claim 1, wherein "" represents the carbon bonded to the pyridazine-amine, or a pharmaceutically acceptable salt thereof.

6. R ５ Below: 【Chemistry 3】 is selected from In the formula, R ５ａ is C １ ~C ４ Alkyl, hydroxy C １ ~C ４ alkyl, and H; R ５ｂ is -OH, C １ ~C ４ Alkyl, hydroxy C １ ~C ４ Alkyl, H, halo, oxo, haloC １ ~C ４ Alkyl, and —CO ２ H; X is independently selected from O or CH ２ m is 0 or 1, and ＊ 4. The compound of claim 1, wherein "" represents the carbon atom attached to the pyridazine-amine, or a pharmaceutically acceptable salt thereof.

7. R ５ Below: 【Chemistry 4】 is selected from In the formula, R ５ａ is C １ ~C ４ Alkyl, hydroxy C １ ~C ４ alkyl, and H; R ５ｂ is -OH, C １ ~C ４ Alkyl, hydroxy C １ ~C ４ Alkyl, H, halo, oxo, haloC １ ~C ４ Alkyl, and —CO ２ H; m is 0 or 1; ＊ 4. The compound of claim 1, wherein "" represents the carbon atom attached to the pyridazine-amine, or a pharmaceutically acceptable salt thereof.

8. R ５ teeth, 【Chemistry 5】 and In the formula, R ５ａ is C １ ~C ４ Alkyl, hydroxy C １ ~C ４ independently selected from alkyl and H; ＊ 4. The compound of claim 1, wherein "" represents the carbon atom attached to the pyridazine-amine, or a pharmaceutically acceptable salt thereof.

9. R ５ａ is methyl or H, in particular R ５ａ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein is methyl.

10. The compound is The compound according to claim 1, which is (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (Example 1), or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

12. A combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents.

13. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, or a combination according to claim 12, for use as a medicament.

14. 11. A compound according to 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 signalling contributes to the pathology and / or symptoms and / or progression of the disease or disorder.

15. 11. A method of 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 according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

16. The disease or disorder is an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease or an autoinflammatory disease, such as autoinflammatory fever syndrome, cryopyrin-associated periodic syndrome, a liver-related disease / disorder, a chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, and alcoholic liver disease, a disease associated with inflammatory arthritis, gout, calcium pyrophosphate deposition disease, osteoarthritis, rheumatoid arthritis, arthropathy, a kidney-related disease, hyperoxaluria, lupus nephritis, type I / II diabetes and related complications, nephropathy, retinopathy, hypertensive nephropathy, hemodialysis-related inflammation, a disease associated with neuroinflammation.

16. The compound for use according to claim 14, or the method of treatment according to claim 15, selected from multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease, cardiovascular / metabolic diseases / disorders, cardiovascular risk reduction, hypertension, atherosclerosis, type I and II diabetes and related complications, peripheral arterial disease, acute heart failure, inflammatory skin diseases, hidradenitis suppurativa, acne, wound healing and scarring, 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, post-myocardial infarction heart failure.

17. A method for inhibiting NLRP3 inflammasome activity in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

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