NLRP3 inflammasome inhibitors

Abstract

The present invention relates to pyridazin-3-yl phenol compounds of Formula (I): wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein, which inhibit NOD-like receptor protein 3 (NLRP3) inflammasome activity. The 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.(I).

Description

[0001] This application is a divisional application. The original application has the application number 202380056099.4, the application date is August 2, 2023, the priority date is August 3, 2022, and the invention title is "NLRP3 Inflammasome Inhibitor". Technical Field

[0002] This invention relates to novel pyridazine-3-ylphenol compounds that can be used as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The invention also relates to methods for preparing said compounds, pharmaceutical compositions comprising said compounds, methods for treating and diagnosing various NLRP3-mediated diseases and disorders using said compounds, and pharmaceuticals containing them. Background Technology

[0003] NOD-like receptor protein 3 (NLRP3) is a protein-coding gene: this protein belongs to the nucleotide-binding and oligomerization domain-like receptor (NLR) family and is also known as "pyrin domain protein 3" (Inoue et al.). , Immunology [Immunology], 2013, 139, 11-18). This gene encodes a protein containing a heat protein domain, a nucleotide binding site domain (NBD), and a leucine-rich repeat (LRR) motif. In response to aseptic inflammatory danger signals, NLRP3 interacts with adaptor proteins, apoptosis-associated speckle-like protein (ASC), and caspaseogen-1 to form the NLRP3 inflammasome. Activation of the NLRP3 inflammasome then leads to the release of the inflammatory cytokines IL-1β (interleukin-1β) and IL-18 (interleukin-18), and when dysregulated, can drive pathology in many disease settings.

[0004] NLRP3 inflammasome activation typically requires two steps. The first step involves a triggering signal in which a Toll-like receptor recognizes either the pathogen-activated molecular pattern (PAMP) or the danger-activated molecular pattern (DAMP), leading to activation of nuclear factor κB (NF-κB)-mediated signaling. This, in turn, upregulates the transcription of inflammasome-related components, including inactive NLRP3 and IL-1β precursors (interleukin-1β precursors) (Bauernfeind et al., J. Immunol. [Journal of Immunology] 2009, 183, 787-791; Franchi et al., Nat. Immunol. [Natural Immunology] 2012 , 13, 325-332, Franchi et al. J. Immunol. [Journal of Immunology] 2014 , 193, 4214-4222). The second step is the oligomerization of NLRP3 and the subsequent assembly of NLRP3, ASC, and caspaseinogen-1 into an inflammasome complex. This triggers the conversion of caspaseinogen-1 to caspase-1 and the production and secretion of mature IL-1β and IL-18 (Kim et al., 193, 4214-4222). J. Inflamm. [Journal of Inflammation] 2015, 12, 41; Ozaki et al., J. Inflamm. Res. [Journal of Inflammation Research] 2015, 8, 15–27; Rabeony et al. , Eur. J. Immunol. [European Journal of Immunology] 2015, 45, 2847-2857.

[0005] NLRP3 inflammasome activation has been linked to various inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases, such as autoinflammatory febrile syndromes (e.g., cryopyrin-associated periodic syndrome (CAPS)) (Mortimer et al.). Nature Immunol. [Nature Immunology] 2016, 17(10), 1176-1188); sickle cell disease; systemic lupus erythematosus (SLE); liver-related diseases / disorders such as chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease (Petrasek et al., J. Clin. Invest. [Journal of Clinical Research] 2012, 122, 3476-89; Petrasek et al., Nat. Rev. Gastroenterol. Hepatol. [Nature Reviews Gastroenterology & Hepatology] 2015, 12, 387-400; Mridha et al. J. Hepatol. [Journal of Hepatology] 2017, 66, 1037-46); inflammatory arthritis-related disorders, such as gout, pseudogout (chondrocalcinosis), and osteoarthritis (Ridker et al.). , N. Engl. J. Med. [New England Journal of Medicine] 2017, 377, 1119-31), and rheumatoid arthritis (Mathews et al.) , Ann. Rheum. Dis. [Annals of Rheumatic Diseases] 2014, 73, 1202-10), acute or chronic joint diseases; kidney-related diseases, such as hyperoxaluria (Knauf et al.) Kidney Int [Kidney International] 2013, 84, 895-901), lupus nephritis, hypertensive nephropathy (Krishnan et al., Br. J. Pharmacol[British Journal of Pharmacology] 2016, 173, 752-65), hemodialysis-related inflammation and diabetic nephropathy, which is a kidney-related complication of diabetes (type 1 and type 2 diabetes), also known as diabetic kidney disease (Shahzad et al.). , Kidney Int. [Kidney International] 2015, 87, 74-84. Emerging research reveals that the NLRP3 inflammasome is involved in increased production of IL-1β and IL-18, which can contribute to the onset and progression of various diseases, such as neuroinflammatory disorders, including brain infections, acute injuries, multiple sclerosis, Alzheimer's disease, and neurodegenerative diseases (Shao et al.). , Front. Pharmacol [Frontiers in Pharmacology] 2015, 6, 262); cardiovascular / metabolic disorders / diseases, such as reduced cardiovascular risk (CvRR), atherosclerosis, type I and type II diabetes and related complications (e.g., nephropathy, retinopathy), peripheral artery disease (PAD), acute heart failure, and hypertension (Ridker et al., N. Engl. J. Med [New England Journal of Medicine] 2017, 377, 1119-31; Vandanmasgar et al. Nat. Med. [Natural Medicine] 2011, 17, 179-88; Hu et al. Proc. Natl. Acad. Sci [Proceedings of the National Academy of Sciences of the United States of America] 2015, 112, 11318-23; Antonopoulos et al., Curr. Opin. Pharmacol. [New Insights in Pharmacology] 2017, 39, 1-8; Toldo S et al., Nat. Rev. Cardiol [Nature Reviews Cardiology] 2018, 15, 203-214); wound healing and scar formation; inflammatory skin diseases such as acne, hidradenitis suppurativa (Sweeney et al.) , Br. J. Dermatol [British Journal of Dermatology] 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 [The Lancet] 2017, 390, 1833-42; Derangere et al. Cell. Death Differ. [Cell Death and Differentiation] 2014, 21, 1914-24; Gelfo et al. Oncotarget [Tumor Targets] 2016, 7, 72167-83; Baiorka et al. Blood[Blood] 2016, 128, 2960-75; Carey et al. , Cell Rep. [Cell Reports] 2017, 18, 3204-18. Those diseases / disorders that are inherently immune or inflammatory are often difficult to diagnose or treat efficiently. Most treatments include symptomatic treatment, slowing disease / disorder progression, lifestyle modifications, and surgery as a last resort (e.g., open-heart surgery for advanced forms of atherosclerosis). Recent research has linked mitochondrial dysfunction to NLRP3 activation in neuroinflammatory-related diseases such as Parkinson's disease (Sarkar et al., Parkinson's disease npj Parkinson's disease [npj Parkinson's Disease] 2017, 3:30; Zhou et al., Nature [Nature], 2011, 469, 221. One of the major problems associated with mitochondrial regulators is their poor metabolic stability; therefore, there is a need for selective and stable inhibitors of this neuroinflammatory property (Lee et al.). , Eur J. Org. Chem [European Journal of Organic Chemistry] 2017, 141, 240.

[0006] Therefore, there is a need for inhibitors of the NLRP3 inflammasome pathway to provide new and / or alternative treatments for these inflammasome-related diseases / disorders, as well as other diseases / disorders such as autoinflammatory febrile syndromes, cryptothermal protein-related periodic syndromes (e.g., CAPS), sickle cell disease, chronic liver disease, non-alcoholic steatohepatitis (NASH), gout, hyperoxaluria, secondary hyperoxaluria, pseudogout (chondrocalcinosis), type I / II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammatory-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancers (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0007] WO 2020 / 234715 describes pyridazine-3-ylphenol compounds as inhibitors of the NLRP3 inflammasome. WO 2022 / 135567 describes pyridazine-containing compounds as inhibitors of the NLRP3 inflammasome. WO 2022 / 166890 describes substituted pyridazine-phenol derivatives as inhibitors of the NLRP3 inflammasome. Summary of the Invention

[0008] This invention provides compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, which inhibit the NLRP3 inflammasome pathway. The invention further provides methods for treating, diagnosing, or preventing NLRP3-related diseases and / or disorders, comprising administering an effective amount of an inventive compound or a pharmaceutically acceptable salt thereof to a subject in need.

[0009] This document describes several embodiments of the present invention.

[0010] As a first aspect, the present invention provides a compound having formula (I) or a pharmaceutically acceptable salt thereof: (I), in R 1 It is Cl, CH3, -OCF3, or CF3; R 2 It is a halogenated, C1-C4 alkyl, or a halogenated C1-C4 alkyl; R 3 It is H, CN, C1-C4 alkyl, or halo-C1-C4 alkyl; R 4 It is –(CH2) n -OH, where n is 1, 2, 3 or 4; R 5 It is an unsubstituted monocyclic or bicyclic heterocyclic group, or one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halogenated, oxo-, and -CO2H; or R 5 It is an unsubstituted aryl or heteroaryl group, or substituted independently by one or two substituents selected from halogenated, halogenated C1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or R 5 It is an unsubstituted C3-C6 cycloalkyl group or a C3-C6 cycloalkyl group independently substituted with 1 to 3 substituents selected from C1-C4 alkyl, halogenated, halogenated C1-C4 alkyl, and –OH; or R 5 It is a C2-C6 alkyl group that is substituted by one or more substituents independently selected from –OH, C1-C4 alkoxy, halogen, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a subformula or class thereof as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. This pharmaceutical composition may be used to treat diseases and / or disorders associated with NLRP3 activity.

[0012] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a subformula or class thereof as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. This pharmaceutical composition may be used to treat diseases and / or disorders associated with NLRP3 activity.

[0013] On the other hand, the present invention provides combinations, particularly pharmaceutical combinations, comprising a therapeutically effective amount of a compound having the formula (I) or a sub-formula or class of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents.

[0014] On the other hand, the present invention provides combinations, particularly pharmaceutical combinations, as disclosed herein, for use as medicines.

[0015] In another aspect, the present invention provides compounds having formula (I) or its sub-formulas or kinds, or pharmaceutically acceptable salts thereof, as disclosed herein, for use in the treatment of diseases or disorders in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of the disease or disorder.

[0016] In another aspect, the present invention provides a method for treating a disease or disorder in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of the disease or disorder, the method comprising administering a therapeutically effective amount of a compound having formula (I), a sub-formula thereof, or a class thereof as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0017] In another aspect, the present invention provides a method for inhibiting NLRP3 inflammasome activity in a subject in need, the method comprising administering to the subject in need a therapeutically effective amount of a compound having formula (I), a sub-formula thereof, or a class thereof, as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0018] In another respect, the present invention relates to the use of compounds having formula (I) or subforms thereof, or pharmaceutically acceptable salts thereof, as disclosed herein, as medicines.

[0019] In another respect, the present invention relates to compounds having formula (I) or its sub-formulas as disclosed herein, or pharmaceutically acceptable salts thereof, for use as medicines.

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

[0021] In another aspect, the present invention provides compounds having formula (I) or a subform thereof, or pharmaceutically acceptable salts thereof, as disclosed herein, for use in the manufacture of medicaments for treating diseases or disorders selected from: inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases.

[0022] In another aspect, the present invention provides radioactive compounds having formula (I) or pharmaceutically acceptable salts thereof, their preparation, and their use as radiotracers / labels for imaging techniques or diagnostic tools for NLRP3-related diseases or disorders (such as those defined herein). Detailed Implementation

[0023] Therefore, the present invention provides compounds having formula (I): (I), in R 1 It is Cl, CH3, -OCF3, or CF3; R 2 It is a halogenated, C1-C4 alkyl, or a halogenated C1-C4 alkyl; R 3 It is H, CN, C1-C4 alkyl, or halo-C1-C4 alkyl; R 4 It is –(CH2) n -OH, where n is 1, 2, 3 or 4; R 5 It is an unsubstituted monocyclic or bicyclic heterocyclic group, or one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halogenated, oxo-, and -CO2H; or R 5 It is an unsubstituted aryl or heteroaryl group, or substituted independently by one or two substituents selected from halogenated, halogenated C1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or R 5 It is an unsubstituted C3-C6 cycloalkyl group or a C3-C6 cycloalkyl group independently substituted with 1 to 3 substituents selected from C1-C4 alkyl, halogenated, halogenated C1-C4 alkyl, and –OH; or R 5 It is a C2-C6 alkyl group that is independently substituted by one or more substituents selected from –OH, C1-C4 alkoxy, halogen, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2; Or its pharmaceutically acceptable salt.

[0024] definition

[0025] For the purposes of interpreting this specification, the following definitions shall apply unless otherwise indicated, and where appropriate, terms used in the singular form shall also include the plural form, and vice versa.

[0026] It must be noted that, unless the context clearly indicates otherwise or obviously contradicts this document, the singular forms “a,” “an,” “the,” and similar terms used in the context of this invention (especially in the context of the claims) as used herein and in the appended claims should be interpreted to include both the singular and plural indicators. Thus, for example, reference to “the compound” includes reference to one or more compounds; and so on.

[0027] As used herein, the term "C1-C4 alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, which is unsaturated, has one to four carbon atoms, and is 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 (isopropyl), and n-butyl.

[0028] As used in this article, the term "halogen" or "halogenated" refers to bromine, chlorine, fluorine, or iodine.

[0029] As used herein, the term "halogenated C1-C4 alkyl" or "halogenated C1-C4 alkyl" refers to a C1-C4 alkyl group as defined above that is substituted with one or more halogenated groups as defined above. Examples of halogenated C1-C4 alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropyl-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutyl-2-yl.

[0030] As used herein, the term "C1-C4 alkoxy" refers to an alkoxy group having the formula -OR a The group, wherein R a It is a C1-C4 alkyl group as defined above. Examples of “C1-C4 alkoxy” include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy.

[0031] As used herein, the term "C1-C4 haloalkoxy" refers to a "C1-C4 alkoxy" group as defined above that is substituted with one or more halogenated groups as defined above. Examples of haloC1-C4 alkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, and trichloromethoxy.

[0032] As used herein, the term "hydroxyC1-C4 alkyl" refers to a C1-C4 alkyl group in which one of the hydrogen atoms of the C1-C4 alkyl group is replaced by OH. Examples of hydroxyC1-C4 alkyl groups include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 4-hydroxy-butyl.

[0033] As used herein, the term "oxo" refers to an oxygen substituent, such as oxygen linked by a double bond (e.g., forming a ketone).

[0034] As used herein, the term "heterocyclic group" or "heterocyclic" refers to a stable 5- or 6-membered non-aromatic monocyclic, bicyclic, or polycyclic group; having 3 to 24, preferably 4 to 16, and most preferably 5 to 10 ring atoms; wherein one or more, preferably one to four, and especially one or two ring atoms are heteroatoms selected from, for example, oxygen, sulfur, and nitrogen (and thus the remaining ring atoms are carbon). The term heterocyclic group does not include heteroaryl groups. Heterocyclic groups can be attached to the remainder of the molecule by heteroatoms selected from, for example, oxygen, sulfur, and nitrogen, or carbon atoms. Heterocyclic groups can include, for example, fused or bridged rings and spirocyclic rings. For example, the term "heterocyclic group" can refer to a 5-7 monocyclic ring containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur. Examples of monocyclic heterocyclic groups include dihydrofuranyl, dioxopentyl, dioxalkyl, dithiaalkyl, piperazinyl, pyrrolidine, dihydropyranyl, oxthiopentyl, dithiopentyl, oxathianyl, thiomorpholinyl, ethylene oxide, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, oxapinyl, oxaazepanyl, oxthiohexyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl. Preferably, the monocyclic heterocyclic group is morpholino, pyrrolidine, or piperidinyl. Examples of bicyclic heterocyclic groups include, for example, aziridine-octyl or octahydroindazine. According to the invention, the term "heterocyclic group" substituted with an "OH" substituent also includes "heterocyclic group" in which the heteroatom (e.g., N or S) is oxidized to obtain, for example, a heterocyclic N-oxide, a heterocyclic S-oxide, or a heterocyclic S-dioxide. Examples of heterocyclic N-oxides include piperidinyl-N-oxide and 1-methylpyrrolidine 1-oxide. Examples of heterocyclic S-oxides or heterocyclic S-dioxides include tetrahydro-2H-thiaran-1-oxide, tetrahydro-2H-thiaran-1,1-dioxide, and tetrahydrothiophene-1-oxide.

[0035] As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring moiety. Typically, an aryl group is a monocyclic, bicyclic, or tricyclic aryl group having 6-20 carbon atoms. In a preferred embodiment, the aryl group is phenyl.

[0036] As used herein, the term "heteroaryl" refers to a 5- or 6-membered aromatic monocyclic group comprising 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups can be bonded via carbon atoms or heteroatoms. Examples of heteroaryl groups include, but are not limited to, furanyl, pyrroleyl, thiopheneyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, or pyridinyl.

[0037] As used herein, the term "C3-C6 cycloalkyl" refers to a stable monocyclic saturated hydrocarbon group consisting only of carbon and hydrogen atoms and having 3 to 6 carbon ring atoms. Examples of monocyclic C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferably, "C3-C6 cycloalkyl" is cyclopropyl or cyclobutyl.

[0038] Unless otherwise specified, the term "compound of the invention" refers to compounds having formula (I) and its subformulas (such as those having formulas (II), (II-A), (III), (III-A), etc., as described herein), their salts, and all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers, and isotopically labeled compounds (including deuterium-substituted compounds). The terms "multiple compounds of the invention" or "one compound of the invention" refer to the compound defined in any of the examples mentioned below.

[0039] Various enumerated embodiments of the invention have been described herein. It should be understood that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.

[0040] As an example 1.0, the present invention therefore provides a compound having formula (I): (I), in R 1 It is Cl, CH3, -OCF3, or CF3; R 2 It is a halogenated, C1-C4 alkyl, or a halogenated C1-C4 alkyl; R 3 It is H, CN, C1-C4 alkyl, or halo-C1-C4 alkyl; R 4 It is –(CH2) n -OH, where n is 1, 2, 3 or 4; R 5 It is an unsubstituted monocyclic or bicyclic heterocyclic group, or one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halogenated, oxo-, and -CO2H; or R 5 It is an unsubstituted aryl or heteroaryl group, or substituted independently by one or two substituents selected from halogenated, halogenated C1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or R 5 It is an unsubstituted C3-C6 cycloalkyl group or a C3-C6 cycloalkyl group independently substituted with 1 to 3 substituents selected from C1-C4 alkyl, halogenated, halogenated C1-C4 alkyl, and –OH; or R 5 It is a C2-C6 alkyl group that is independently substituted with one or more substituents selected from –OH, C1-C4 alkoxy, halogen, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2. Or its pharmaceutically acceptable salt.

[0041] As Example 2.0, a compound according to Example 1.0 or a pharmaceutically acceptable salt thereof is provided, wherein

[0042] R 1 It is -OCF3 or CF3; R 2 It is a C1-C4 alkyl or a halo-C1-C4 alkyl; R 3 It is H, C1-C4 alkyl, or halo-C1-C4 alkyl; R 4 It is –CH2-OH; R 5 It is an unsubstituted monocyclic or bicyclic heterocyclic group, or one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halogenated, oxo-, and -CO2H; or R 5 It is an unsubstituted aryl or heteroaryl group, or substituted independently by one or two substituents selected from halogenated, halogenated C1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or R 5 It is an unsubstituted C3-C6 cycloalkyl group or a C3-C6 cycloalkyl group independently substituted with 1 to 3 substituents selected from C1-C4 alkyl, halogenated, halogenated C1-C4 alkyl, and –OH; or R 5It is a C2-C6 alkyl group that is substituted by one or more substituents independently selected from –OH, C1-C4 alkoxy, halogen, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2.

[0043] As Example 3.0, a compound or a pharmaceutically acceptable salt thereof according to Example 1.0 or 2.0 is provided, wherein...

[0044] R 1 It is -OCF3 or CF3; R 2 It is a C1-C4 alkyl group; R 3 It is H; R 4 It is –CH2-OH; R 5 It is an unsubstituted monocyclic or bicyclic heterocyclic group, or one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halogenated, oxo-, and -CO2H; or R 5 It is an unsubstituted aryl or heteroaryl group, or substituted independently by one or two substituents selected from halogenated, halogenated C1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or R 5 It is an unsubstituted C3-C6 cycloalkyl group or a C3-C6 cycloalkyl group independently substituted with 1 to 3 substituents selected from C1-C4 alkyl, halogenated, halogenated C1-C4 alkyl, and –OH; or R 5 It is a C2-C6 alkyl group that is substituted by one or more substituents independently selected from –OH, C1-C4 alkoxy, halogen, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2.

[0045] As Example 4.0, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 It is an unsubstituted monocyclic or bicyclic heterocyclic group or substituted with one or two substituents independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH, halo, oxo and -CO2H.

[0046] As Example 4.1, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 Selected from the following: , Where R 5aIndependently selected from C1-C4 alkyl, hydroxyC1-C4 alkyl, and H; and R 5b Independently selected from -OH, hydroxyl C1-C4 alkyl, H, halogenated, oxo-, halogenated C1-C4 alkyl, and -CO2H; X is O or CH2; and m is 0 or 1, and wherein " "" indicates the carbon atom attached to pyridazinamine.

[0047] As an example 4.2, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 Selected from the following: , Where R 5a Independently selected from C1-C4 alkyl, hydroxyC1-C4 alkyl, and H; and R 5b Independently selected from -OH, C1-C4 alkyl, hydroxyC1-C4 alkyl, H, halogenated, oxo-, halogenatedC1-C4 alkyl, and -CO2H; X is O or CH2; and m is 0 or 1, and wherein " "" indicates the carbon atom attached to pyridazinamine.

[0048] As an example 4.3, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 Selected from the following: , Where R 5a Independently selected from C1-C4 alkyl, hydroxyC1-C4 alkyl, and H; and R 5b Independently selected from -OH, C1-C4 alkyl, hydroxy C1-C4 alkyl, H, halogenated, oxo-, halogenated C1-C4 alkyl, and -CO2H; and m is 0 or 1, and wherein " "" indicates the carbon atom attached to pyridazinamine.

[0049] As an example 4.4, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 yes , Where R 5a Independently selected from C1-C4 alkyl, hydroxyC1-C4 alkyl and H, wherein " "" indicates the carbon atom attached to pyridazinamine.

[0050] As an example 4.5, a compound according to Example 4.4 or a pharmaceutically acceptable salt thereof is provided, wherein R 5a It is methyl or H, especially R. 5a It is a methyl group.

[0051] As Example 5.0, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 It is an unsubstituted aryl or heteroaryl group or substituted with one or two substituents independently selected from halogenated, halogenated C1-C4 alkyl, C1-C4 alkyl and -SO2NH2.

[0052] As Example 5.1, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 Preferably, the structure is selected from the following: , Where R 5c It is independently selected from H, C1-C4 alkyl and -SO2NH2; and s is 0, 1 or 2.

[0053] As an example 5.2, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 Preferably, the structure is selected from the following: , Where R 5c It is independently selected from H, C1-C4 alkyl groups and -SO2NH2.

[0054] As an example 5.3, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 Preferably, the structure is selected from the following:

[0055] Where R 5c Independently selected from H and C1-C4 alkyl groups.

[0056] As an example 6.0, the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0, wherein R 5 It is an unsubstituted C3-C6 cycloalkyl group or a C3-C6 cycloalkyl group independently substituted with 1 to 3 substituents selected from C1-C4 alkyl, halogenated, halogenated C1-C4 alkyl and –OH.

[0057] As an example 6.1, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 Selected from the following structures: , Where R 5e R 5e’ R 5d R5d’ and R 5f It is independently selected from H, C1-C4 alkyl, halogen, halogenated C1-C4 alkyl and –OH.

[0058] As an example 6.2, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 Selected from the following structures: , Where R 5d and R 5d’ It is independently selected from H, halogenated, halogenated C1-C4 alkyl and C1-C4 alkyl.

[0059] As an example 6.3, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 Selected from the following structures: , Where R 5d It is independently selected from H, halogenated, halogenated C1-C4 alkyl, and C1-C4 alkyl.

[0060] As Example 7.0, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 It is a C2-C6 alkyl group that is substituted by one or more substituents independently selected from –OH, C1-C4 alkoxy, halogen, -NH2, -NH(C1-C4 alkyl)2 and -N(C1-C4 alkyl)2.

[0061] As an example 7.1, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-3.0 is provided, wherein R 5 Selected from the following structures: , Where R 5h Selected from -NH2, -OH, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2.

[0062] As Example 8.0, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0-7.1 is provided, wherein R 3 It's H.

[0063] As Example 9.0, a compound according to Example 1.0 is provided, wherein the compound is

[0064] ( R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (Example 1), Or its pharmaceutically acceptable salt.

[0065] As Example 9.1, a compound according to Example 9.0 is provided, wherein the compound is hippurate.

[0066] As Example 9.2, a compound according to Example 9.0 is provided, wherein the compound is a hydrochloride salt.

[0067] As an example 9.3, a compound according to Example 9.0 is provided, wherein the compound is a hydrate, particularly in crystalline form, and more particularly wherein the ratio of the compound to water molecules is 1:1.

[0068] As an example 10.0, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0 to 9.0, and one or more pharmaceutically acceptable carriers.

[0069] As an example 11.0, a combination is provided comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0 to 9.0, and one or more therapeutic agents.

[0070] As an example 12.0, a combination according to example 11.0 is provided, wherein one or more therapeutic agents are independently selected from farnesoid X receptor (FXR) agonists; anti-fatty degeneration agents; anti-fibrotic agents; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiotherapy, and surgery; uric acid-lowering therapy; anabolic agents and chondrogenic therapy; IL-17 blockers; complement inhibitors; Bruton's tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TLR7 / 8 inhibitors); CAR-T therapy; antihypertensive agents; cholesterol-lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; β2-agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs (“NSAIDs”); acetylsalicylic acid (ASA); regenerative therapy; cystic fibrosis treatment; and atherosclerosis treatment.

[0071] As an example 13.0, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0 to 9.0, or a pharmaceutical composition according to Example 10.0, or a combination according to Examples 11.0 or 12.0, is provided for use as a medicine.

[0072] As an example 14.0, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0 to 9.0 is provided for use in the treatment of a disease or disorder in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of the disease or disorder.

[0073] As an example 15.0, a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0 to 9.0 is provided for use in the manufacture of a medicament for treating a disease or disorder in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of the disease or disorder.

[0074] As an example 16.0, a method for treating a disease or disorder in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of the disease or disorder is provided, the method comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0 to 9.0.

[0075] As an example 17.0, a compound for use according to Examples 14.0 or 15.0, or a treatment method according to Example 16.0, is provided, wherein the disease or disorder is selected from inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases, such as autoinflammatory febrile syndromes (e.g., cryptothermal protein-related periodic syndrome), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy such as acute and chronic arthropathy), and kidney-related diseases (e.g., hyperoxaluria, lupus). Nephritis, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammatory diseases (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and II diabetes and related 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 cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0076] As an example 18.0, a method for inhibiting NLRP3 inflammasome activity in a subject in need is provided, the method comprising administering to the subject in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1.0 to 9.0.

[0077] Surprisingly, it was found that for R among them 4 It is –(CH2) n Compounds of formula (I) with -OH (where n is 1, 2, 3 or 4), and wherein R 4 Compared to analogs of compounds of formula (I) having C1-C4 alkyl or C1-C4 haloalkyl groups, hERG IC was observed. 50 The increase in R. The effect of this technology is achieved through the inclusion of R 4 The difference in hERG values ​​between Example 1 (–CH2-OH) and Reference Examples 1 and 2 is used to demonstrate this. Higher hERG IC 50 It is beneficial for evaluating the cardiac safety of the compound.

[0078] Surprisingly, in vivo experiments also revealed that compounds of formula (I) exhibited lower toxicity compared to analogs of compounds of formula (I).

[0079] Depending on the choice of starting materials and procedures, the compound may exist as one of the possible stereoisomers or as a mixture thereof (e.g., as a pure optical isomer or as a mixture of stereoisomers, such as racemic and diastereomeric mixtures), depending on the number of asymmetric carbon atoms. This invention aims to include all such possible isomers, including racemic mixtures, diastereomeric 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. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included. This invention also aims to include any pseudo-asymmetric carbon atom, which is indicated herein as (R)- and (S)-, and is invariant upon specular reflection but reversible by exchanging any two entities (PAC 1996, 68, 2193). Basic terminology of stereochemistry [Basic Terminology of Stereochemistry] IUPAC recommendations 1996 [Recommended by IUPAC in 1996]).

[0080] As used herein, the term "salt" (or salts) refers to an acid addition salt or a base addition salt of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" means a salt that retains the biological efficacy and properties of the compounds of the present invention and is typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0081] Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids.

[0082] Inorganic acids that can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0083] Organic acids that can be used to derive salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, hippuric acid, etc.

[0084] Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases.

[0085] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In some embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0086] 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; and basic ion exchange resins. Some organic amines include isopropylamine, benzathine penicillin, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0087] On the other hand, the present invention provides compounds or examples of any general formula (e.g., formula (I) etc.) as defined herein in the form of salts of the following: acetates, ascorbic acid salts, adipates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromates, bicarbonates / carbonates, bisulfates / sulfates, camphor sulfonates, decanoates, chlorides / hydrochlorides, chlortheophyllonates, citrates, ethanedisulfonates, fumarates, glucohepanoates, glucuronates, glucuronates, glutamates, glutarate, glycolates, hippurates, hydroiodates / iodides, hydroxyethylsulfonates, etc. Salts, lactates, lacturonates, dodecyl sulfates, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, mucilages, naphthates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, sebacic acid salts, stearates, succinates, sulfosalicylates, sulfates, tartrates, toluenesulfonates, triphenylacetic acid salts, trifluoroacetic acid salts, or sine salts. In certain aspects, the present invention provides compounds having any general formula (e.g., formula (I) etc.) in the form of hippurate or hydrochloride.

[0088] In another aspect, the present invention provides compounds or examples of any general formula (e.g., formula (I) etc.) as defined herein in the form of salts of sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine penicillin, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine salts.

[0089] Any formulas given herein are also intended to represent both unlabeled and isotopically labeled forms of these compounds. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Isotopes that may be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen.

[0090] The compounds of the present invention, including their salts, hydrates and solvates, can be isolated in one or more crystalline forms under suitable conditions.

[0091] The compounds of the present invention, namely compounds of formula (I) containing groups capable of acting as hydrogen bond donors and / or acceptors, are capable of forming cocrystals with suitable cocrystal forgings. These cocrystals can be prepared from compounds of formula (I) using known cocrystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting the compound of formula (I) with the cocrystal forging in solution and separating the resulting cocrystal. Suitable cocrystal forgings include those described in WO 2004 / 078163. Therefore, the present invention further provides cocrystals comprising compounds of formula (I).

[0092] Furthermore, the compounds of the present invention (including their salts) can also be obtained in their hydrated form, or include other solvents for their crystallization. The compounds of the present invention can inherently or by design form solvates having pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0093] In addition, certain isotopes are incorporated, especially deuterium (i.e., 2 H or D) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements or therapeutic index or improved tolerability. It should be understood that, in this context, deuterium is considered a substituent of compounds having formula (I). The concentration of deuterium can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a specified isotope and its natural abundance. If the substituent in the compound of the present invention indicates deuterium, then such a compound has an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping on each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0094] Other examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as... 2H, 3 H, 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl、 125 I. This invention includes various isotope-labeled compounds as defined herein, such as those containing a radioactive isotope (e.g., 3 H and 14 Those compounds in C), or those containing non-radioactive isotopes (such as...) 2 H and 13 C). Such isotopically labeled compounds can be used for metabolic studies (using...). 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H), 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 for use in the patient's radiation therapy. In particular, 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 methods similar to those described in the appended examples and preparations, using an appropriate isotopically labeled reagent instead of the previously used unlabeled reagent.

[0095] Pharmaceutical Composition

[0096] As used herein, the term "pharmaceutical composition" refers to the compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0097] As used herein, the term “pharmaceuticalally acceptable carrier” means a substance that can be used 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 delay agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, 2013, pp. 1049-1070).

[0098] The term "therapeuticly effective amount" for the compounds of this invention refers to an amount of the compound of this invention that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, relief of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In one non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of this invention that, when administered to a subject, is effective in: (1) at least partially relieving, inhibiting, preventing, and / or improving symptoms or disorders or diseases that are (i) mediated by NLRP3, or (ii) associated with NLRP3 activity, or (iii) characterized by NLRP3 activity (normal or abnormal); or (2) reducing or inhibiting NLRP3 activity; or (3) reducing or inhibiting NLRP3 expression. In another non-limiting embodiment, the term "therapeuticly effective amount" for the compounds of this invention refers to an amount that, when administered to cells, or tissues, or non-cellular biological materials or media, is effective in at least partially reducing or inhibiting NLRP3 activity; or at least partially reducing or inhibiting NLRP3 expression.

[0099] As used herein, the term "subject" refers to a primate (e.g., a human (male or female)), dog, rabbit, guinea pig, pig, rat, and mouse. In some embodiments, the subject is a primate. In yet another embodiment, the subject is a human.

[0100] As used herein, the term "inhibit (inhibition or inhibiting)" means to reduce or suppress a given condition, symptom, disorder, or disease, or to significantly reduce the baseline activity of a biological activity or process. Specifically, inhibition of NLRP3 or the NLRP3 inflammasome pathway includes the ability to reduce the production of IL-1β and / or IL-18 induced by NLRP3 or the NLRP3 inflammasome pathway. This can be achieved through mechanisms including, but not limited to, inactivation, destabilization of NLRP3, and / or alteration of NLRP3 distribution.

[0101] As used herein, the term "NLRP3" refers to, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous NLRP molecules, isotypes, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and their active fragments.

[0102] As used herein, the term “treatment” for any disease or disorder means relief or improvement of the disease or disorder (i.e., slowing or halting the development of the disease or at least one of its clinical symptoms); or relief or improvement of at least one physical parameter or biomarker associated with the disease or disorder, including those that the patient may not be able to identify.

[0103] As used herein, the term “prevent, preventing, or prevention” for any disease or disorder refers to preventive treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0104] As used in this article, a subject is considered "needing" or "in need of" the treatment if the subject will benefit from it biologically, medically, or in terms of quality of life.

[0105] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise obviously contradicted by the context. The use of any and all instances or exemplary language (e.g., "as") provided herein is intended only to better illustrate the invention and not to limit the scope of the invention as otherwise claimed.

[0106] Any asymmetric atom (e.g., carbon, etc.) in the compounds of the present invention may exist in racemic or enantiomer-enriched forms, for example, ( R )-、( S )-or( R,S )-configuration. In some embodiments, each asymmetric atom has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess. R )-or( S )-configuration.

[0107] Therefore, as used herein, the compounds of the present invention may be in the form of one of the possible stereoisomers, rotational isomers, tautomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0108] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, or racemates based on the physicochemical differences of the components, for example by chromatography and / or fractional crystallization.

[0109] The racemic derivatives of any of the compounds or intermediates of the present invention can be resolved into optical enantiomers by known methods, for example, by separating their diastereomer salts obtained with optically active acids or bases, releasing optically active acidic or basic compounds. In particular, the basic moiety can therefore be used to resolve the compounds of the present invention into their optical enantiomers, for example by fractional crystallization with salts formed from optically active acids such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic products can also be resolved by chiral chromatography, for example, high-performance liquid chromatography (HPLC) using chiral adsorbents.

[0110] Method for synthesizing the compounds of the present invention

[0111] The compounds of this invention can be prepared according to the routes described in the following schemes and / or examples. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise obviously contradicted by the context. The use of any and all examples or exemplary language (e.g., “as”) provided herein is intended only to better illustrate the invention and not to limit the scope of the invention as otherwise claimed. In the following general methods, R 1 R 2 R 3 R 4 R 5 Halogenated materials are as defined in the examples above, or as specified in the scheme. Unless otherwise stated, starting materials are commercially available or prepared by known methods.

[0112] Reaction Scheme 1

[0113] Compounds having formula (I) as described herein can be prepared by the reaction sequence shown in Scheme 1 (hereinafter), thereby appropriately substituted 3,6-dihalopyridazine (M1), wherein R 3 As defined in this article and R 6 It can be methyl, with a suitable amine (M2), where R5 As defined herein, the intermediate is reacted at low temperatures (typically between 0°C and room temperature) in the presence of a base (e.g., DIPEA) to give 6-halopyridazine-3amine (M3), which is then reduced, for example, with LiAlH4 to 6-halopyridazine-4-alkyl-hydroxy-3amine (M4). This intermediate is then subjected to a Suzuki-type cross-coupling reaction with a suitable borate (M5) in a miscible 20 solvent (e.g., DME or dioxane) in an aqueous base solution (typically Na2CO3 or NaHCO3) and a suitable palladium catalyst (e.g., Pd(PPh3)4). The reaction yields a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0114]

[0115] Option 1.

[0116] The methods described above can be extended to prepare compounds having general formula (I) as described herein, or pharmaceutically acceptable salts thereof. Based on the starting materials and chosen route as mentioned in Scheme 1, those skilled in the art will know how to prepare compounds having formula (I) or pharmaceutically acceptable salts thereof. Certain variations or alternative methods are described in the Experimental Section below.

[0117] This invention further includes any variations of the inventive process, wherein an intermediate product available at any stage is used as a starting material for the remaining steps, or wherein the starting material is formed in situ under reaction conditions, or wherein the reaction components are used in the form of their salts or optically pure materials. The compounds and intermediates of this invention can also be converted into each other according to methods generally known to those skilled in the art.

[0118] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical compositions can be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical compositions of the present invention can be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions). Tablets can be film-coated or enteric-coated according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and one or more of the following: 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, also containing... c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; and, if desired, also containing d) Disintegrants, such as starch, agar, alginate or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavorings and sweeteners.

[0119] Method of using the present invention

[0120] There is evidence suggesting the role of NLRP3-induced IL-1 and IL-18 in inflammatory responses associated with or resulting from a variety of disorders (Menu et al.). , Clinical and Experimental Immunology [Clinical and Experimental Immunology], 2011, 166, 1-15; Strowig et al. Nature [Nature], 2012, 481, 278-286. NLRP3 mutations have been found to cause a rare group of autoinflammatory diseases known as CAPS (Ozaki et al.). , J. Inflammation Research [Journal of Inflammation Research], 2015, 8, 15-27; Schroder et al. Cell [Cell], 2010, 140: 821-832; Menu et al. , Clinical and Experimental Immunology [Clinical and Experimental Immunology], 2011, 166, 1-15). CAPS is a genetic disorder characterized by recurrent fever and inflammation and consisting of three autoinflammatory disorders forming a clinical continuum. These disorders, in order of increasing severity, are: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile cutaneous neuroarthritis syndrome (CINCA; also known as neonatal onset multisystem inflammatory disease, NOMID), and all of these have been shown to be caused by gain-of-function mutations in the NLRP3 gene, which lead to increased secretion of IL-1β. NLRP3 is also involved in many other autoinflammatory disorders, including pyogenic arthritis, pyoderma gangrenosa and acne vulgaris (PAPA), Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook et al.). , Eur. J. Immunol[European Journal of Immunology], 2010, 40, 595-653.

[0121] Many autoimmune diseases have been shown to involve NLRP3, including, in particular, multiple sclerosis, type 1 diabetes (T1D), psoriasis, rheumatoid arthritis (RA), Behcet's disease, Schnitzler syndrome, and macrophage activation syndrome (Braddock et al.). Nat. Rev. Drug Disc. [Nature Reviews Drug Discovery] 2004, 3, 1-10; Inoue people, Immunology [Immunology], 2013, 139, 11-18; Coll et al., Nat. Med. [Natural Medicine] 2015, 21(3), 248-55; Scott et al., Clin. Exp. Rheumatol. [Clinical and Experimental Rheumatology] 2016, 34(1), 88-93), systemic lupus erythematosus and its complications such as lupus nephritis (Lu et al., J. Immunol. [Journal of Immunology], 2017, 198(3), 1119-29), and systemic sclerosis (Artlett et al., Arthritis Rheum. [Arthritis and Rheumatism] 2011, 63(11), 3563-74). NLRP3 has also been shown to play a role in many lung diseases, including chronic obstructive pulmonary disease (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol. [American Journal of Pathology], 2014, 184: 42-54; Kim et al., Am. J. Respir. Crit. Care Med [American Journal of Respiratory and Critical Care Medicine], 2017, 196(3), 283-97). NLRP3 is also believed to play a role in many central nervous system disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, and brain damage caused by pneumococcal meningitis (Walsh et al., Nature Reviews [Nature Reviews], 2014, 15, 84-97; and Dempsey et al., Brain. Behav. Immun. [Brain, Behavior and Immunity] 2017, 61, 306-16), intracranial aneurysms (Zhang et al., J. Stroke and Cerebrovascular Dis.[Journal of Stroke and Cerebrovascular Diseases], 2015, 24, 5, 972-9), and traumatic brain injury (Ismael et al., J. Neurotrauma. [Journal of Neurotrauma], 2018, 35(11), 1294-1303). NRLP3 activity has also been shown to be involved in a variety of metabolic diseases, including type 2 diabetes (T2D) and its organ-specific complications, atherosclerosis, obesity, gout, pseudogout, and metabolic syndrome (Wen et al.). Nature Immunology [Nature Immunology], 2012, 13, 352-357; Duewell et al. , Nature [Nature], 2010, 464, 1357-1361; Strowig et al. Nature [Nature], 2014, 481, 278-286), and non-alcoholic steatohepatitis (Mridha et al.) J. Hepatol [Journal of Hepatology] 2017, 66(5), 1037-46). The role of NLRP3 via IL-1β has also been proposed in the following diseases: atherosclerosis, myocardial infarction (van Hout et al.). , Eur. Heart J. [European Heart Journal] 2017, 38(11), 828-36), heart failure (Sano et al.) J. Am. Coll. Cardiol [Journal of the American College of Cardiology] 2018, 71(8), 875-66), aortic aneurysm and dissection (Wu et al.) , Arterioscler. Thromb. Vase. Biol [Arteriosclerosis, Thrombosis and Vascular Biology], 2017, 37(4), 694-706), and other cardiovascular events (Ridker et al.) , N. Engl. J. Med [New England Journal of Medicine], 2017, 377(12), 1119-31.

[0122] Other diseases that have been shown to involve NLRP3 include: eye diseases such as wet and dry age-related macular degeneration (Doyle et al.). Nature Medicine [Natural Medicine], 2012, 18, 791-798; Tarallo et al. Cell [Cell] 2012, 149(4), 847-59), diabetic retinopathy (Loukovaara et al.) Acta Ophthalmol [Acta Ophthalmologica Sinica], 2017, 95(8), 803-8), non-infectious uveitis and optic nerve injury (Puyang et al.) , Sci. Rep[Scientific Reports] 2016, 6, 20998); Liver diseases, including non-alcoholic steatohepatitis (NASH) and acute alcoholic hepatitis (Henao-Meija et al.). Nature [Nature], 2012, 482, 179-185); inflammatory responses in the lungs and skin (Primiano et al., J. Immunol. [Journal of Immunology] 2016, 197(6), 2421-33), including contact hypersensitivity reactions (such as bullous pemphigoid (Fang et al., J Dermatol Sci. [Journal of Dermatology] 2016, 83(2), 116-23), atopic dermatitis (Niebuhr et al., Allergy [Allergy], 2014, 69(8), 1058-67), purulent hidradenitis (Alikhan et al., J. Am. Acad. Dermatol. [Journal of the American Academy of Dermatology], 2009, 60(4), 539-61), and sarcoidosis (Jager et al., Am. J. Respir. Crit. Care Med. [American Journal of Respiratory and Critical Care Medicine], 2015, 191, A5816); Inflammatory response in joints (Braddock et al.) Nat. Rev. Drug Disc [Nature Reviews Drug Discovery], 2004, 3, 1-10); Amyotrophic Lateral Sclerosis (Gugliandolo et al.) , Int. J. Mol. Sci [International Journal of Molecular Sciences], 2018, 19(7), E1992); Cystic fibrosis (Iannitti et al.) , Nat. Commun [Nature Communications], 2016, 7, 10791); stroke (Walsh et al.) Nature Reviews [Nature Reviews], 2014, 15, 84-97; Chronic kidney disease (Granata et al.) PLoS One [PLOS ONE] 2015, 10(3), eoi22272); and inflammatory bowel diseases, including ulcerative colitis and Crohn's disease (Braddock et al.). Nat. Rev. Drug Disc [Nature Reviews Drug Discovery], 2004, 3, 1-10; Neudecker et al. , J. Exp. Med [Journal of Experimental Medicine] 2017, 214(6), 1737-52; Lazaridis et al. Dig. Dis. Sci [Digestive Diseases and Sciences] 2017, 62(9), 2348-56. The NLRP3 inflammasome has been found to be activated in response to oxidative stress. NLRP3 has also been shown to be involved in inflammatory hyperalgesia (Dolunay et al.). Inflammation[Inflammation], 2017, 40, 366-86.

[0123] It has been shown that activation of the NLRP3 inflammasome enhances certain pathogenic infections, such as influenza and leishmaniasis (Tate et al.). Sci Rep [Scientific Reports], 2016, 10(6), 27912-20; Novias et al., PLOS Pathogens [PLOS Pathogens] 2017, 13(2), e1006196.

[0124] NLRP3 has also been involved in the pathogenesis of many cancers (Menu et al., Clinical and Experimental Immunology [Clinical and Experimental Immunology], 2011 (166, 1-15). For example, several previous studies have shown the role of IL-1β in cancer invasion, growth, and metastasis, and randomized, double-blind, placebo-controlled trials have demonstrated that inhibiting IL-1β with canakinumab can reduce the incidence of lung cancer and overall cancer mortality (Ridker et al.). Lancet [The Lancet], 2017, 390(10105), 1833-42. In vitro, inhibition of the NLRP3 inflammasome or IL-1β has also been shown to suppress the proliferation and migration of lung cancer cells (Wang et al.). Oncol Rep. [Reports on Oncology], 2016, 35(4), 2053-64. The role of the NLRP3 inflammasome has been proposed in the following diseases: myelodysplastic syndromes, myelofibrosis and other myeloproliferative neoplasms, and acute myeloid leukemia (AML) (Basiorka et al.). Blood [Blood], 2016, 128(25), 2960-75.) and the formation of various other cancers, including gliomas (Li et al.) Am. J. Cancer Res [American Journal of Cancer Research] 2015, 5(1), 442-9), Inflammation-induced tumors (Allen et al.) , J. Exp. Med [Journal of Experimental Medicine] 2010, 207(5), 1045-56; Hu et al. PNAS [Proceedings of the National Academy of Sciences of the United States of America], 2010, 107(50), 21635-40), multiple myeloma (Li et al.) Hematology [Hematology], 2016 21(3), 144-51), and squamous cell carcinoma of the head and neck (Huang et al.) , J. Exp. Clin. Cancer Res[Journal of Experimental and Clinical Cancer Research], 2017, 36(1), 116). It has also been demonstrated that activation of the NLRP3 inflammasome mediates chemoresistance of tumor cells to 5-fluorouracil (Feng et al.). J. Exp. Clin. Cancer Res [Journal of Experimental and Clinical Cancer Research], 2017, 36(1), 81), and activation of the NLRP3 inflammasome in the peripheral nerves contributes to chemotherapy-induced neuropathic pain (Jia et al.). Mol. Pain [Molecular Pain], 2017, 13, 1-11). NLRP3 has also been shown to be essential for the efficient control of viruses, bacteria, and fungi.

[0125] Activation of NLRP3 leads to apoptosis, and this characteristic plays an important role in the clinical manifestation of disease (Yan-gang et al.). Cell Death and Disease [Cell Death and Disease], 2017, 8(2), 2579; Alexander et al. Hepatology [Hepatology], 2014, 59(3), 898-910; Baldwin et al. , J. Med. Chem. [Journal of Medicinal Chemistry], 2016, 59(5), 1691-1710; Ozaki et al. J. Inflammation Research [Journal of Inflammation Research], 2015, 8, 15-27; Zhen et al., Neuroimmunology Neuroinflammation [Neuroimmunology and Neuroinflammation], 2014, 1(2), 60-65; Mattia et al. J. Med. Chem [Journal of Medicinal Chemistry], 2014, 57(24), 10366-82; Satoh et al. Cell Death and Disease [Cell Death and Disease], 2013, 4, 644). Therefore, it is expected that inhibitors of NLRP3 will block pyroptosis and the release of pro-inflammatory cytokines (such as IL-1β) from cells.

[0126] Compounds having any general formula (e.g., formula (I) etc.) in free form or in pharmaceutically acceptable salt form, or compounds according to any of the foregoing examples, or compounds according to any of the exemplary examples (e.g., example 1 disclosed herein), exhibit valuable pharmacological properties, such as NRLP3 inhibitory properties with respect to the NLRP3 pathway (e.g., as indicated by in vitro tests provided in the following sections), and are therefore designated for therapeutic use or as investigational chemicals, such as as tool compounds.

[0127] The compounds of the present invention can be used to treat diseases, disorders, or conditions selected from the following indications: inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases, for example, in which NLRP3 signaling contributes to pathology, and / or symptoms, and / or progression, and are responsive to NLRP3 inhibition and can be treated or prevented according to any one of Examples 1.0 to 18.0 or any of the exemplary examples of the present invention (e.g., Example 1 disclosed herein), including: I. Inflammation, including inflammation arising from inflammatory disorders such as autoinflammatory diseases, inflammation as a symptom of non-inflammatory disorders, inflammation due to infection, or inflammation secondary to trauma, injury, or autoimmune events. Examples of treatable or preventable inflammation include inflammatory responses associated with or resulting from the following conditions: (a) Skin conditions such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (b) Joint conditions such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, crystal-induced arthritis (pseudogout, gout) or seronegative spondyloarthritis (e.g., ankylosing spondylitis, psoriatic arthritis, or Reiter's disease). (c) Muscle disorders, such as polymyositis or myasthenia gravis; (d) Gastrointestinal disorders such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcers, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may have effects away from the gut (e.g., migraines, rhinitis, or eczema). (e) Respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic, or dust-induced asthma, and especially chronic or long-term asthma, such as late-onset asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis, drug-induced rhinitis, 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 pneumonia, or idiopathic interstitial pneumonia; (f) Vascular diseases, such as atherosclerosis, Bechtel disease, vasculitis, or Wegener's granulomatosis. (g) Immune disorders, such as autoimmune disorders, such as systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease. (h) Eye conditions, such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (i) Neurological disorders, such as multiple sclerosis or encephalomyelitis; (j) Infections or infection-related conditions, such as acquired immunodeficiency 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 hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis, Mycobacterium avium intracellularis, Pneumocystis carinii pneumonia, orchitis / epidydimitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (k) Kidney diseases, such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia, or nephrotic syndrome; (l) Lymphatic disorders, such as Castleman's disease; (m) Immune system disorders or diseases involving the immune system, such as hyperIgE syndrome, lepromatous leprosy, hemophagocytic histiocytosis, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease. (n) Liver diseases, such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), or primary biliary cirrhosis. (o) Cancer, including the cancers listed below; (p) Burns, trauma, external injury, bleeding, or stroke; (q) Radiation exposure; and / or (r) Obesity; and / or (s) Pain, such as inflammatory hyperalgesia.

[0128] II. Inflammatory diseases, including inflammation resulting from inflammatory disorders such as autoinflammatory diseases, such as cryptothermal protein-associated periodic syndrome (CAPS), Mucklet-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosa and acne syndrome (PAPA), adult-onset Still's disease (AOSD), A20 haploinadequacy (HA20), pediatric granulomatous arthritis (PGA), PLACG2-associated antibody deficiency and immune dysregulation (PLAID), PLACG2-associated autoinflammatory, antibody deficiency and immune dysregulation (APLAID), or sideroblastic anemia with B-cell immunodeficiency, periodic fever and developmental delay (SIFD).

[0129] III. Immunological diseases, such as autoimmune diseases, including acute diffuse encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), antisynthetic enzyme syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polygonal insufficiency, 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, and Kawasaki disease. Diseases 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, oculoclonus-myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Rett syndrome, Sjögren's syndrome, systemic sclerosis, systemic connective tissue disorder, and Takayasu's arteritis. Arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Beliefs' disease, Chagas' disease, familial autonomic dysfunction, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromuscular rigidity, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, vitiligo or vulvar pain, hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome, such as T-cell conjugation therapy (CAR-T or bi / trispecific antibodies). IV. Cancers, including 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), leukemias including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), promyelocytic leukemia (APML or APL), adrenal cancer, anal cancer, basal 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 myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing family cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, and catarrhal cancer. Bosie sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumors, lymphoma (including cutaneous T-cell lymphoma), malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, plasma cell disorders including monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma and active multiple myeloma, multiple myeloma, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, mature T and NK tumors, non-Hodgkin's sarcoma. Lymphoma, mature B-cell tumors such as non-Hodgkin's lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary adenoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymic cancer, thyroid cancer (including undifferentiated thyroid cancer), uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia. Macroglobulinemia, Wilms' tumor, myeloproliferative neoplasms (MPN) (including myelofibrosis), brain tumors (including primary brain cancer and brain metastases), myelodysplastic dysplasia / myeloproliferative neoplasms (MDS / MPN), bone marrow / lymphomas with eosinophilia and PDGFRA, PDGFRB or FGFR1 rearrangement or with PCM1-JAK2, B-cell leukemia / lymphoma, T-cell leukemia / lymphoma, histiocytic and dendritic cell tumors, and post-transplant lymphoproliferative disorder (PTLD). V. Infections, including viral infections (e.g., from influenza virus, human immunodeficiency virus (HIV), alpha viruses (such as chikungunya virus and Ross River virus), flaviviruses (such as dengue virus and Zika virus), herpesviruses (such as EB 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 papillomavirus), and bacterial infections (e.g., from Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella pertussis, Burkholderia pseudomallei, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Haemophilus influenzae, Pasteurella multocida. (Multicida), Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi, or Yersinia pestis The diseases include: pestis, fungal infections (e.g., from Candida or Aspergillus species), protozoan infections (e.g., from Plasmodium, Babesia, Giardia, Nemoba, Leishmania or Trypanosoma), helminth infections (e.g., from Schistosoma, Ascaris, Tapeworm or Trematode), 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 injury caused by 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 post-MI ischemia-reperfusion injury), stroke (including ischemic stroke), transient ischemic attack, myocardial infarction (including recurrent myocardial infarction), heart failure (including congestive heart failure and heart failure with preserved ejection fraction), embolism, aneurysm (including abdominal aortic aneurysm), reduced cardiovascular risk (CvRR), and pericarditis (including Dressler's syndrome), post-myocardial infarction heart failure; atrial fibrillation. IX. Respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma (such as allergic asthma and steroid-resistant asthma), asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis; X. Liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) (including advanced fibrotic stages F3 and F4), alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH); XI. Kidney diseases, including acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy; XII. Eye diseases, including ocular epithelial diseases, 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 reactions, sunburn, skin lesions, hidradenitis suppurativa (HS), other skin diseases that cause cysts, and acne conglobata; XIV. Lymphatic disorders, such as lymphangitis and Kassman's disease; XV. Mental disorders, such as depression and psychological stress; schizophrenia, bipolar disorder; XVI. Graft-versus-host disease; XVII. Bone diseases, including osteoporosis and osteosclerosis; XVIII. Blood disorders, including sickle cell disease; XVIX. Abnormal pain, including mechanical abnormal pain; and XVX. Any disease in which an individual has been identified as carrying a germline or somatic non-silent mutation in NLRP3.

[0130] More specifically, the compounds of the present invention can be used to treat indications selected from: inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases, such as autoinflammatory febrile syndromes (e.g., cryptothermal protein-related periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy such as acute and chronic arthropathy), calcium pyrophosphate dihydrate crystal deposition disease (CPPD), and kidney-related diseases (e.g., hyperoxaluria, lupus-related diseases). Nephritis, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammatory diseases (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and II diabetes and related 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 cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis). Specifically, autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammatory disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0131] In particular, the compounds of the present invention or pharmaceutically acceptable salts thereof may be used to treat diseases or disorders preferably selected from the following: autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammatory-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancers (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0132] Therefore, as another aspect, the present invention provides the use of compounds having any general formula (e.g., formula (I) etc.), or compounds according to any of the foregoing embodiments (e.g., any of Examples 1.0 to 18.0), or compounds according to any of the exemplary examples (e.g., Example 1 as disclosed herein), or pharmaceutically acceptable salts thereof, in a therapeutic context. In another embodiment, the therapeutic is selected from diseases that can be treated by inhibiting the NLRP3 inflammasome pathway. In another embodiment, the disease is selected from the foregoing list, suitably as inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases, such as autoinflammatory febrile syndromes (e.g., cryptothermal protein-related periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy such as acute and chronic arthropathy), and kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes). Diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammatory diseases (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related 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 cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). Specifically, autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammatory disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0133] Therefore, as another aspect, the present invention provides compounds having any general formula (e.g., formula (I) etc.), or compounds according to any of the foregoing embodiments (e.g., any of Examples 1.0 to 18.0), or compounds according to any of the exemplary examples (e.g., Example 1 as disclosed herein), or pharmaceutically acceptable salts thereof, for use in a therapy. In another embodiment, the therapy is selected from diseases that can be treated by inhibiting the NLRP3 inflammasome pathway. In another embodiment, the disease is selected from the foregoing list, suitably as inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases, such as autoinflammatory febrile syndromes (e.g., cryptothermal protein-related periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy such as acute and chronic arthropathy), and kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes). Diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammatory diseases (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related 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 cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). Specifically, autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammatory disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0134] On the other hand, the present invention provides a method for treating a disease by inhibiting NLRP3, the method comprising administering a therapeutically effective amount of a compound having any general formula (e.g., formula (I) etc.), or a compound according to any of the foregoing examples (e.g., any of Examples 1.0 to 18.0), or a compound according to any of the exemplary examples (e.g., Example 1 as disclosed herein), or a pharmaceutically acceptable salt thereof. In another embodiment, the disease is selected from the foregoing list, suitably as inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases, such as autoinflammatory febrile syndromes (e.g., cryptothermal protein-related periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy such as acute and chronic arthropathy), and kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes). Diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammatory diseases (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related 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 cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). Specifically, autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammatory disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0135] In another aspect, the present invention provides compounds having any general formula (e.g., formula (I) etc.), or compounds according to any of the foregoing examples (e.g., any of Examples 1.0 to 18.0), or compounds according to any of the exemplary examples (e.g., Example 1 disclosed herein), or pharmaceutically acceptable salts thereof, for the treatment of diseases, disorders, or conditions mediated substantially or entirely by NLRP3 inflammasome activity as disclosed herein, and / or NLRP3-induced IL-1β and / or NLRP3-induced IL-18. Some of the diseases, disorders, or conditions mentioned herein are caused by mutations in NLRP3 (particularly those leading to increased NLRP3 activity).

[0136] The combination products and combination therapies of the present invention

[0137] "Combination" refers to a fixed combination in the form of a single dose unit, or combination administration (whereby the compound of the invention and a combination partner (e.g., another drug explained below, also referred to as a "therapeutic agent" or "co-agent")) can be administered independently at the same time or separately at time intervals, especially where these time intervals allow the combination partner to exhibit a synergistic (e.g., co-effect) effect. Individual components may be packaged in a kit or separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration. Terms such as "co-administration" or "combination administration" as used herein are intended to cover the administration of a selected combination partner to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the agents are not necessarily administered via the same route of administration or are administered simultaneously. As used herein, the term "drug combination" means a mixture of more than one therapeutic agent or The products resulting from combinations include both fixed and non-fixed combinations of therapeutic agents. As used herein, the term "drug combination" refers to a fixed combination in the form of a single dose unit, or a non-fixed combination or kit for combined administration, wherein two or more therapeutic agents may be administered independently at the same time or separately at time intervals, particularly where these time intervals allow the combination couple to exhibit synergistic (e.g., co-existing) effects. The term "fixed combination" means that therapeutic agents (e.g., the compounds of the present invention and the combination couple) are administered to a patient simultaneously as a single entity or dose. The term "non-fixed combination" means that therapeutic agents (e.g., the compounds of the present invention and the combination couple) are administered to a patient simultaneously, in parallel, or sequentially as separate entities (without a specific time limit), wherein such administration provides a therapeutically effective level of two compounds in the patient's body. The latter also applies to cocktail therapies, such as the administration of three or more therapeutic agents.

[0138] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic condition or disorder described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as administration in a single capsule having a fixed proportion of the active ingredients. Alternatively, such administration encompasses co-administration in multiple or separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Additionally, such administration also encompasses the sequential use of each type of therapeutic agent at approximately the same time or at different times. In any case, the treatment regimen will provide the beneficial effects of the combination of drugs in treating the condition or disorder described herein.

[0139] The compounds of this invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of this invention can be administered separately via the same or different routes of administration as other pharmaceutical agents, or together in the same pharmaceutical composition. The therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids, which, when administered to a patient in combination with the compounds of this invention, possess therapeutic activity or enhance therapeutic activity.

[0140] In one embodiment, the present invention provides a product comprising a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent as a combination formulation for simultaneous, separate, or sequential use in a therapy. In one embodiment, the therapy is for treating a disease or condition mediated by NLRP3. The product provided as a combination formulation comprises a composition comprising a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, and another therapeutic agent together in the same pharmaceutical composition, or in separate forms (e.g., in the form of a kit) comprising a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0141] In one embodiment, the present invention provides a pharmaceutical combination comprising a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, or a compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt thereof, and another therapeutic agent. Optionally, the pharmaceutical combination may comprise a pharmaceutically acceptable carrier as described above.

[0142] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one contains a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, or a compound or a pharmaceutically acceptable salt thereof according to any of the foregoing embodiments. In one embodiment, the kit includes means for individually retaining the compositions, such as a container, separate bottle, or separate foil pouch. An example of such a kit is blister packaging, as typically used for packaging tablets, capsules, etc.

[0143] The kits of this invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer separate compositions at different dose intervals, or to titrate individual compositions relative to each other. To aid compliance, the kits of this invention typically include administration instructions.

[0144] In the combination therapy of the present invention, the compound of the present invention and another therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present invention and another therapeutic agent can be combined to form a combination therapy in the following ways: (i) before the combination product is dispensed to a physician (e.g., in the case of a kit containing the compound of the present invention and another therapeutic agent); (ii) shortly before administration, by the physician himself (or under the guidance of a physician); (iii) by the patient himself, for example, during the sequential administration of the compound of the present invention and another therapeutic agent.

[0145] Therefore, the present invention provides the use of a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof for treating NLRP3-mediated diseases or conditions, wherein the medicament is prepared for administration in combination with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating NLRP3-mediated diseases or conditions, wherein the medicament is administered in combination with a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, or a compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt thereof.

[0146] The present invention also provides a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, or a compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by NLRP3, wherein the compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, or a compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt thereof, is prepared for administration together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by NLRP3, wherein the other therapeutic agent is prepared for administration together with a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, or a compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt thereof. The present invention also provides a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, or a compound or a pharmaceutically acceptable salt thereof according to any of the foregoing embodiments, for use in a method of treating a disease or condition mediated by NLRP3, wherein the compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, or a compound or a pharmaceutically acceptable salt thereof according to any of the foregoing embodiments, is administered together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by NLRP3, wherein the other therapeutic agent is administered together with a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, or a compound or a pharmaceutically acceptable salt thereof according to any of the foregoing embodiments.

[0147] The present invention also provides the use of a compound having any general formula (e.g., formula (I) etc.), or a compound according to any of the foregoing embodiments (e.g., according to any of Examples 1.0 to 18.7) or a pharmaceutically acceptable salt thereof, for the treatment of NLRP3-mediated diseases or conditions, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent for the treatment of NLRP3 inflammasome pathway-mediated diseases or conditions, wherein the patient has previously (e.g., within 24 hours) been treated with a compound having any general formula (e.g., formula (I) etc.) or a pharmaceutically acceptable salt thereof, or a compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt thereof.

[0148] In one embodiment, another therapeutic agent is a therapeutic agent that can be used to treat inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases as disclosed herein.

[0149] In one embodiment, another therapeutic agent that can be used in combination therapy is selected from farnesoid X receptor (FXR) agonists; anti-fatty degeneration agents; anti-fibrotic agents; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiation therapy, and surgery; uric acid-lowering therapy; anabolic agents and chondrogenic therapy; IL-17 blockers; complement inhibitors; Bruton's tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TLR7 / 8 inhibitors); CAR-T therapy; antihypertensive agents; cholesterol-lowering agents; leukotriene A4 hydrolase (LTA4H) inhibitors; SGLT2 inhibitors; β2-agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs (“NSAIDs”); acetylsalicylic acid (ASA) drugs, including aspirin; acetaminophen; regenerative therapy; cystic fibrosis treatment; and atherosclerosis treatment.

[0150] Suitable leukotriene A4 hydrolase (LTA4H) inhibitors for use in combination include, but are not limited to, compounds disclosed in WO2015 / 092740, particularly (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butyric acid (LYS006), and compounds disclosed in WO 2022 / 219546.

[0151] Suitable sodium-dependent glucose transporter 2 (SGLT2) inhibitors for use in combination include, but are not limited to, compounds disclosed in US 8,163,704, WO 2011 / 048112, WO 2011 / 048148, or WO 2010 / 128152.

[0152] Suitable β2-agonists for use in combination include, but are not limited to, artoterol, bambuterol, bitoterol, brombuterol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline, ibuterol, neo-isoproterenol, isoproterenol, levosalbutanol, mabuterol, meluadrine, metaprotenerol, nolomirole, osinerol, pibuterol, procaterol, reproterol, and ritodrine. (ritodrine), rimoterol, salbutamol, saline, sibenadet, 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-naphthoxy ]-N,N-dimethylacetamide hydrochloride monohydrate, carmoterol, QAB-149 and 5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolidinone, 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-[2 H-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-n-butoxyphenyl)-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-1,4-benzoxazine-3-(4H)-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, wherein each is optionally in the form of a racemic mixture, an enantiomer, a diastereomer, or a mixture thereof, and is also optionally in the form of a pharmacologically compatible acid addition salt.

[0153] Suitable cartilage regeneration therapies for use in combination include, but are not limited to, the ANGPTL3 mimic peptide disclosed in WO 2014 / 138687, or the cartilage formation activator disclosed in WO 2015 / 175487.

[0154] 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, antibody molecules disclosed in WO 2015 / 112900. Suitable anti-LAG-3 inhibitors include, but are not limited to, antibody molecules disclosed in WO 2015 / 138920. Suitable anti-TIM-3 inhibitors include, but are not limited to, antibody molecules disclosed in WO 2015 / 117002. Suitable anti-TIM-3 inhibitors include, but are not limited to, antibody molecules disclosed in WO 2015 / 117002. Suitable anti-PDL1 inhibitors include, but are not limited to, antibody molecules disclosed in WO 2016 / 061142.

[0155] Suitable Toll-like receptor inhibitors (TLR7 / 8 inhibitors) for use in combination include, but are not limited to, the compounds disclosed in WO2018 / 04081.

[0156] Suitable FXR agonists for use in combination include, but are not limited to, obeticholic acid (also known as OCA, Intercept Pharmaceuticals), GS9674, elafibranor (GFT505), GW4064, UPF987, FXR-450, fexaramine, methylcolate, deoxycholate, 5β-cholanic acid, 5β-cholanic acid 7α,12α-diol, NIHS700, lecithin A, lecithin E, MFA-1 INT767 (also known as WO The following compounds are disclosed in WO 2014 / 085474: 6α-ethyl-CDCA, 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]oct-8-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid (also known as Tropifexor), or pharmaceutically acceptable salts thereof, or compounds disclosed in WO 2012 / 087519, or compounds disclosed in WO 2015 / 069666.

[0157] Suitable JAK inhibitors for use in combination include, but are not limited to, ruxolitinib.

[0158] Suitable NSAIDs for use in combination include, but are not limited to, acemetacin, acetylsalicylic acid, alclofenac, amfenac, ampiroxicam, antolmetinguacil, anirolac, triamcinolone, azapropazone, benorilate, bermoprofen, bindarit, bromofenac, buccolonic acid, bucolon, bumadizon, butibufen, butixirat, carbasalatcalcium, carprofen, and choline magnesium trisalicylate.trisalicylate, celecoxib, cinmetacin, cinnoxicam, clidanac, clobuzarit, deboxamet, dexibuprofen, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, enfenamic acid aure, etersalat, etodolac, etofenamate, etoricoxib, feclobuzon, felbinac, fenbufen, fenclofenac, fenoprofen, fentiazac, fepradinol, feprazon, flobufen, floctafenin e), flufenamic acid, flufenisal, flunoprofen, flurbiprofen, flurbiprofenaxetil, furofenac, furprofen, glutametacin, ibufenac, ibuprofen, indobufen, indomethacin, indomethacin farnesyl ester dometacinfarnesil, indoprofen, isoxepac, isoxicam, ketoprofen, ketorolac, lobenzarit, lonazolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, meclofen, mefenamic acidacid), meloxicam, mesalazine, miroProfen, mofezolac, nabumeton, naproxen, niflufenicol, olsalazine, oxaprozin, oxipinac, oxyphenbutazone, parecoxib, phenylbutazone, pelubiprofen, p- Pimeprofen, Pirazolac, Priroxicam, Pirprofen, Pranoprofen, Prifelon, Prinomod, Proglumetacin, Proquazon, Protizininsaure, Rofecoxib, Romazarit, Salicylamide, Salicylic Acid Salmi Stein, Salnacedin, Salsalate, Sulindac, Sudoxicam, Suprofen, Talniflumate, Tenidap, Tenosal, Tenoxicam, Tepoxalin, Tiaprofenic acid, Taramid, Tilnoprofenarbamel, Timegadine, Tenoridin, Tiopinac, Tolfenamic acid acid), tolmetin, ufennat, valdecoxib, ximoprofen, zaltoprofen, zoliprofen, and combinations thereof.

[0159] Suitable BTK inhibitors include, for example, ibrutinib, acalabrutinib (ACP-196), evobrutinib; fenebrutinib; tirabrutinib (ONO-4059, GS-4059); zanubrutinib (BGB-3111); and spebrutinib. nib)(CC-292, AVL-292), Poseltinib (HM-71224, LY3337641), Vecabrutinib (SNS-062), BMS-986142; BMS986195; PRN2246; PRN1008, M7583, CT1530, BIIBO68, AC-0058TA, ARQ-531, TAK-020, TG1701 or WO 2015 / 079417、WO 2015 / 083008、WO 2015 / 110923、WO 2014 / 173289、WO 2012 / 021444、WO 2013 / 081016、WO 2013 / 067274、WO 2012 / 170976、WO 2011 / 162515, US 2017 / 119766, WO 2016 / 065226, US 9,688,676, WO 2016 / 201280, WO 2017 / 059702, US 9,630,968, US 2014 / 0256734, WO 2017118277、WO The compounds described in 2014 / 039899, ​​WO / 16 / 105531, WO 2018 / 005849, WO 2013 / 185082 or J. Med. Chem. [Journal of Medicinal Chemistry], 2016, 59(19), 9173–9200. Among those of particular interest, BTK inhibitors include the compound of Example 31 described in WO 2014 / 039899, ​​and compounds having the following structure: , The compounds described as compound 14f in Journal of Medicinal Chemistry, 2016, 59 (19), 9173-9200; and the compounds of Example 2 described in US 2017 / 119766 and Example 223 described in WO 2016 / 065226 are the following: , Or compound 1 as described in WO 2016 / 201280, compound 1 as described in WO 2017 / 059702, or compound 1 as described in WO 2017 / 118277; or a pharmaceutically acceptable salt thereof.

[0160] Among other compounds of particular interest, BTK inhibitors include the compounds described in WO 2015 / 079417, such as those selected from: N-(3-(5-((1-acryloylazapyridine-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-((1-propynylazapyridine-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methyl)... (N-(3-(6-amino-5-(2-(N-methylpropionylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Remibrutinib); N-(3-(6-amino-5-(2-(N-methylpropionylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylbut-2-enamido)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-(2-fluoroethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(but-2-enamido)propoxy) (S)-N-(3-(6-amino-5-(2-(N-methylbut-2-acrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; and N-(3-(6-amino-5-(3-(N-methacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; or pharmaceutically acceptable salts thereof. Attached Figure Description

[0161] Figure 1 The form H is shown A X-ray powder diffraction pattern.

[0162] Figure 2 The form H is shownA Differential scanning calorimetry (DSC) traces.

[0163] Figure 3 The form H is shown A Thermogravimetric analysis (TGA) traces.

[0164] Figure 4 The X-ray powder diffraction pattern of form A is shown.

[0165] Figure 5 The differential scanning calorimetry (DSC) trace of form A is shown.

[0166] Figure 6 The TGA trace of form A is shown.

[0167] Figure 7 The X-ray powder diffraction pattern of form B is shown.

[0168] Figure 8 The differential scanning calorimetry (DSC) trace of form B is shown.

[0169] Figure 9 The TGA trace of form B is shown.

[0170] Figure 10 The X-ray powder diffraction pattern of form example 1 hippurate (1:1) is shown.

[0171] Figure 11 The differential scanning calorimetry (DSC) trace of Form 1 hippurate (1:1) is shown.

[0172] Figure 12 The TGA trace of Form 1 hippurate (1:1) is shown.

[0173] Figure 13 The X-ray powder diffraction pattern of the hydrochloride (1:1) of Example 1 is shown.

[0174] Figure 14 Differential scanning calorimetry (DSC) traces of hydrochloride in form (1:1) are shown.

[0175] Figure 15 The TGA trace of Form 1 hydrochloride (1:1) is shown.

[0176] Example

[0177] Examples of the present invention

[0178] This disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that these examples are provided to illustrate certain embodiments, and the scope of this disclosure is not intended to be limited thereto. It should be further understood that various other embodiments, modifications, and equivalents thereof may be employed without departing from the spirit of this disclosure and / or the scope of the appended claims, as would be apparent to those skilled in the art.

[0179] The compounds disclosed herein can be prepared by methods known in the field of organic synthesis. In all methods, it should be understood that protecting groups against sensitive or reactive groups may be used, as necessary, in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (TW Green and PGM Wuts (2014) Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons). These groups are removed at a convenient stage of compound synthesis using methods readily apparent to those skilled in the art.

[0180] Unless otherwise specified, use reagents and solvents received from commercial suppliers.

[0181] Chemical names were generated using ChemBioDraw Ultra v14 from CambridgeSoft.

[0182] Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporation was carried out under reduced pressure, typically between about 15 mmHg and 100 mmHg (= 20–133 mbar). The structures of the final products, intermediates, and starting materials were confirmed by standard analytical methods, such as trace analysis and spectroscopic characterization (e.g., MS, IR, NMR). Abbreviations used are those conventional in the art.

[0183] abbreviation

[0184] Analysis details NMR: In Bruker Ascend™ ( 400 MHz ) Spectrometer or Bruker Ultra Shield TM 400 (400MHz) or Bruker AscendTM (400 MHz) or Bruker cryo system Measurements were performed on a (600 MHz) spectrometer, with or without tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ values) were reported as low-field ppm of TMS, and the spectral splitting mode was specified as single signal ( s Dual signal () d ), triple signal ( t ), quadruple signal ( q ), five-fold signal ( quint ), seven-fold signal (s ept ), multiple signals, unresolved or overlapping signals ( m ), wide signal ( br The deuterated solvent is given in parentheses and has chemical shifts for dimethyl sulfoxide (δ 2.50 ppm), methanol (δ 3.31 ppm), chloroform (δ 7.26 ppm), or other solvents as indicated in the NMR spectral data.

[0185] UPLC-MS (Method 1): System: Waters Acquity UPLC with Waters SQ detector.

[0186] Column: CORTECS C18 2.7 µm, 2.1 x 50 mm, column temperature: 80°C.

[0187] Gradient: from 1% to 50% B in 1.4 min; from 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.

[0188] UPLC-MS Basics: System: Waters Acquity UPLC with Waters SQ detector.

[0189] Column: Type: XBridge® BEH™ C18 2.5 µm, 2.1 x 50 mm, Column temperature: 80°C.

[0190] Gradient: from 2% to 98% B in 1.4 min, A = water + 5 mM NH4OH, B = acetonitrile + 5 mM NH4OH, flow rate: 1.0 mL / min.

[0191] UPLC-MS (Method 2): System: Waters Acquity UPLC with Waters SQ detector.

[0192] Column: Waters Acquity UPLC BEH C18, Column temperature: 40°C.

[0193] Gradient: from 5% to 95% B over 8 min; 95% B held 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.

[0194] Mass spectrometry results are reported as mass-to-charge ratio.

[0195] Preparation method Rapid column chromatography system: System 1: Teledyne ISCO, CombiFlash Rf.

[0196] Column: Pre-filled RediSep Rf filter cartridge.

[0197] Typically, the sample is adsorbed onto Isolute.

[0198] System 2: Isolera One Biotage Chromatography System

[0199] Column: Pre-filled Biotage SNAP filter cartridge

[0200] All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of this invention are commercially available or can be prepared by organic synthesis methods known to those skilled in the art.

[0201] Synthesis of intermediates

[0202] Intermediate 1: Methyl(R)-6-chloro-3-((1-methylpiperidin-3-yl)amino)pyridazine-4-carboxylate

[0203] At RT, triethylamine (3.03 mL, 21.74 mmol) and (R)-1-methylpiperidin-3-amine (1.99 g, 17.39 mmol) were added to a solution of methyl 3,6-dichloropyridazine-4-carboxylate (3.0 g, 14.49 mmol) in anhydrous THF (20 mL). The mixture was heated 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 silica gel column chromatography (using DCM and MeOH (0 to 10%)) to give the title compound as an orange solid.

[0204] UPLC / MS (Method 1): Rt = 0.28 min; MS m / z 285.2 [M+H] + . 1 H NMR (400 MHz, 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).

[0205] Intermediate 2: (R)-(6-chloro-3-((1-methylpiperidin-3-yl)amino)pyridazin-4-yl)methanol

[0206] Under a nitrogen atmosphere at -10°C, LiAlH4 (1 M, 1.84 mL, 1.84 mmol in THF) was added to a solution of intermediate 1 (0.5 g, 1.76 mmol) in anhydrous THF (10 mL). The mixture was stirred at -10°C for 40 min, then quenched by dropwise addition of a saturated Rochelle salt solution and stirred at RT for 15 min, followed by the addition of EtOAc. The phases were separated, and the aqueous layer was extracted (twice) with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated to provide an oil. The crude product was purified by silica gel column chromatography (using DCM and MeOH (5% aqueous NH4OH), from 0 to 20%) to give the title compound.

[0207] UPLC / MS basic method: Rt = 0.58 min; MS m / z 257.3 [M+H] + . 1H NMR (400 MHz, 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).

[0208] Intermediate 3: 2-Iodo-3-methyl-5-(trifluoromethyl)phenol (can be prepared as described in WO 2020 / 234715, Int B007)

[0209] To an ice-cold solution of 3-methyl-5-(trifluoromethyl)phenol (13.03 g, 74 mmol) in 370 mL toluene, NaH (60% dispersion in mineral oil, 5.92 g, 148 mmol) was added. The suspension was stirred at 0°C for 30 min, then iodine (18.77 g, 74 mmol) was added slowly in portions while 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 silica gel (220 g) column chromatography (using cyclohexane and EtOAc (from 5% to 100%)) to give the title compound as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.08 – 7.04 (m, 2H), 5.74 (s, 1H), 2.50 (s, 3H).

[0210] Intermediate 4: 3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-5-(trifluoromethyl)phenol (can be prepared as described in WO 2020 / 234715, Int B010)

[0211] (1) 1-(ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl)benzene

[0212] (Chloromethoxy)ethane (3.35 g, 35.50 mmol) was added dropwise to a white suspension of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (intermediate 3, 8.50 g, 28.10 mmol) and Cs₂CO₃ (9.17 g, 28.10 mmol) in 30 mL of anhydrous 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 using cyclohexane and EtOAc (from 0% to 5%) to give the title compound.

[0213] (2) 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane

[0214] 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]dioxane (20.15 mL, 139 mmol), and NEt3 (28.6 mL, 205 mmol) in 60 mL of 1,4-dioxane was purged with nitrogen. Pd(OAc)2 (0.81 g, 3.61 mmol) and biphenyl-2-yl-dicyclohexylphosphine (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 NH4Cl, water, and brine. The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by silica gel column chromatography (using cyclohexane and CH2Cl2 (from 0% to 20%)) to obtain the title compound.

[0215] (3) 3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-5-(trifluoromethyl)phenol was added slowly at 0°C to a solution of 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (7.00 g, 19.43 mmol) in 250 mL of CH2Cl2. 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 CH2Cl2 (from 0% to 100%) to give the title compound. 1H 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).

[0216] Instance composition

[0217] Example 1: (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0218] (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-dioxaneborane-2-yl)-5-(trifluoromethyl)phenol (intermediate 4, 0.3 g, 0.99 mmol), and 2M Na₂CO₃ aqueous solution (1.2 mL) were suspended in dioxane (7 mL), and the mixture was purged with nitrogen for 5 min. Pd(PPh₃)₄ (47.8 mg, 0.041 mmol) was added, and the mixture was stirred at 120°C for 1 h under microwave irradiation. The reaction mixture was diluted with DCM and brine, and the phases were separated. The aqueous layer was extracted with DCM, and the combined organic layers were dried / filtered using an Isolute phase separator and evaporated to dryness. The residue was purified by silica gel column chromatography (using DCM and MeOH (5% aqueous NH4OH), from 0% to 20%) to give a pale yellow solid. The 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.

[0219] UPLC / MS (Method 1): Rt = 0.61 min; MS m / z 397.4 M+H] + . 1¹H 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 blocked by 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).

[0220] Alternative synthesis in Example 1: Example 1 can be prepared according to the following scheme: .

[0221] Step 1:

[0222] 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 20°C–30°C for 1 h. Compound 2 (100 g, 476.1 mmol, 1 eq.) and DCM (600 g) were charged into reactor 2. Reactor 2 was cooled to -10°C–0°C. The mixture from reactor 1 was added dropwise to reactor 2, and reactor 1 was rinsed with MTBE (150 g). The entire reactor was stirred at -10°C–0°C for 1–3 h. Reactor 2 was then adjusted to 20°C–30°C and stirred for 17–20 h. 200 g of 0.1 N HCl (aqueous) was added dropwise to reactor 2 at 20°C–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 at 20°C–30°C to adjust the pH to 6–7. The organic layer was collected and washed with water (200 g), then concentrated under vacuum below 40°C to obtain crude compound 3 in an oily state.

[0223] 1H NMR (300 MHz, CDCl3) δ 5.67 (s, 1H), 3.78 (s, 3H), 2.40 (s, 3H).

[0224] Step 2

[0225] Compounds 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 at 90°C–100°C for 20 h. After the reaction was complete, the mixture was cooled to 15°C–25°C. Water (200 g) and toluene (450 g) were added to the reaction mixture. 10% citric acid (aqueous) was added dropwise to reactor 1 at 20°C–30°C to adjust the pH to between 6 and 7. The aqueous and organic layers were separated, and the organic layer was washed twice with 10% NaCl (aqueous) (200 g). The organic layer was collected and concentrated under vacuum below 70°C to obtain a crude product in an oily state.

[0226] 1 H NMR (300 MHz, CDCl3) δ 11.91 (s, 1H), 7.11 (s, 1H), 6.98 (s, 1H), 2.71 (s, 3H), 2.66 (s, 3H).

[0227] LCMS ( m / z (ESI) C 10 H 10 F3O2 + [M+H] + The calculated value is: 219.0

[0228] Step 3

[0229] Compound 5 (100 g, 458.3 mmol, 1.0 eq.) and 2M KOH (aqueous) (800 g) were charged into reactor 1, and the reaction mixture was stirred for 1 h at 20°C–30°C. Compound 6 (212.1 g, 2.86 mol, 6.2 eq.) and water (410 g) were charged into reactor 2. 733 g of 2M KOH (aqueous) was added to reactor 1 at -5°C–0°C and stirred for 1 h. The aqueous layer from reactor 1 was slowly added to reactor 2 at -5°C–0°C. The reaction mixture was stirred for another 20 h at -5°C–0°C. The pH was adjusted to 9–10 with acetic acid at -5°C–5°C. DCM (768 g) was charged into reactor 2, and the organic layer was separated and collected. The pH was further adjusted to between 4 and 5 with acetic acid. The pH was then adjusted to between 8 and 9 using NH3·H2O within a temperature range of 10°C–20°C. N2H4·H2O (80% w / w, 71.7 g) was added to the mixture within a temperature range of 10°C–20°C. The temperature of the mixture was then adjusted to between 90°C and 100°C, and the entire mixture was stirred for 20 h. The mixture was cooled to a temperature range of 30°C–40°C, and the pH was adjusted to between 6 and 7 using 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°C–50°C. After 5 h, the mixture was cooled to 15°C–25°C, stirred for another 3 h at 15°C–25°C, and then filtered. The wet filter cake was slurried with MeOH (600 g) and water (800 g) at a temperature of 40°C-50°C, and then the mixture was cooled to 15°C-25°C after 5 h, and then stirred for 3 h. The wet filter cake was dried at a temperature of 40°C-50°C for 20 h to obtain product 7 (42.1 g) as a white solid.

[0230] 1 H NMR (300 MHz, DMSO- d 6 ) δ 13.21 (br s, 1H), 10.38 (br s, 1H), 7.41(d, J = 9.7 Hz, 1H), 7.10 (d, J = 13.1 Hz, 2H), 6.94 (d, J = 9.7 Hz, 1H), 2.19 (s, 1H).

[0231] LCMS ( m / z , ESI) UPLC-MS (Method 2) C 12 H 10 F3N2O2 + [M+H] + The calculated value is 271.1

[0232] Step 4

[0233] 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 into reactor 1. The mixture was stirred at 15°C–25°C for 17 h. After the reaction was complete, water (280 g) was charged into reactor 2 and the entire reactor was heated to 50°C. The mixture was slowly transferred from reactor 1 to reactor 2 at 45°C–55°C. After stirring the reaction mixture at 45°C–55°C for 16 h, the mixture was filtered and the wet filter cake was washed with water (40 mL). The wet filter cake was charged into reactor 2, water (140 g) was added, and the pH was adjusted to between 7 and 8 with 2% ammonia solution (14 g). The reaction mixture was filtered, and the resulting wet filter cake was washed twice with water (25 g). 2). The wet filter cake was dried at 60°C to obtain 14.6 g of product as a white solid.

[0234] 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.23 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 6.95 (s, 1H), 6.89 (s, 1H), 1.89 (s, 3H).

[0235] HRMS (High Resolution Mass Spectrometry) m / z (ESI) C 12 H9ClF3N2O + [M+H] + The calculated value is: 289.0284

[0236] Step 5

[0237] 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°C–30°C. The mixture was then stirred at 50°C for 2 h. BnCl (8.3 g, 1.1 eq.) was then added dropwise to the reactor. The mixture was stirred at 50°C for 10 h. The mixture was cooled to room temperature, and water (51 g) was added to the mixture. After stirring for 30 min, the organic layer was collected, and H₂O (330 g) was then added dropwise to the organic layer at a temperature of 20°C–30°C, followed by stirring for 3 h. The reaction mixture was filtered, and the filter cake was washed with water (51 g). The wet filter cake was then dried under vacuum at 55°C to obtain 21.1 g of product as a light brown solid.

[0238] 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.80 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7.17 (d, J = 12.1 Hz, 2H), 7.12 – 6.97 (m, 5H), 4.96 (s, 2H), 1.90 (s, 3H).

[0239] HRMS (High Resolution Mass Spectrometry) m / z (ESI) C 19 H 15 ClF3N2O + [M+H] + The calculated value is 379.1378.

[0240] Step 6

[0241] Compounds 9 (20 g, 52.8 mmol, 1 eq.) and 10 (13.8 g, 73.9 mmol, 1.4 eq.) were used. tBuOLi (25.4 g, 316.8 mmol, 6 eq.) and CPME (260 mL) were loaded into the 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°C–70°C for 16 h. After the reaction was complete, the mixture was cooled to 20°C–30°C. 4% HCl (aqueous) (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 each time). 2). Adjust the pH of the aqueous layer to between 8 and 9 using 20% ​​NaOH (aqueous), and extract twice with isopropyl acetate (200 mL). 2). The combined organic layers were concentrated to approximately 260 g, and then 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 filter cake. After drying at 50°C for 16 h, a dry product of 16.9 g as a grayish-white solid was obtained.

[0242] 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.11 – 6.99 (m, 7H), 6.66 (d, J = 9.3 Hz, 1H), 6.56 (d, J = 7.8 Hz, 1H), 4.93 (s, 2H), 3.92 – 3.80 (m, 1H), 2.64 (d, J = 9.0 Hz, 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).

[0243] HRMS (High Resolution Mass Spectrometry) m / z (ESI) C 25 H 28 F3N4O + [M+H] + The calculated value is 457.2232.

[0244] Step 7

[0245] Compound 11 (54 g, 118.3 mmol, 1 eq.), 8% H2O2 (aqueous) (7.23 g, 212.9 mmol, 1.8 eq.), TFA (26.97 g, 236.6 mmol, 2 eq.), 1,1'-bis(diphenylphosphino)ferrocene dioxide (dppfO2) (0.69 g, 1.18 mmol, 0.01 eq.), and MeOH (504 mL) were charged into a reactor. The reaction mixture was pumped at 30°C through a blue light reactor (450 nm). After completion, the mixture was quenched with 10% Na2SO3 (aqueous). The pH of the mixture was adjusted to between 8 and 9 with 10% Na2CO3 (aqueous). The mixture was extracted twice with isopropyl acetate (600 mL). 2). The combined organic layers were then concentrated under vacuum at 40°C–50°C, and the crude product was purified by column chromatography. 46 g of the product as a grayish-white solid was obtained.

[0246] 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.37 – 7.23 (m, 8H), 5.98 (d, J = 7.8 Hz, 1H), 5.61 (t, J = 5.2 Hz, 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).

[0247] HRMS (High Resolution Mass Spectrometry) m / z (ESI) C 26 H 30 F3N4O2 + [M+H] + The calculated value is 487.2321.

[0248] Step 8

[0249] Compound 12 (25.3 g, 52.08 mmol, 1 eq.), 20% Pd(OH)₂ / C (50% wet, 7.3 g), and MeOH (860 mL) were charged into a reactor. The mixture was stirred at 25°C and 1 bar H₂ pressure for 17 h. After the reaction was complete, the mixture was filtered through an MCC pad. The filtrate was concentrated and then acetonitrile (approximately 150 g) was added in a temperature range of 40°C–50°C. The mixture was cooled to 10°C–20°C and then filtered. The wet filter 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°C–30°C. The wet filter cake was dried at 50°C to obtain 14.4 g of product.

[0250] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.12 (br s, 1H), 7.22 (s, 1H), 7.11 (s,1H), 7.06 (s, 1H), 5.95 (d, J = 7.9 Hz, 1H), 5.58 (br s, 1H), 4.42 (s, 2H), 4.35-4.18 (m, 1H), 2.84 (d, J = 10.4 Hz, 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).

[0251] HRMS (High Resolution Mass Spectrometry) m / z (ESI) C 19 H 24 F3N4O2 + [M+H] + The calculated value is 397.1160.

[0252] Crystallization form of Example 1: 1. Preparation of crystalline form: 1.1: Form H A Preparation: 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 below) was added to 1 mL acetonitrile / water (94.35 / 4.11, v / v, a w = 0.6), and then the suspension was stirred at RT. After 3 days, the suspension was filtered and the wet filter cake was air-dried for 4 h to provide (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol hydrate H A .

[0253] 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 IPA / water (80 / 20, w / w) at 70°C with a stirring rate of 250 rpm. The temperature was cooled to 45°C over 30 min, and then a small amount of H prepared in Example (A) was added. A (10 mg). After holding for 3 h, add 5 g of water dropwise over 20 min, then hold for 4 h. Cool the temperature to 0°C over 7 h, then filter the suspension, followed by washing the wet filter cake with IPA / water (70 / 30, w / w). Dry the wet filter cake under vacuum at 45°C for 4 h and under vacuum at 50°C for 3 h.

[0254] 1.2: Preparation of Form A: Example (A): Under nitrogen atmosphere, water (19.7 kg), intermediate 2 (1.25 kg, 4.87 mol, 1.0 equivalent), 2-methyltetrahydrofuran (21.4 kg), intermediate 4 (1.76 kg, 5.83 mol, 1.2 equivalent), NaOtBu (1.40 kg, 14.57 mol, 3 equivalent), and 1,1'-bis(di-isopropylphosphino)ferrocene palladium dichloride (0.175 kg, 0.29 mol, 0.06 equivalent) were charged into a reactor. The resulting solution was stirred at 70°C for 16 h, and the reaction mixture was then extracted twice with aqueous HCl. The resulting aqueous phases were combined and extracted with 2-methyltetrahydrofuran. The organic phase was collected and treated with N-acetylcysteine ​​and SiliaMetS® thiol (Si-THU) to remove Pd residues. The organic phase was then concentrated until dry (solvent removed) and crystallized with MeOH and water. The resulting wet product was recrystallized in EtOH and n-heptane. After drying, compound 7a was finally obtained as a grayish-white solid in a yield of 23% (402 g, 1.01 mol).

[0255] (400 MHz, DMSO- d 6 ): 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, 1.70(qd, 1H, CHCH2CH2),1.55 (qd, 1H, CH2CH2N), 1.46 (t, 1H, CH2CH2N).

[0256] 13 C NMR (100 MHz, DMSO- d 6 ): 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).

[0257] 19 F NMR (376 MHz, DMSO- d 6 ): δ: -61.4.

[0258] LCMS (m / z, ESI+) UPLC-MS (Method 2): Calculated value of C19H23F3N4O2: 396.18. Detected [M+H]+: 397.1818.

[0259] 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 ethanol and 0.8 g water at 70°C with a stirring rate of 250 rpm. The temperature was cooled to 40°C over 30 min, and then 80 mg of Mod A was added. After holding for 3 hours, 20 mL of n-heptane was added dropwise over 1 hour, and then stirring was continued at 40°C for 12 hours. The temperature was cooled to 30°C over 2 hours and then held for 4 hours. After that, the temperature was cooled to 20°C over 2 hours and then held for 4 hours. Finally, the temperature was cooled to 0°C over 7 hours, and the remaining wet filter cake was washed with n-heptane. After filtration and washing, the obtained wet filter cake was dried under vacuum at 40°C.

[0260] 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 the solution was then filtered through a 22 μm membrane. The solution / suspension was reheated to 70°C to obtain a clear solution, and then the temperature was cooled to 55°C over 2 h. After standing the solution for 2 h, the temperature was cooled to 5°C over 10 h and held overnight. The suspension was filtered and the wet filter cake was vacuum dried at 50°C for 2 h to provide (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol form B.

[0261] 1.4: Preparation of hippurate (1:1) in Example 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 hippuric acid were added to 30 mL of MEK and stirred continuously at approximately 250 rpm at 50°C. After 4 hours, the temperature was cooled to 25°C and maintained overnight over 2 hours. The suspension was filtered, and the wet filter cake was washed with MEK and then dried under vacuum at 50°C for 4 hours to provide (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol hippurate (1:1).

[0262] 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 obtain a suspension. The temperature was raised to 50°C and maintained for 4 h. After 4 h, the temperature was cooled to 25°C and maintained over the weekend. The suspension was filtered, and the wet filter cake was washed with MEK and then vacuum dried at 50°C for 4 h to provide (R)-2-(5-(hydroxymethyl)-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol hydrochloride (1:1).

[0263] 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 (12 mol / L) were added to 0.7 mL of MeOH at RT, yielding a clear solution. After adding 1.4 mL of MTBE, a small amount of the HCl salt prepared in Example (A) was added. After aging for 2 h, 1.4 mL of MTBE was added over 30 min, and the mixture was maintained for 4 h. The temperature was cooled to 5°C and maintained overnight. The suspension was filtered, and the wet filter cake was vacuum dried at 50°C for 2 h.

[0264] 2. Characterization of crystalline form: 2.1 Analytical Equipment

[0265] 2.1.1 X-ray powder diffraction method

[0266] X-ray powder diffraction (XRPD) patterns were obtained using a Bruker Advance D8 with reflection geometry. The powder was analyzed using a zero-background Si flat sample holder. The radiation was Cu Kα (λ = 1.5418 Å). The patterns were measured between 2° and 40°2θ. The error range for the 2θ angle is ±0.2°.

[0267] Sample quantity: 5-10 mg

[0268] Sample rack: Zero-background Si flat plate sample holder

[0269] XRPD parameters:

[0270] The most characteristic peaks in each form of XRPD spectrum are labeled A (strong), B (medium), C (medium), and D (medium).

[0271] 2.1.2 Differential Scanning Calorimetry (DSC) Method

[0272] The DSC traces were recorded on a TA Discovery DSC (TA Instruments, Inc., Tzero disk, 901683.901) with an aluminum disk; heating rate 10 K / min, temperature range: 0°C to 300°C.

[0273] 2.1.3 Thermogravimetric Analysis (TGA) Method

[0274] TGA traces were recorded on a TA Discovery TGA (TA Instruments) with an aluminum disk; heating rate 10 K / min, temperature range: room temperature to 300°C.

[0275] 2.2: Crystalline form H A The representation of: 2.2.1 Form H A XRPD data Form H A The XRPD data is given in Table 1 below.

[0276] Table 1

[0277] 2.2.2 Form H A Differential scanning calorimetry (DSC) data

[0278] Figure 2 The form H is shown A The DSC traces show that the initial melting temperature of the first endothermic peak is 109.1°C (first endothermic peak: 124.5°C), and the initial melting temperature of the second endothermic peak is 235.8°C (second endothermic peak: 236.9°C).

[0279] 2.2.3 Thermogravimetric analysis (TGA)

[0280] Figure 3 The form H is shown A TGA traces.

[0281] 2.3: Characterization of crystalline form A: 2.3.1 XRPD data of form A: The XRPD data for form A is given in Table 2 below.

[0282] Table 2

[0283] 2.3.2. Differential Scanning Calorimetry (DSC) Data of Form A

[0284] Figure 5The DSC trace for form A is shown. The onset melting temperature of the endothermic peak is 233.6°C (endothermic peak: 234.4°C).

[0285] 2.3.3 Thermogravimetric analysis (TGA)

[0286] Figure 6 The TGA trace of form A is shown.

[0287] 2.4: Characterization of crystalline form B: 2.4.1 XRPD data in form B: The XRPD data for form B is given in Table 3 below.

[0288] Table 3

[0289] 2.4.2. Differential Scanning Calorimetry (DSC) Data of Form B

[0290] Figure 8 The DSC trace for form B is shown. The onset melting temperature of the endothermic peak is 220.1°C (endothermic peak: 223.4°C).

[0291] 2.4.3 Thermogravimetric analysis (TGA) for Form B

[0292] Figure 9 The TGA trace of form B is shown.

[0293] 2.5: Characterization of Example 1, Hypopurate (1:1), Crystalline Form: 2.5.1 XRPD data for formal example 1, hippurate (1:1): XRPD data for formal example 1 hippurate (1:1) are given in Table 4 below.

[0294] Table 4

[0295] 2.5.2. Formal Example 1: Differential Scanning Calorimetry (DSC) Data for Hippurate (1:1)

[0296] Figure 11 The DSC trace of hippurate (1:1) from Example 1 is shown. The onset melting temperature of the endothermic peak is 215.9°C (endothermic peak: 217.1°C).

[0297] 2.5.3 Thermogravimetric analysis (TGA) of hippurate (1:1) in Example 1

[0298] Figure 12 The TGA trace of Form 1 hippurate (1:1) is shown.

[0299] 2.6: Characterization of Example 1 Crystalline Form Hydrochloride (1:1): 2.6.1 XRPD data for Form Example 1 hydrochloride (1:1): XRPD data for Form Example 1 hydrochloride (1:1) are given in Table 5 below.

[0300] Table 5

[0301] 2.6.2. Formal Example 1: Differential Scanning Calorimetry (DSC) Data for Hydrochloride (1:1)

[0302] Figure 14 The DSC traces of Example 1 hydrochloride (1:1) are shown. The onset melting temperature of the first endothermic peak is 68.3°C (endothermic peak: 91.7°C), and the onset melting temperature of the second endothermic peak is 243.0°C (endothermic peak: 246.8°C).

[0303] 2.6.3 Thermogravimetric analysis (TGA) of Example 1 hydrochloride (1:1)

[0304] Figure 15 The TGA trace of form instance 1 hydrochloride (1:1) is shown.

[0305] Reference Example 1: (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0306] This compound can be prepared as described in Example Ex 005 of WO 2020 / 234715.

[0307] Reference Example 2: (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0308] This compound can be prepared as described in Example Ex 064 of WO 2020 / 234715.

[0309] Reference Example 3: 3-Methyl-2-(4-(((R)-1-methylpiperidin-3-yl)amino)-5,7-dihydrofurano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0310] This compound can be prepared as described in Example 42 of WO 2022 / 135567.

[0311] Biological assays and data

[0312] The activity of the compounds according to the invention can be evaluated by the following in vitro methods. Compounds having formula (I) or pharmaceutically acceptable salts thereof exhibit valuable pharmacological properties, such as the ability to readily inhibit NLRP3 activity (e.g., as indicated in the tests provided in the following sections), and are therefore designated for therapies related to NLRP3 inflammasome activity.

[0313] IL-1β secretion assay: THP-1 mononuclear cells (ATCC: TIB-202) were maintained in RPMI medium (RPMI / Hepes + 10% fetal bovine serum + sodium pyruvate + 0.05 mM β-mercaptoethanol (1000x stock solution) + penicillin-streptomycin) according to the supplier's instructions. Cells were differentiated in batches for 3 h with 0.5 µM phorbol 12-myristate 13-acetate (PMA; Sigma-Aldrich # P8139), the medium was changed, and cells were seeded at 50,000 cells / well in 384-well flat-bottom cell culture plates (Greiner, #781986) and allowed to differentiate overnight. A 1:3.16 serial dilution of the compound in DMSO was added to the cells at a 1:100 ratio and incubated for 1 h. NLRP3 inflammasomes were activated by adding 15 µM (final concentration) of nigrain (Enzo Life Sciences, #BML-CA421-0005) and incubating for 3 h. 10 µL of supernatant was removed, and IL-1β levels were monitored using HTRF (homogeneous time-resolved fluorescence) assays (CisBio, #62IL1PEC) according to the manufacturer's instructions. Cell viability and pyroptosis were monitored by adding PrestoBlue cell viability reagent (Life Technologies, #A13261) directly to the cell culture plates.

[0314] TNF-α secretion assay : THP-1 mononuclear cells were maintained in RPMI medium as described above according to the supplier's instructions. Undifferentiated cells were seeded at 50,000 cells / well in 384-well flat-bottom cell culture plates (Glenore, #781986) and allowed to stand overnight. Experimental compounds were prepared and added as described above. TNF-α secretion was triggered by adding 1 µg / mL LPS (Sigma, #L4391) or 100 ng / mL Pam3CSK4 (Invivogen, #tlrl-pms) according to the experiment, and the 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.

[0315] Data Interpretation: The IC is calculated using the following formula by fitting a curve of inhibition percentage relative to inhibitor concentration via logistic regression. 50 value: y = A2 + (A1 – A2) / (1 + (x / IC 50 )^ p) Where y is the inhibition percentage at inhibitor concentration x, A1 is the minimum inhibition value (0%), and A2 is the maximum inhibition value (100%). The exponent p is the Hill coefficient. Curve fitting was performed using an internally developed software suite.

[0316] 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-κB-dependent initiation step and the addition of an NLRP3 activator. To ensure that the inhibitor does not interfere with the initiation step, Pam3CSK4-stimulated NF-κB-dependent TNF-α secretion was monitored as a reverse screening. The inhibitory effects (IC50) of the compounds of the present invention were measured for both assays. 50 The data are given in the table below. IL-1β secretion data were calculated as the arithmetic mean of at least three individual experiments, and TNF-α secretion data were consistent across at least two individual replicates.

[0317]

[0318] hERG channel testing using QPatch technology 4

[0319] CHO cells stably expressing the hERG channel (AVIVA Biosciences Corp., San Diego, California) were patched in single-well mode using a QPatch-HT automated patch-clamp instrument (Sophion Bioscience A / S, Barrerup, Denmark). Intracellular solutions consisted of 120 mM KCl, 5 mM CaCl2, 2 mM MgCl2, 10 mM ethylene glycol bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 10 mM 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), and 4 mM adenosine triphosphate dipotassium (ATP-K2), with the pH adjusted to 7.2 using KOH. Extracellular solutions consisted of 145 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 0.3% dimethyl sulfoxide (DMSO), with the pH adjusted to 7.4 using NaOH. All measurements were performed at room temperature with a 4 min pre-incubation of the blocking agents. The cell voltage was clamped at -90 mV, and the hERG current was activated by a voltage step to +20 mV for 4 s. The hERG tail current was then stepped down to -50 mV. Measurements were taken at mV for 4 s and then back to -90 mV. This protocol was repeated every 20 s. Peak hERG current was automatically corrected by subtracting leakage current, which was estimated by measuring the average current from the resting membrane potential to the short depolarization step to -50 mV at the start of the voltage protocol, just before the long depolarization step to +20 mV. The test sample was diluted with DMSO stock solution and extracellular solution. The final concentration of the mediator DMSO did not exceed 0.3%. The effect of the test sample on hERG tail current was evaluated, and each plate contained 1, 10, and 30 µM and a positive control (amitriptyline, 1 and 3 µM). If the inhibitory activity was >50% at the highest test concentration, the data points were fitted to the standard Hill equation, and the IC50 value was determined using a fixed 0% minimum current and 100% maximum current (residual current (%) = MaxI + ((MinI - MaxI) / (1 + ((Conc. / IC50))). 50 (^Hill))), where MaxI = 100, MinI = 0. If hERG activity is less than 50% at the highest test concentration, then hERG IC 50 The value is estimated to be greater than this (e.g., > 30 uM).

[0320] 4) Robert A Pearlstein, K Andrew MacCannell, Gül 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, José S. Duca Current Topics in Medicinal Chemistry [Topic](2016), 16:1792-1818.

[0321] hERG electrophysiological inhibition assays using Qube technology

[0322] A Chinese hamster ovary (CHO) cell line was created using the commercially available T-REx™ system (Invitrogen) to overexpress the α subunit of the hERG channel under the control of a tetracycline-regulated promoter. CHO (T-REx™) hERG cells were maintained in Ham's F-12 nutrient medium (Lifetechnologies) supplemented with 10% fetal bovine serum (HyClone), 1% penicillin-streptomycin, 10 μg / mL blastcin, and 50 μg / mL giomycin (all from Lifetechnologies and Thermo Fisher Scientific). For hERG expression induction, 1 μg / mL tetracycline (Sigma-Aldrich) was added to the growth medium 24 hours prior to current recording. To prepare the cell suspension for the Qube experiment, the cells were removed from the culture flask by incubating in Detachin (Genlantis) at 37°C for about 5 min and resuspended in CHO serum-free medium (CHO-SFM II, Life Sciences) at a density of 2-3 million cells / mL.

[0323] Patch-clamp experiments were performed at 35°C on a 384 x 10-well chip on the Qube APC (Automated Patch Clamp) platform (Sophion Biosciences, Barrerup, Denmark). Intracellular KF-Ringer's solution consisted of 120 mM KF, 20 mM KCl, 210 mM ethylene glycol-bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), and 10 mM (4-(2-hydroxyethyl)-1-piperazine ethanesulfonate (HEPES), with pH adjusted to 7.2 using KOH. Extracellular solution consisted of 145 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, and 0.3% dimethyl sulfoxide (DMSO), with pH adjusted to 7.4 using NaOH. hERG current was obtained by applying the following voltage scheme: cells were held at a resting membrane potential of -90 mV for 100 ms, then clamped at -50 mV for 100 ms for leakage estimation, depolarized to +20 mV for 4 seconds (peak current measurement), and finally repolarized to -50 mV. The data was recorded at a constant value of -90 mV for 4 seconds (tail current recording), then returned to a holding potential of -90 mV. Data were sampled at 10 kHz with a cutoff frequency of 2 kHz and filtered using a Bessel filter. The scheme was repeated every 15 s, 30 times before compound application and 30 times thereafter.

[0324] All compounds were prepared as 10 mM stock solutions in 100% DMSO and then serially diluted 1:3 in Labcyte 384-well Echo qualified LDV (low diamond volume) microplates. Qube assay plates were prepared by transferring 0.15–0.3 μL of compounds from the serial dilution plates to the 384-well Grana plates using a Labcyte Echo 650 liquid processor (Beckman). Prior to the experiment, the compounds in each well were further diluted in extracellular solution using a Biomek i7 liquid processor (Beckman) to produce final concentrations of 0.37, 1.1, 3.3, 10, 15, and 30 µM (1:333 dilution to maintain a final DMSO concentration ≤ 0.3% in all samples). Each plate contained amitriptyline hydrochloride (positive control) and DMSO (0.3%, mediator control).

[0325] The results were initially reviewed using the Qube-specific Sofin Analyzer software (Sofin Biosciences), and then analyzed using data analysis and visualization in the Discovery (DAVID) software package (Novartis AG). The effect of the compound on the inhibition of hERG current (normalized percentage of inhibition) was calculated as follows: %Inh = (I 化合物- I 媒介物 ) / I 媒介物 -100 ,in I 化合物 and I 媒介物 These are the average of the last three leakage-corrected hERG tail currents before and after compound application. For the compound concentration response, a custom four-parameter fit of the Hill equation was used to derive the IC50 value (with a fixed minimum current of 0% and a maximum current of 100%): I(C) = I b + ((I f - I b ) C n ) / IC 50 + C n Where C is the input concentration, I(C) It is the residual current after the test compound has suppressed it. I b It is the maximum current before the compound is applied. I f It is a fixed minimum current. All data and measurement-specific information are stored in the company's internal biochemical assay database (Pharon).

[0326]

[0327] Clinically, it is known that activity on hERG channels leads to QTc prolongation, which is undesirable. This QTc prolongation means that the myocardium requires a longer recovery time between heartbeats than normal, which may lead to adverse safety effects. Therefore, in vitro hERG assays are used to assess the interaction between drug molecules and channels and to help medicinal chemists identify candidate drugs that do not produce this serious toxicity in clinical settings. Higher hERG IC50 levels... 50 It is beneficial for evaluating the cardiac safety of the compound.

[0328] hERG QPatch ICs were found in reference examples 1 and 2. 50 The values ​​are 13.1 and 3.9 respectively, and hERG Qube IC 50 The values ​​were 4.71 and 5.62, respectively. Surprisingly, Instance 1 was found to have a significantly increased hERG QPatch IC. 50 and hERG QubeIC 50This provides compounds with improved drug safety characteristics. Therefore, R is introduced into compounds having formula (I) having the following general formula (I). 4 (It is –(CH2)) n -OH, where n is 1, 2, 3 or 4). (I) Compounds that unexpectedly lead to improved drug safety characteristics.

Claims

1. A compound, wherein the compound has the following structure: Or its pharmaceutically acceptable salt.

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

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