NLRP3 inflammasome inhibitors

Abstract

The present disclosure relates to novel 2,2-difluoro-benzo-dioxole derivatives of formula (I), wherein A1, A2, A3, A4, R1a, R1b, R2, R3a, R3b, R3c and R3d are defined herein, which inhibit NOD-like receptor protein 3 (NLRP3) inflammasome activity. The disclosure further relates to the processes for their preparation, pharmaceutical compositions and medicaments containing them, and their use in the treatment of diseases and disorders mediated by NLRP3.

Description

[0001] PAT059896-PCT-SEC01 -1-

[0002] NLRP3 inflammasome inhibitors

[0003] FIELD OF THE DISCLOSURE

[0004] The present disclosure relates to novel 2,2-difluoro-benzo-dioxole derivatives that are useful as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The present disclosure also relates to processes for the preparation of said compounds, pharmaceutical compositions comprising said compounds, methods of using said compounds in the treatment and diagnosis of various diseases and disorders mediated by NLRP3, and medicaments containing them.

[0005] BACKGROUND

[0006] The NOD-like receptor protein 3 (NLRP3) is a protein-coding gene: the protein belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as “pyrin domain-containing protein 3” (Inoue et al., Immunology, 2013, 139, 11-18). This gene encodes a protein containing a pyrin domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif. In response to sterile inflammatory danger signals, NLRP3 interacts with an adapter protein, apoptosis-associated speck-like protein (ASC) and procaspase- 1 to form the NLRP3 inflammasome. NLRP3 inflammasome activation then leads to the release of the inflammatory cytokines I L-1 p (interleukin-1 P) and IL-18 (interleukin-18), and when dysregulated, can drive pathology in a number of disease settings.

[0007] NLRP3 inflammasome activation normally requires two steps. The first step involves a priming signal in which pathogen activated molecular patterns (PAMPs) or danger-activated molecular patterns (DAMPs) are recognized by Toll-like receptors, leading to activation of nuclear factor kappa B (NF-KB)-mediated signaling, which in turn up-regulates transcription of inflammasome-related components, including inactive NLRP3 and prolL-1 (pro-interleukin- 1 ) (Bauernfeind et al J. Immunol. 2009, 183, 787 - 791 ; Franchi et al Nat. Immunol. 2012, 13, 325 - 332, Franchi et al J. Immunol. 2014, 193, 4214 - 4222). The second step is the oligomerization of NLRP3 and subsequent assembly of NLRP3, ASC, and procaspase-1 into an inflammasome complex. This triggers the transformation of procaspase-1 to caspase-1 , and the production and secretion of mature IL-1 p and IL-18 (Kim et al J. Inflamm. 2015, 12, 41 ; Ozaki et al J. Inflamm. Res. 2015, 8, 15 - 27; Rabeony et al. Eur. J. Immunol. 2015, 45, 2847 - 2857).

[0008] NLRP3 inflammasome activation has been linked to various inflammasome-related diseases I disorders, immune diseases, inflammatory diseases, auto-immune diseases and auto- inflammatory diseases, for example, autoinflam matory fever syndrome such as cryopyrin- PAT059896-PCT-SEC01 -2- associated periodic syndrome (CAPS) (Mortimer et al Nature Immunol. 2016, 17(10), 1176- 1188); sickle cell disease; systemic lupus erythematosus (SLE); liver related diseases I disorders such as chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease (Petrasek et al J. Clin. Invest. 2012, 122, 3476-89; Petrasek et al. Nat. Rev. Gastroenterol. Hepatol. 2015, 12, 387-400; Mridha et al J. Hepatol. 2017, 66, 1037-46); inflammatory arthritis related disorders, such as gout, pseudogout (chondrocalcinosis), osteoarthritis (Ridker et al N. Engl. J. Med. 2017, 377, 1119- 31), and rheumatoid arthritis (Mathews et al Ann. Rheum. Dis. 2014, 73, 1202-10), acute or chronic arthropathy; kidney related diseases such as hyperoxaluria (Knauf et al. Kidney Int. 2013, 84, 895-901), lupus nephritis, hypertensive nephropathy (Krishnan et al Br. J. Pharmacol. 2016, 173, 752-65), hemodialysis related inflammation and diabetic nephropathy which is a kidney-related complication of diabetes (Type 1 , Type 2 and mellitus diabetes), also called diabetic kidney disease (Shahzad et al Kidney Int. 2015, 87, 74-84). Emerging studies have revealed the involvement of the increased production of I L-1 and IL-18 by the NLRP3 inflammasome can contribute to the onset and progression of various diseases such as neuroinflammation-related disorders, e.g. brain infection, acute injury, multiple sclerosis, Alzheimer’s disease, and neurodegenerative diseases (Shao et al. Front. Pharmacol. 2015, 6, 262); cardiovascular / metabolic disorders I diseases, e.g. cardiovascular risk reduction (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. 2017, 377, 1119-31 ; Vandanmasgar et al Nat. Med. 2011 , 17, 179-88; Hu et al Proc. Natl. Acad. Sci. 2015, 112, 11318-23; Antonopoulos et al Curr. Opin. Pharmacol. 2017, 39, 1-8; Toldo S et al Nat. Rev. Cardiol. 2018, 15, 203-214); wound healing and scar formation; inflammatory skin diseases, e.g. acne, hidradenitis suppurativa (Sweeney et al Br. J. Dermatol. 2015, 173, 1361), asthma, sarcoidosis, age- related macular degeneration; cancer related diseases I disorders, e.g. myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer, colon cancer (Ridker et al Lancet 2017, 390, 1833-42; Derangere et al Cell. Death Differ. 2014, 21 , 1914-24, Gelfo et al Oncotarget 201Q, 7, 72167-83, Baiorka et al Blood 2016, 128, 2960-75; Carey et al Cell. Rep. 2017, 18, 3204-18). Those diseases I disorders that are immune or inflammatory in nature usually are difficult to diagnose or treat efficiently. Most treatments include treating of the symptoms, slowing down the progression of the disease I disorder, change in lifestyle and surgery as a last resort (e.g., open heart surgery for advance forms of atherosclerosis). Recent studies have linked mitochondrial dysfunction and NLRP3 activation in neuroinflammation related diseases such as Parkinson’s (Sarkar et al npj Parkinson’s disease 2017, 3:30; Zhou et al Nature, 2011 , 469, 221). One of the major problems associated with the mitochondrial modulators is their poor metabolic stability; thus there is a PAT059896-PCT-SEC01 -3- need for selective and stable inhibitors in neuroinflammation of this nature (Lee et al EurJ.

[0009] Org. Chem. 2017, 141 , 240).

[0010] Therefore, there is a need for inhibitors of the NLRP3 inflammasome pathway to provide new and / or alternative treatments for these inflammasome-related diseases I disorders and others such as autoinflammatory fever syndrome cryopyrin-associated periodic syndrome {e.g. CAPS), sickle cell disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, hyperoxaluria, secondary hyperoxaluria, pseudogout (chondrocalcinosis), Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).

[0011] WO2020 / 234715 describes pyridazin-3-yl phenol compounds as NLRP3 inflammasome inhibitors. WO2021 / 193897 describes substituted pyridazine compounds as NLRP3 inflammasome inhibitors. WO2022 / 135567 describes pyridazine containing compounds as NLRP3 inflammasome inhibitors. WO2024 / 145623 describes heterocyclic and heteroaryl compounds as inhibitors of NLRP3.

[0012] SUMMARY

[0013] The disclosure provides compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combination thereof, which compounds inhibit the NLRP3 inflammasome pathway. The disclosure further provides methods of treating, diagnosis, or preventing, disease and I or disorders related to NLRP3, comprising administering to a subject in need thereof an effective amount of the compounds of the disclosure, or a pharmaceutically acceptable salt thereof.

[0014] Various embodiments of the disclosure are described herein.

[0015] As a first aspect, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof: PAT059896-PCT-SEC01 -4- wherein

[0016] R1aand R1 bare selected from H, F, Ci-C4alkyl and haloCi-C4alkyl;

[0017] A1is N or CRA1;

[0018] A2is N or CRA2;

[0019] A3is N or CRA3;

[0020] A4is N or CRA4; wherein no more than one of A1, A2, A3and A4are N;

[0021] RA1, RA2, RA3and RA4are independently selected from H, Ci-C4alkyl, Ci-C4alkoxy and haloCi- C4alkyl;

[0022] R2is selected from Ci-C4alkyl and Ci-C4-alkoxy-C2-C4alkyl;

[0023] R3a, R3b, R3cand R3dare independently selected from H, F and Ci-C4alkyl.

[0024] In another aspect, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I), or subformulae or species thereof as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is useful in the treatment of diseases and I or disorders related to the NLRP3 activity.

[0025] In another aspect, the disclosure provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound according to the definition of compound of formula (I), or subformulae or species thereof as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more therapeutic agents.

[0026] In another aspect, the disclosure provides a compound of formula (I), a pharmaceutical composition or a combination, in particular a pharmaceutical combination, as disclosed herein, for use as a medicament. PAT059896-PCT-SEC01 -5-

[0027] In another aspect, the disclosure provides a compound of formula (I), or subformulae or species thereof as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of a disease or disorder in which the NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression, of said disease or disorder.

[0028] In another aspect, the disclosure provides a method of treating a disease or disorder in which the NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression, of said disease or disorder, comprising administering a therapeutically effective amount of a compound of formula (I), subformulae or species thereof as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0029] In another aspect, the disclosure provides a method of inhibiting the NLRP3 inflammasome activity in a subject in need thereof, the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), subformulae or species thereof as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0030] In another aspect, the disclosure provides a compound of formula (I), or subformulae thereof, as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of a disease or disorder selected from inflammasome-related disease I disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto- inflammatory diseases.

[0031] In another aspect, the disclosure provides a compound of formula (I), or subformulae thereof, as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder selected from inflammasome-related disease I disorders, immune diseases, inflammatory diseases, autoimmune diseases, or auto-inflammatory diseases.

[0032] DETAILED DESCRIPTION

[0033] The disclosure therefore provides a compound of formula (I), or a pharmaceutically acceptable salt of stereoisomer thereof, PAT059896-PCT-SEC01 -6- wherein

[0034] R1aand R1 bare selected from H, F, Ci-C4alkyl and haloCi-C4alkyl;

[0035] A1is N or CRA1;

[0036] A2is N or CRA2;

[0037] A3is N or CRA3;

[0038] A4is N or CRA4; wherein no more than one of A1, A2, A3and A4are N;

[0039] RA1, RA2, RA3and RA4are independently selected from H, Ci-C4alkyl, Ci-C4alkoxy and haloCi- C4alkyl;

[0040] R2is selected from Ci-C4alkyl and Ci-C4-alkoxy-C2-C4alkyl;

[0041] R3a, R3b, R3cand R3dare independently selected from H, F and Ci-C4alkyl.

[0042] Definitions

[0043] For purpose of interpreting this specification, the following definitions will apply unless specified otherwise and when appropriate, terms used in the singular will also include the plural and vice versa.

[0044] It must be noted that as used herein and in the appended claims, the singular forms "a", "an" and “the”, and similar terms, used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural referents unless the context clearly dictates otherwise, or clearly contradicted by the context. Thus, for example, reference to "the compound" includes reference to one or more compounds; and so forth.

[0045] As used herein, the term “Ci-C4alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to four carbon atoms, and which is attached to the rest of the molecule by a single bond. Examples of Ci-C4alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1- methylethyl ( / so-propyl), n-butyl. PAT059896-PCT-SEC01 -7-

[0046] As used herein, the term "halogen" or "halo" refers to bromo, chloro, fluoro, or iodo.

[0047] As used herein, the term "haloCi-C4alkyl" or “halogenCi-C4alkyl” refers to a Ci-C4alkyl radical, as defined above, substituted by one or more halo radicals, as defined above. Examples of haloCi-C4alkyl or halogenCi-C4alkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 ,3-dibromopropan-2-yl, 3- bromo-2-fluoropropyl and 1 ,4,4-trifluorobutan-2-yl.

[0048] As used herein, the term "Ci-C4alkoxy" refers to a radical of the formula -ORawhere Rais a Ci-C4alkyl radical as generally defined above. Examples of "Ci-C4alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy.

[0049] As used herein, the term "Ci-C4alkoxy-C2-C4alkyl " refers to a radical of the formula -C2- C4alkyl-O-Rawhere Rais a Ci-C4alkyl radical as generally defined above. Examples of " C1- C4alkoxy-C2-C4alkyl " include, but are not limited to, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxypropyl, butoxypropyl, and isobutoxypropyl.

[0050] Unless specified otherwise, the term “compounds of the (present) disclosure” refers to compounds of formula (I), and subformulae thereof, and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions). The term "compounds of the (present) disclosure" or "a compound of the (present) disclosure" refers to a compound as defined in any one of embodiments mentioned below.

[0051] Various enumerated embodiments of the disclosure are described herein, it will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure.

[0052] As an embodiment 1.0, the disclosure therefore provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, PAT059896-PCT-SEC01 -8- wherein

[0053] R1aand R1 bare selected from H, F, Ci-C4alkyl and haloCi-C4alkyl;

[0054] A1is N or CRA1;

[0055] A2is N or CRA2;

[0056] A3is N or CRA3;

[0057] A4is N or CRA4; wherein no more than one of A1, A2, A3and A4are N;

[0058] RA1, RA2, RA3and RA4are independently selected from H, Ci-C4alkyl, Ci-C4alkoxy and haloCi- C4alkyl;

[0059] R2is selected from Ci-C4alkyl and Ci-C4-alkoxy-C2-C4alkyl;

[0060] R3a, R3b, R3cand R3dare independently selected from H, F and Ci-C4alkyl.

[0061] As an embodiment 2.0, there is provided a compound according to embodiment 1.0, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0062] R1aand R1 bare selected from H, F, CH3 and CF3;

[0063] RA1, RA2, RA3and RA4are independently selected from H, Ci-C4alkyl, Ci-C4alkoxy and haloCi- C4alkyl;

[0064] R2is selected from -CH3, -CH2CH3, -CH(CH3)2and -CH2CH2OCH3;

[0065] R3a, R3b, R3cand R3dare independently selected from H, F and Ci-C4alkyl.

[0066] As an embodiment 3.0, there is provided a compound according to embodiment 1.0 or 2.0, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0067] R1ais H and R1bis H or CH3 or CF3; or

[0068] R1ais F and R1bis H; or

[0069] R1ais CH3and R1 bis H;

[0070] RA1, RA2, RA3and RA4are independently selected from H and Ci-C4alkoxy;

[0071] R2is selected from -CH3, -CH2CH3 and -CH(CHs)2;

[0072] R3a, R3b, R3cand R3dare independently selected from H, F and CH3. PAT059896-PCT-SEC01 -9-

[0073] As an embodiment 4.0, there is provided a compound according to any one of embodiments 1.0-3.0, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1ais H;

[0074] R1bis H or CH3;

[0075] RA1, RA2, RA3and RA4are independently selected from H and Ci-C4alkoxy;

[0076] R2is selected from CH3, -CH2CH3and -CH(CH3)2;

[0077] R3a, R3b, R3cand R3dare independently selected from H, F and CH3.

[0078] As an embodiment 5.0, there is provided a compound according to any one of embodiments 1.0-4.0, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is CH3, R3a, R3b, R3cand R3dare H; or

[0079] R2is CH3, R3bis F, R3a, R3cand R3dare H; or

[0080] R2is CH3, R3dis CH3, R3a, R3band R3care H; or

[0081] R2is CH3, R3Cis CH3, R3a, R3band R3dare H.

[0082] As an embodiment 6.0, there is provided a compound according to any one of embodiments 1.0-5.0, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula wherein * indicates a stereocenter with ( / ^-configuration.

[0083] As an embodiment 7.0, there is provided a compound according to any one of embodiments 1.0-5.0, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IB) PAT059896-PCT-SEC01 -10- wherein RA1is H or -OCH3, and

[0084] RA3is H or -OCH3, and * indicates a stereocenter with ( / ^-configuration.

[0085] As an embodiment 8.0, there is provided a compound according to any one of embodiments 1.0-5.0, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IC) and * indicates a stereocenter with ( / ^-configuration.

[0086] As an embodiment 9.0, there is provided a compound according to any one of embodiments 1.0-5.0, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (ID) wherein * indicates a stereocenter with ( / ^-configuration. PAT059896-PCT-SEC01 -11-

[0087] As an embodiment 10.0, there is provided a compound according to any one of embodiments 1.0-5.0, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula wherein * indicates a stereocenter with (Reconfiguration.

[0088] As an embodiment 11.0, there is provided a compound according to any one of embodiments 1.0-5.0, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula wherein * indicates a stereocenter with ( / ^-configuration.

[0089] As an embodiment 12.0, there is provided a compound according to embodiment 1.0, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from (R)-2,2-difluoro-5-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1- yl)benzo[d][1 ,3]dioxol-4-ol;

[0090] (R)-2,2-difluoro-5-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)benzo[d][1 ,3]dioxol-4-ol;

[0091] (R)-5-(4-((1-ethylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2,2- difluorobenzo[d][1,3]dioxol-4-ol;

[0092] (R)-5-(1-((1-ethylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-4-yl)-2,2- difluorobenzo[d][1,3]dioxol-4-ol;

[0093] (R)-2,2-difluoro-5-(4-((1-isopropylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1- yl)benzo[d][1 ,3]dioxol-4-ol;

[0094] (R)-2,2-difluoro-5-(1-((1-isopropylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-4- yl)benzo[d][1 ,3]dioxol-4-ol; PAT059896-PCT-SEC01 -12-

[0095] (R)-2,2-difluoro-5-(5-((1-methylpiperidin-3-yl)amino)pyrido[2,3-d]pyridazin-8- yl)benzo[d][1 ,3]dioxol-4-ol;

[0096] (R)-2,2-difluoro-5-(5-methoxy-4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1- yl)benzo[d][1 ,3]dioxol-4-ol;

[0097] (R)-2,2-difluoro-5-(8-((1-methylpiperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5- yl)benzo[d][1,3]dioxol-4-ol; and

[0098] (R)-2,2-difluoro-5-(7-methoxy-4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1- yl)benzo[d][1 ,3]dioxol-4-ol.

[0099] As an embodiment 13.0, there is provided a compound according to embodiment 1.0, wherein the compound is of formula or a pharmaceutically acceptable salt thereof.

[0100] As an embodiment 14.0, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1.0- 13.0, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

[0101] As an embodiment 15.0, there is provided a combination comprising a therapeutically effective amount of a compound according to any one of embodiments 1.0-13.0, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more therapeutic agents.

[0102] As an embodiment 16.0, there is provided a compound according to any one of embodiments 1.0-13.0, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of embodiment 15.0, or the combination according to embodiment 11.0, for use as a medicament.

[0103] As an embodiment 17.0, there is provided a compound according to any one of embodiments 1.0-13.0, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of a disease or disorder in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression, of said disease or disorder. PAT059896-PCT-SEC01 -13-

[0104] As an embodiment 18.0, there is provided a method of treating a disease or disorder in which the NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression, of said disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1.0-13.0, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0105] As an embodiment 19.0, there is provided a compound for use according to embodiment 16.0 or 17.0, or the method of treating according to embodiment 18.0, wherein the disease or disorder is selected from inflammasome-related diseases I disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g cryopyrin-associated periodic syndrome), liver related diseases I 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 e.g acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, aseptic meningoencephalitis of autoimmune origin, migraine, brain infection, acute injury, traumatic brain disorders such as stroke and traumatic brain injury, neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, motor neuron disease, Huntington’s disease, multiple system atrophy, progressive supranuclear palsy, frontotemporal dementia, ataxia and neurodegenerative prion disease, psychiatric brain disorders such as depression, anxiety, autism, bipolar disorder and schizophrenia), cardiovascular / metabolic diseases I disorders (e.g. cardiovascular risk reduction (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 I disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis, chronic myelomonocytic leukemia (CM ML)).

[0106] As an embodiment 20.0, there is provided a method of inhibiting the NLRP3 inflammasome activity in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1.0-13.0, or a pharmaceutically acceptable salt or stereoisomer thereof. PAT059896-PCT-SEC01 -14-

[0107] Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, for example as pure optical isomers, or as stereoisomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. The present disclosure is meant to include all such possible stereoisomers, including racemic mixtures, diastereoisomeric mixtures, and optically pure forms. Optically active (R)- and (S)- stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included. The disclosure is also meant to include any pseudo-asymmetric carbon atom, represented herein as (R)- and (S)-, and which are invariant on reflection in a mirror but are reversed by exchange of any two entities, (PAC 1996, 68, 2193, Basic terminology of stereochemistry IUPAC recommandations 1996).

[0108] As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the disclosure. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this disclosure and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and I or base salts by virtue of the presence of amino and I or carboxyl groups, or groups similar thereto.

[0109] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

[0110] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0111] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0112] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. PAT059896-PCT-SEC01 -15-

[0113] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

[0114] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0115] In another aspect, the present disclosure provides compounds of any general formula (e.g. compound of formula (I) and compound of any one of embodiments 1.0-x.0.) or example defined herein in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide I hydrobromide, bicarbonate I carbonate, bisulfate I sulfate, camphorsulfonate, caprate, chloride I hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide I iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate I hydrogen phosphate I dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate, or xinafoate salt form.

[0116] In another aspect, the present disclosure provides compounds of any general formula (e.g. compound of formula (I) and compound of any one of embodiments 1.0-x.0) or example defined herein in sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine or tromethamine salt form.

[0117] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into compounds of the disclosure include, for example, isotopes of hydrogen. PAT059896-PCT-SEC01 -16-

[0118] Further, incorporation of certain isotopes, particularly deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index or tolerability. It is understood that deuterium in this context is regarded as a substituent of a compound of formula (I). The concentration of deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this disclosure is denoted as being deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term “isotopic enrichment factor” can be applied to any isotope in the same manner as described for deuterium.

[0119] Further examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as2H,3H,11C,13C,14C,15N,18F,31P,32P,35S,36CI,125l respectively. The disclosure includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as3H and14C, or those into which non-radioactive isotopes, such as2H and13C are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F or125l labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

[0120] PHARMACEUTICAL COMPOSITION

[0121] As used herein, the term “pharmaceutical composition” refers to a compound of the disclosure, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration. PAT059896-PCT-SEC01 -17-

[0122] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22ndEd. Pharmaceutical Press, 2013, pp. 1049-1070).

[0123] The term "a therapeutically effective amount" of a compound of the present disclosure refers to an amount of the compound of the present disclosure that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and I or ameliorate a condition, or a disorder or a disease (i) mediated by NLRP3, or (ii) associated with NLRP3 activity, or (iii) characterized by activity (normal or abnormal) of NLRP3; or (2) reduce or inhibit the activity of NLRP3; or (3) reduce or inhibit the expression of NLRP3. In another non-limiting embodiment, the term “a therapeutically effective amount” of a compound of the present disclosure refers to the amount that when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit the activity of NLRP3; or at least partially reduce or inhibit the expression of NLRP3.

[0124] As used herein, the term “subject” refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats and mice. In certain embodiments, the subject is a primate. In yet another embodiment, the subject is a human.

[0125] As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. Specifically, inhibiting NLRP3 or inhibiting NLRP3 inflammasome pathway comprises reducing the ability of NLRP3 or NLRP3 inflammasome pathway to induce the production of IL-1 beta and / or IL-18. This can be achieved by mechanisms, including, but not limited to, inactivating, destabilizing, and / or altering distribution of NLRP3. PAT059896-PCT-SEC01 -18-

[0126] As used herein, the term "NLRP3" is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and anti-sense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0127] As used herein, the term “treat”, “treating” or "treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e. , slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.

[0128] As used herein, the term “prevent”, “preventing” or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0129] As used herein, a subject is “in need of” or “in need thereof” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

[0130] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed.

[0131] Any asymmetric atom {e.g., carbon or the like) of the compound(s) of the present disclosure can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (Reconfiguration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)-configuration.

[0132] Accordingly, as used herein a compound of the present disclosure can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates, or mixtures thereof. PAT059896-PCT-SEC01 -19-

[0133] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and I or fractional crystallization.

[0134] Any resulting racemates of compounds of the present disclosure or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present disclosure into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.

[0135] METHOD OF SYNTHESIZING THE COMPOUNDS

[0136] The compounds of the present disclosure may be prepared in accordance with the routes described in the following Schemes and / or the Examples. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed. In the following general methods, A1, A2, A3, A4, R1a, R1b, R2, R3a, R3b, R3c, R3dand halo are as previously defined in the above embodiments, or limited to designations in the Scheme. Unless otherwise stated, starting materials are either commercially available or are prepared by known methods.

[0137] Reaction Scheme 1 :

[0138] PAT059896-PCT-SEC01 -20- wherein A1, A2, A3, A4, R1a, R1b, R2, R3a. R3b, R3c, R3dare as defined in embodiment 1.0, halo is as defined previously and PG is a suitable protection group such as benzyl. Compounds of formula (I), as described herein, may be prepared by a reaction sequence shown in Reaction Scheme 1 , whereby an appropriately substituted 1 ,4- dichloropyridopyridazine, 5,8-dichloropyridopyridazine or 1 ,4-dichlorophthalazine (M1) is reacted with an appropriate amine (M2) in the presence of a base, e.g. DI PEA, at elevated temperatures, typically between 85 and 100 °C (optionally under microwave irradiation), to give 1-chloropyridopyridazin-4-amine, 4-chloropyridopyridazin-1-amine, 5-chloro- pyridopyridazin-8-amine, 8-chloro-pyridopyridazin-5-amine or 4-chlorophthalazin-1 -amine (M3). The intermediate (M3) is then subjected to a Suzuki-type cross coupling reaction with the appropriate boronate (M4) in the form of a boronic acid or boronic ester, e.g. 4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan, using a suitable palladium catalyst, e.g. XPhos Pd G4 or PdCl2(dppf).CH2Cl2, and an aqueous base, typically K3PO4 or K2CO3, in a miscible solvent such as THF or dioxane to provide directly or after a deprotection step a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0139] Reaction Scheme 2 PAT059896-PCT-SEC01 -21- wherein A1, A2, A3, A4, R1a, R1b, R2, R3a. R3b, R3c, R3dare as defined in embodiment 1.0, halo is as defined previously and PG is a suitable protection group such as benzyl. Alternatively, compounds of formula (I) may be prepared by a reaction sequence shown in Reaction Scheme 2, whereby an appropriately substituted 1 ,4-dichloropyridopyridazine, 5,8- dichloropyridopyridazine or 1 ,4-dichlorophthalazine (M1) is reacted with an appropriate Boc- protected amine (M5) in the presence of a base, e.g. DI PEA, at elevated temperatures, typically between 85 and 100 °C (optionally under microwave irradiation), to give Boc- protected 1-chloropyridopyridazin-4-amine, 4-chloropyridopyridazin-1 -amine, 5-chloro- pyridopyridazin-8-amine, 8-chloro-pyridopyridazin-5-amine or 4-chlorophthalazin-1 -amine (M6). The intermediate (M6) is then deprotected to afford intermediate (M7). Intermediate (M7) could undergo N-alkylated with different alkyl halides (R2-halo) or reductive amination to give 1-chloropyridopyridazin-4-amine, 4-chloropyridopyridazin-1-amine, 5-chloro- pyridopyridazin-8-amine, 8-chloro-pyridopyridazin-5-amine or 4-chlorophthalazin-1-amine (M3). The intermediate, (M3) is then subjected to a Suzuki-type cross coupling reaction with the appropriate boronate (M4) in the form of a boronic acid or boronic ester, e.g. 4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan, using a suitable palladium catalyst, e.g. XPhos Pd G4 or PAT059896-PCT-SEC01 -22-

[0140] PdCl2(dppf).CH2Cl2, and an aqueous base, typically K3PO4 or K2CO3, in a miscible solvent such as THF or dioxane to provide directly or after a deprotection step a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0141] The disclosure further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure material. Compounds of the disclosure and intermediates can also be converted into each other according to methods generally known to those skilled in the art.

[0142] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for particular 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 pertain to inhalation or intranasal application. The pharmaceutical compositions of the present disclosure can be made up in a solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including, without limitation, solutions, suspensions or emulsions). Tablets may be either film coated or enteric coated according to methods known in the art. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) Diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and I or glycine; b) Lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and I or polyethyleneglycol; for tablets also c) Binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and I or polyvinylpyrrolidone; if desired d) Disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavours and sweeteners.

[0143] METHOD OF USE

[0144] There is evidence for a role of NLRP3-induced IL-1 and IL-18 in the inflammatory responses occurring in connection with, or as a result of, a multitude of different disorders (Menu et al, Clinical and Experimental Immunology, 2011 , 166, 1-15; Strowig et al, Nature, 2012, 481 , PAT059896-PCT-SEC01 -23-

[0145] 278-286). NLRP3 mutations have been found to be responsible for a set of rare autoinflammatory diseases known as CAPS (Ozaki et al, J. Inflammation Research, 2015, 8,15-27; Schroder et al, Cell, 2010, 140: 821-832; Menu et al, Clinical and Experimental Immunology, 2011 , 166, 1-15). CAPS are heritable diseases characterized by recurrent fever and inflammation and are comprised of three autoinflammatory disorders that form a clinical continuum. These diseases, in order of increasing severity, are familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile cutaneous neurological articular syndrome (CINCA; also called neonatal-onset multisystem inflammatory disease, NOMID), and all have been shown to result from gain-of-function mutations in the NLRP3 gene, which leads to increased secretion of I L-1 p. NLRP3 has also been implicated in a number of autoinflammatory diseases, including pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook et al, Eur. J. Immunol., 2010, 40, 595-653).

[0146] A number of autoimmune diseases have been shown to involve NLRP3 including, in particular, multiple sclerosis, type-1 diabetes (T1 D), psoriasis, rheumatoid arthritis (RA), Behcet's disease, Schnitzler syndrome, macrophage activation syndrome (Braddock et al. Nat. Rev. Drug Disc. 2004, 3, 1-10; Inoue et al., Immunology, 2013, 139, 11-18, Coll et al, Nat. Med. 2015, 21 (3), 248-55; Scott et al, Clin. Exp. Rheumatol. 2016, 34(1), 88-93), systemic lupus erythematosus and its complications such as lupus nephritis (Lu et al, J. Immunol., 2017, 198(3), 1119-29), and systemic sclerosis (Artlett et al, Arthritis Rheum. 2011 , 63(11), 3563-74). NLRP3 has also been shown to play a role in a number of lung diseases including chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al, Am. J. Pathol., 2014, 184: 42-54; Kim et al. Am. J. Respir. Crit. Care Med, 2017, 196(3), 283-97). NLRP3 has also been suggested to have a role in a number of central nervous system conditions, including Multiple Sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis (Walsh et al, Nature Reviews, 2014, 15, 84-97; and Dempsey et al. Brain. Behav. Immun. 2017, 61 , 306-16), intracranial aneurysms (Zhang et al. J. Stroke and Cerebrovascular Dis., 2015, 24, 5, 972-9), and traumatic brain injury (Ismael et al. J. Neurotrauma., 2018, 35(11), 1294-1303). NRLP3 activity has also been shown to be involved in various metabolic diseases including type 2 diabetes (T2D) and its organ-specific complications, atherosclerosis, obesity, gout, pseudogout, metabolic syndrome (Wen et al, Nature Immunology, 2012, 13, 352-357; Duewell et al, Nature, 2010, 464, 1357-1361 ; Strowig et al, Nature, 2014, 481 , 278- 286), and non-alcoholic steatohepatitis (Mridha et al. J. Hepatol. 2017, 66(5), 1037-46). A role for NLRP3 via IL-1 beta has also been suggested in atherosclerosis, myocardial infarction (van Hout et al. Eur. Heart PAT059896-PCT-SEC01 -24-

[0147] J. 2017, 38(11), 828-36), heart failure (Sano et al. J. Am. Coll. Cardiol. 2018, 71(8), 875-66), aortic aneurysm and dissection (Wu et al. Arterioscler. Thromb. Vase. Biol., 2017,37(4), 694- 706), and other cardiovascular events (Ridker et al., N. Engl. J. Med., 2017, 377(12), 1119- 31).

[0148] Other diseases in which NLRP3 has been shown to be involved include: ocular diseases such as both wet and dry age-related macular degeneration (Doyle et al. Nature Medicine, 2012, 18, 791-798; Tarallo et al. Ce / / 2012, 149(4), 847-59), diabetic retinopathy (Loukovaara et al. Acta Ophthalmol., 2017, 95(8), 803-8), non-infectious uveitis and optic nerve damage (Puyang et al. Sci. Rep. 2016, 6, 20998); liver diseases including non-alcoholic steatohepatitis (NASH) and acute alcoholic hepatitis (Henao-Meija et al, Nature, 2012, 482, 179-185); inflammatory reactions in the lung and skin (Primiano et al. J. Immunol. 2016, 197(6), 2421- 33) including contact hypersensitivity (such as bullous pemphigoid (Fang et al. J Dermatol Sci. 2016, 83(2), 116-23)), atopic dermatitis (Niebuhr et al. Allergy, 2014, 69(8), 1058-67), Hidradenitis suppurativa (Alikhan et al. J. Am. Acad. Dermatol., 2009 ,60(4), 539-61), and sarcoidosis (Jager et al. Am. J. Respir. Crit. Care Med., 2015, 191, A5816); inflammatory reactions in the joints (Braddock et al, Nat. Rev. Drug Disc, 2004, 3, 1-10); amyotrophic lateral sclerosis (Gugliandolo et al. Int. J. Mol. Sci., 2018, 19(7), E1992); cystic fibrosis (lannitti et al. Nat. Commun., 2016, 7, 10791); stroke (Walsh et al, Nature Reviews, 2014, 15, 84-97); chronic kidney disease (Granata et al. PLoS One 2015, 10(3), eoi22272); and inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Braddock et al., Nat. Rev. Drug Disc, 2004, 3, 1-10; Neudecker et al. J. Exp. Med. 2017, 214(6), 1737-52; Lazaridis et al. Dig. Dis. Sci. 2017, 62(9), 2348-56). The NLRP3 inflammasome 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, 2017, 40, 366-86).

[0149] Activation of the NLRP3 inflammasome has been shown to potentiate some pathogenic infections such as influenza and Leishmaniasis (Tate et al., Sci Rep., 2016, 10(6), 27912-20; Novias et al., PLOS Pathogens 2017, 13(2), e1006196).

[0150] NLRP3 has also been implicated in the pathogenesis of many cancers (Menu et al, Clinical and Experimental Immunology, 2011, 166, 1-15). For example, several previous studies have suggested a role for IL-1 beta in cancer invasiveness, growth and metastasis, and inhibition of IL-1 beta with canakinumab has been shown to reduce the incidence of lung cancer and total cancer mortality in a randomised, double-blind, placebo-controlled trial (Ridker et al. Lancet., 2017, 390(10105), 1833-42). Inhibition of the NLRP3 inflammasome or IL-1 beta has also been shown to inhibit the proliferation and migration of lung cancer cells in vitro (Wang et al. PAT059896-PCT-SEC01 -25-

[0151] Oncol Rep., 2016, 35(4), 2053-64). A role for the NLRP3 inflammasome has been suggested in myelodysplastic syndromes, myelofibrosis and other myeloproliferative neoplasms, and acute myeloid leukemia (AML) (Basiorka et al. Blood, 2016, 128(25), 2960-75.) and also in the carcinogenesis of various other cancers including glioma (Li et al. Am. J. Cancer Res.

[0152] 2015, 5(1), 442-9), inflammation- induced tumors (Allen et al. J. Exp. Med. 2010, 207(5), 1045-56; Hu et al. PNAS., 2010, 107(50), 21635-40), multiple myeloma (Li et al. Hematology, 2016 21(3), 144-51), and squamous cell carcinoma of the head and neck (Huang et al. J. Exp. Clin. Cancer Res., 2017, 36(1), 116). Activation of the NLRP3 inflammasome has also been shown to mediate chemoresistance of tumor cells to 5-Fluorouracil (Feng et al. J. Exp. Clin. Cancer Res., 2017, 36(1), 81), and activation of NLRP3 inflammasome in peripheral nerve contributes to chemotherapy-induced neuropathic pain (Jia et al. Mol. Pain., 2017, 13, 1-11). NLRP3 has also been shown to be required for the efficient control of viruses, bacteria, and fungi.

[0153] The activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang et al., Cell Death and Disease, 2017, 8(2), 2579; Alexander et al., Hepatology, 2014, 59(3), 898-910; Baldwin et al., J. Med. Chem.,

[0154] 2016, 59(5), 1691- 1710; Ozaki et al., J. Inflammation Research, 2015, 8, 15-27; Zhen et al., Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia et al., J. Med. Chem., 2014, 57(24), 10366-82; Satoh et al., Cell Death and Disease, 2013, 4, 644). Therefore, it is anticipated that inhibitors of NLRP3 will block pyroptosis, as well as the release of pro- inflammatory cytokines (e.g. IL-1 beta) from the cell.

[0155] The compounds of any general formula (e.g. formula (I), etc.), or a compound according to any one of the preceding embodiments, or a compound according to any one of the exemplified examples (e.g. Example 1 as disclosed herein), in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. NRLP3 inhibiting properties on the NLRP3 pathway, e.g. as indicated by in vitro tests as provided in the next section, and are therefore indicated for therapy or for use as research chemicals, e.g. as tool compounds.

[0156] Compounds of the disclosure may be useful in the treatment of an indication selected from: inflammasome-related disease I disorders, immune diseases, inflammatory diseases, autoimmune diseases, or auto-inflammatory diseases, for example, of diseases, disorders or conditions in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression, and which may be responsive to NLRP3 inhibition and which may be treated or PAT059896-PCT-SEC01 -26- prevented, or a compound according to any one of the exemplified examples (e.g. Example 1 as disclosed herein), of the present disclosure include:

[0157] I. Inflammation, including inflammation occurring as a result of an inflammatory disorder, e.g. an autoinflammatory disease, inflammation occurring as a symptom of a noninflammatory disorder, inflammation occurring as a result of infection, or inflammation secondary to trauma, injury or autoimmunity. Examples of inflammation that may be treated or prevented include inflammatory responses occurring in connection with, or as a result of:

[0158] (a) a skin condition such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopical dermatitis, contact dermatitis, allergic contact dermatitis, seborrhoetic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythemas, or alopecia;

[0159] (b) a joint condition such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, crystal induced arthropathy (e.g. pseudo-gout, gout), or a seronegative spondyloarthropathy (e.g. ankylosing spondylitis, psoriatic arthritis or Reiter's disease);

[0160] (c) a muscular condition such as polymyositis or myasthenia gravis;

[0161] (d) a gastrointestinal tract condition such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer, coeliac disease, proctitis, pancreatitis, eosinopilic gastro-enteritis, mastocytosis, antiphospholipid syndrome, or a food-related allergy which may have effects remote from the gut (e.g., migraine, rhinitis or eczema);

[0162] (e) a respiratory system condition such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic or dust asthma, and particularly chronic or inveterate asthma, such as late asthma and airways hyper- responsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, rhinitis caseosa, hypertrophic rhinitis, rhinitis pumlenta, rhinitis sicca, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis e.g. hay fever, and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia;

[0163] (f) a vascular condition such as atherosclerosis, Behcet's disease, vasculitides, or Wegener's granulomatosis;

[0164] (g) an immune condition, e.g. autoimmune condition, such as systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenia purpura, or Graves disease;

[0165] (h) an ocular condition such as uveitis, allergic conjunctivitis, or vernal conjunctivitis;

[0166] (i) a nervous condition such as multiple sclerosis or encephalomyelitis; PAT059896-PCT-SEC01 -27-

[0167] (j) an infection or infection-related condition, 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 (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, mycobacterium tuberculosis, mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis / epidydimitis, legionella, Lyme disease, influenza A, epstein-barr virus, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease;

[0168] (k) a renal condition such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, uremia, or nephritic syndrome;

[0169] (l) a lymphatic condition such as Castleman's disease;

[0170] (m) a condition of, or involving, the immune system, such as hyper IgE syndrome, lepromatous leprosy, hemophagocytic histocytosis, familial hemophagocytic lymphohistiocytosis, or graft versus host disease;

[0171] (n) a hepatic condition 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;

[0172] (o) a cancer, including those cancers listed herein below;

[0173] (p) a burn, wound, trauma, haemorrhage or stroke;

[0174] (q) radiation exposure; and / or

[0175] (r) obesity; and / or

[0176] (s) pain such as inflammatory hyperalgesia.

[0177] II. Inflammatory disease, including inflammation occurring as a result of an inflammatory disorder, e.g. an autoinflammatory disease, such as cryopyrin-associated periodic syndromes (CAPS), Muckle- Wei Is syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), adult-onset Still's disease (AOSD), haploinsufficiency of A20 (HA20), pediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2- associated autoinflammatory, antibody deficiency and immune dysregulation (APLAID), or sideroblastic anaemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD).

[0178] III. Immune diseases, e.g. auto-immune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti-synthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, Coeliac disease, Crohn's disease, type 1 diabetes (T1 D), Goodpasture's syndrome, Graves' PAT059896-PCT-SEC01 -28- disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's disease, lupus erythematosus including systemic lupus erythematosus (SLE), multiple sclerosis (MS) including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS), myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus, pernicious anaemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Reiter's syndrome, Sjogren's syndrome, systemic sclerosis a systemic connective tissue disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Beliefs disease, Chagas' disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, vitiligo or vulvodynia, Hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome such as T-cell engager therapy (CAR-T or bi / trispecific antibody);

[0179] IV. Cancer including lung cancer, renal cell carcinoma, non-small cell lung carcinoma (NSCLC), Langerhans cell histiocytosis (LCH), myeloproliferative neoplasms (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndrome (MDS), leukaemia including acute lymphocytic leukaemia (ALL) and acute myeloid leukaemia (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 tumours, breast cancer, cervical cancer, chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML), chronic myelomonocytic leukaemia (CMML), clonal cytopenia of undetermined significance (CCUS), juvenile myelomonocytic leukemia (JMML), colorectal cancer, endometrial cancer, oesophagus cancer, Ewing family of tumours, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumours, gastrointestinal stromal tumour (GIST), gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumour, 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 cavity and paranasal sinuses cancer, nasopharyngeal cancer, neuroblastoma, Mature T and NK neoplasms, non-Hodgkin lymphoma, mature B-cell neoplasms such as non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumours, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymus cancer, thyroid cancer PAT059896-PCT-SEC01 -29- including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumour, Myeloproliferative neoplasms (MPN) including myelofibrosis, brain tumor including primary brain cancer and brain metastasis, Myelodysplastic / myeloproliferative neoplasms (MDS / MPN), Myeloid / lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 , or with PCM1-JAK2, B- lymphoblastic leukemia / lymphoma, T-lymphoblastic leukemia / lymphoma, Histiocytic and dendritic cell neoplasms, Posttransplant lymphoproliferative disorders (PTLD);

[0180] V. Infections including viral infections (e.g. from influenza virus, human immunodeficiency virus (HIV), alphavirus (such as Chikungunya and Ross River virus), flaviviruses (such as Dengue virus and Zika virus), herpes viruses (such as Epstein Barr Virus, cytomegalovirus, Varicella-zoster virus, and KSHV), poxviruses (such as vaccinia virus (Modified vaccinia virus Ankara) and Myxoma virus), adenoviruses (such as Adenovirus 5), or papillomavirus), 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, Hemophilus influenzae, Pasteurella 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), fungal infections (e.g. from Candida or Aspergillus species), protozoan infections (e.g. from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes), helminth infections (e.g. from schistosoma, roundworms, tapeworms or flukes), and prion infections;

[0181] VI. Central nervous system diseases such as Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, intracranial aneurysms, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis;

[0182] VII. Metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudo-gout;

[0183] VIII. Cardiovascular diseases such as hypertension, ischaemia, reperfusion injury including post-MI ischemic 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, aneurysms including abdominal aortic aneurysm, cardiovascular risk reduction (CvRR), and pericarditis including Dressier's syndrome, post-Myocardial Infarction Heart Failure; Atrial fibrillation PAT059896-PCT-SEC01 -30-

[0184] IX. Respiratory diseases including chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis;

[0185] X. Liver diseases including non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) including advanced fibrosis stages F3 and F4, alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH);

[0186] XI. Renal diseases including acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy;

[0187] XII. Ocular diseases including those of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma;

[0188] XIII. Skin diseases including dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cystcausing skin diseases, and acne conglobata;

[0189] XIV. Lymphatic conditions such as lymphangitis, and Castleman's disease;

[0190] XV. Psychological disorders such as depression, and psychological stress; schizophrenia, bi-polar disease;

[0191] XVI. Graft versus host disease;

[0192] XVII. Bone diseases including osteoporosis, osteopetrosis;

[0193] XVIII. Blood disease including sickle cell disease;

[0194] XVIX. Allodynia including mechanical allodynia; and

[0195] XVX. Any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[0196] More specifically the compounds of the disclosure may be useful in the treatment of an indication selected from: inflammasome-related disase I disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes {e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver related disease I 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 e.g acute, chronic, Calcium pyrophosphate dihydrate crystal deposition disease (CPPD)), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type 1 1 Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), cardiovascular / PAT059896-PCT-SEC01 -31- metabolic diseases / disorders (e.g. cardiovascular risk reduction (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 I disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type 1 1 Type II diabetes and related complications (e.g. nephropathy, retinopathy), gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).

[0197] In particular, compounds of the disclosure, or a pharmaceutically acceptable salt thereof, may be useful in the treatment of a disease or disorder preferably selected from autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type 1 1 Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).

[0198] Thus, as a further aspect, the present disclosure provides the use of a compound of any general formula (e.g. formula (I) etc.), or a compound according to any one of the preceding embodiments, or a compound according to any one of the exemplified examples (e.g. Example 1 as disclosed herein), or a pharmaceutically acceptable salt thereof, in therapy. In a further embodiment, the therapy is selected from a disease, which may be treated by inhibition of NLRP3 inflammasome pathway. In another embodiment, the disease is selected from the afore-mentioned list, suitably inflammasome-related diseases I disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver related disease / disorders (e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic PAT059896-PCT-SEC01 -32- steatohepatitis, and alcoholic liver disease), inflammatory arthritis related disorders (e.g. gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy e.g acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type 1 1 Type II diabetes and related complications (e.g. nephropathy, retinopathy) hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), cardiovascular / metabolic diseases / disorders (e.g. cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral 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 I disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type 1 1 Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).

[0199] Thus, as a further aspect, the present disclosure provides a compound of any general formula (e.g. formula (I) etc.), or a compound according to any one of the preceding embodiments, or a compound according to any one of the exemplified examples (e.g. Example 1 as disclosed herein), or a pharmaceutically acceptable salt thereof, for use in therapy. In a further embodiment, the therapy is selected from a disease, which may be treated by inhibition of NLRP3 inflammasome pathway. In another embodiment, the disease is selected from the afore-mentioned list, suitably inflammasome-related diseases I disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver related disease / 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 e.g acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple PAT059896-PCT-SEC01 -33- sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), cardiovascular / metabolic diseases I disorders (e.g. cardiovascular risk reduction (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 I disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type 1 1 Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).

[0200] In another aspect, the disclosure provides a method of treating a disease which is treated by inhibiting NLRP3 comprising administration of a therapeutically effective amount of a compound of any general formula (e.g. formula (I) etc.), or a compound according to any one of the preceding embodiments, or a compound according to any one of the exemplified examples (e.g. Example 1 as disclosed herein), or a pharmaceutically acceptable salt thereof. In a further embodiment, the disease is selected from the afore-mentioned list, suitably inflammasome-related diseases I disorders, immune diseases, inflammatory diseases, autoimmune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver related diseases I 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 e.g acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), cardiovascular / metabolic diseases I disorders (e.g. cardiovascular risk reduction (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 PAT059896-PCT-SEC01 -34- diseases I disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type 1 1 Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).

[0201] In a further aspect, the present disclosure provides a compound of any general formula (e.g. formula (I) etc.), or a compound according to any one of the preceding embodiments, or a compound according to any one of the exemplified examples (e.g. Example 1 as disclosed herein), or a pharmaceutically acceptable salt thereof, useful in the treatment of a disease, disorder or condition substantially or entirely mediated by NLRP3 inflammasome activity, as disclosed herein, and / or NLRP3-induced IL-1 beta, and / or NLRP3-induced IL-18. Some of the diseases, disorders or conditions mentioned herein arise due to mutations in NLRP3, in particular, result in an increased NLRP3 activity.

[0202] Thus, as a further aspect, the present disclosure provides the use of a compound of any general formula (e.g. formula (I) etc.), or a compound according to any one of the preceding embodiments, or a compound according to any one of the exemplified examples (e.g. Example 1 as disclosed herein), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. In a further embodiment, the medicament is for the treatment of a disease, which is treated by inhibition of NLRP3 inflammasome pathway. In another embodiment, the disease is selected from the afore-mentioned list, suitably inflammasome- related diseases I disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver related diseases I 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 e.g acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, PAT059896-PCT-SEC01 -35- neurodegenerative diseases, Alzheimer’s disease), cardiovascular / metabolic diseases I disorders (e.g. cardiovascular risk reduction (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 I disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type 1 1 Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).

[0203] PHARMACEUTICAL COMPOSITION OR COMBINATION

[0204] The pharmaceutical composition or combination of the present disclosure can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50 - 70 kg, or about 1 - 500 mg, or about 1 - 250 mg, or about 1 - 150 mg, or about 1 - 100 mg, or about 1 - 50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

[0205] The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present disclosure can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10'3molar and 10'9molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1 - 500 mg / kg, or between about 1 - 100 mg / kg.

[0206] Combination product and combination therapy PAT059896-PCT-SEC01 -36-

[0207] “Combination” refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of the present disclosure and a combination partner (e.g. another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g. powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient) and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents. The term “pharmaceutical combination” as used herein refers to either a fixed combination in one dosage unit form, or non-fixed combination or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. The term “fixed combination” means that the therapeutic agents, e.g. a compound of the present disclosure and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the therapeutic agents, e.g. a compound of the present disclosure and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more therapeutic agent.

[0208] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple, or in separate containers (e.g. tablets, capsules, powders, and liquids) for each active ingredient. Powders and I or liquids may be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, PAT059896-PCT-SEC01 -37- the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0209] The compound of the present disclosure may be administered either simultaneously with, or before or after, one or more other therapeutic agent. The compound of the present disclosure may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the disclosure.

[0210] In one embodiment, the disclosure provides a product comprising a compound of any general formula (e.g. formula (I) etc.), or a pharmaceutical acceptable salt thereof, and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by NLRP3. Products provided as a combined preparation include a composition comprising the compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.

[0211] In one embodiment, the disclosure provides a pharmaceutical combination comprising a compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments, or a pharmaceutical acceptable salt thereof, and another therapeutic agent(s). Optionally, the pharmaceutical combination may comprise a pharmaceutically acceptable carrier, as described above.

[0212] In one embodiment, the disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments, or a pharmaceutical acceptable salt thereof. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like. PAT059896-PCT-SEC01 -38-

[0213] The kit of the disclosure may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the disclosure typically comprises directions for administration.

[0214] In the combination therapies of the disclosure, the compound of the disclosure and the other therapeutic agent may be manufactured and I or formulated by the same or different manufacturers. Moreover, the compound of the disclosure and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the disclosure and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the disclosure and the other therapeutic agent.

[0215] Accordingly, the disclosure provides the use of a compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, for treating a disease or condition mediated by NLRP3, wherein the medicament is prepared for administration with another therapeutic agent. The disclosure also provides the use of another therapeutic agent for treating a disease or condition mediated by NLRP3 wherein the medicament is administered with a compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments , or a pharmaceutical acceptable salt thereof.

[0216] The disclosure also provides a compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments, or a pharmaceutical acceptable salt thereof, for use in a method of treating a disease or condition mediated by NLRP3, wherein the compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments, or pharmaceutical acceptable salt thereof, is prepared for administration with another therapeutic agent. The disclosure 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 with a compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments, or pharmaceutical acceptable salt thereof. The disclosure also provides a compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments, or pharmaceutical PAT059896-PCT-SEC01 -39- acceptable salt thereof, for use in a method of treating a disease or condition mediated by NLRP3, wherein the compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments, or pharmaceutical acceptable salt thereof, is administered with another therapeutic agent. The disclosure 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 with a compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments, or a pharmaceutical acceptable salt thereof.

[0217] The disclosure also provides the use of a compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (e.g. according to any one of embodiments 1.0 to 18.7), or pharmaceutical acceptable salt thereof, for treating a disease or condition mediated by NLRP3, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent. The disclosure also provides the use of another therapeutic agent for treating a disease or condition mediated by NLRP3 inflammasome pathway, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of any general formula (e.g. formula (I) etc.), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments, or a pharmaceutical acceptable salt thereof.

[0218] In one embodiment, the other therapeutic agent is a therapeutic agent useful in the treatment of inflammasome-related diseases I disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, as disclosed herein.

[0219] In one embodiment, the other therapeutic agent useful in the combination therapy is selected from farnesoid X receptor (FXR) agonists; anti-steatotics; anti-fibrotics; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiation therapy and surgical procedures; urate- lowering therapies; anabolics and cartilage regenerative therapy; blockade of IL-17; complement inhibitors; Bruton’s tyrosine Kinase inhibitors (BTK inhibitors); Toll Like receptor inhibitors (TLR7 / 8 inhibitors); CAR-T therapy; anti-hypertensive agents; cholesterol lowering agents; leukotriene A4 hydrolase LTA4H) inhibitors; SGLT2 inhibitors; p2-agonists; antiinflammatory agents; nonsteroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acid drugs (ASA) including aspirin; paracetamol; regenerative therapy treatments; cystic fibrosis treatments; and atherosclerotic treatment. PAT059896-PCT-SEC01 -40-

[0220] Suitable leukotriene A4 hydrolase (LTA4H) inhibitors for use in the combination include, but are not limited to, compounds disclosed in WO2015 / 092740., in particular (S)-3-amino-4-(5- (4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid (LYS006), and compounds disclosed in WO2022 / 219546.

[0221] Suitable sodium- dependent glucose transporter 2 (SGLT2) inhibitors for use in the combination include, but are not limited to, compounds disclosed in US 8,163,704, WO2011 / 048112, WO2011 / 048148, or in W02010 / 128152.

[0222] Suitable p2-agonists for use in the combination include, but are not limited to, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline, ibuterol, Isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaprotenerol, nolomirole, orciprenaline, pirbuterol, procaterol, reproterol, ritodrine, rimoterol, salbutamol, salmefamol, salmeterol, 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- naphthyloxy]-N,N-di methylacetamide hydrochloride monohydrate, carmoterol, QAB-149 and 5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1 H-quinolin-2-one, 4-hydroxy-7- [2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolone, 1-(1- fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino] ethanol, 1-[3-(4- methoxybenzyl amino)-4-hydroxyphenyl]-2-[4(1-benzimidazolyl)-2-methyl-2- butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethyl aminophenyl)-2-methyl-2- propyl amino]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-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy- 3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1 ,2,4-triazol-3-yl]-2-methyl-2- butylaminojethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1 ,4benzoxazin-3-(4H) -one, 1-(4-amino-3-chloro-5trifluoromethylphenyl)-2-tert-butylamino)ethanol, 1-(4-ethoxy carbonylamino-3-cyano-5-fluoro phenyl)-2-(tert-butylamino)ethanol, and combinations thereof, each of which is optionally in the form of a racemate, enantiomer, diastereomer, or mixtures thereof, and also optionally in the form of a pharmacologically-compatible acid addition salt.

[0223] Suitable cartilage regenerative therapy for use in the combination includes, but are not limited to, ANGPTL3 peptidomimetics disclosed in WO2014 / 138687, or a chondrogenesis activator disclosed in WO2015 / 175487.

[0224] Suitable checkpoint inhibitors for use in the combination include, but are not limited to, anti-

[0225] PD1 inhibitors, anti-LAG-3 inhibitors, anti-TIM-3 inhibitors, anti-PDL1 inhibitors. Suitable anti- PAT059896-PCT-SEC01 -41-

[0226] PD1 inhibitors, include, but are not limited to, an antibody molecule disclosed in WO2015 / 112900. Suitable anti-LAG-3 inhibitors, include, but are not limited to, an antibody molecule disclosed in WO2015 / 138920. Suitable anti-TIM-3 inhibitors include, but are not limited to, an antibody molecule disclosed in WO2015 / 117002. Suitable anti-TIM-3 inhibitors include, but are not limited to, an antibody molecule disclosed in WO2015 / 117002. Suitable anti PDL1 inhibitors include, but are not limited to, an antibody molecule disclosed in WO20 16 / 061142.

[0227] Suitable Toll Like receptor inhibitors (TLR7 / 8 inhibitors) for use in the combination include, but are not limited to, a compound disclosed in W02018 / 04081.

[0228] Suitable FXR agonists for use in the combination include, but are not limited to, obeticholic acid (so called OCA, Intercept), GS9674, elafibranor (GFT505), GW4064, UPF987, FXR-450, fexaramine, methylcolate, methyl deoxycholate, 5p-cholanic acid, 5p-chloanic acid 7a, 12a diol, NIHS700, marchantin A, marchantin E, MFA-1 INT767 (also called 6a-ethyl-CDCA disclosed in WO2014 / 085474), MET409 (Metacrine), EDP-305 (Enanta), 2-[(1 R,3r,5S)-3-({5- cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1 ,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan- 8-yl]-4-fluoro-1 ,3-benzothiazole-6-carboxylic acid (also known under the name Tropifexor), or a pharmaceutically acceptable salt thereof, or a compound disclosed in WO2012 / 087519, or a compound disclosed in WO2015 / 069666.

[0229] Suitable JAK inhibitors for use in the combination include, but are not limited to Ruxolitinib.

[0230] Suitable NSAIDs for use in the combination include, but are not limited to, Aceclofenac, acemetacin, acetylsalicylic acid, alclofenac, alminoprofen, amfenac, Ampiroxicam, Antolmetinguacil, Anirolac, antrafenine, azapropazone, benorylate, Bermoprofen, bindarit, bromfenac, bucloxic acid, Bucolom, Bufexamac, Bumadizon, butibufen, Butixirat, Carbasalatcalcium, carprofen, choline magnesium trisalicylate, celecoxib, Cinmetacin, Cinnoxicam, clidanac Clobuzarit Deboxamet, dexibuprofen, Dexketoprofen, diclofenac, diflunisal, droxicam, Eltenac, Enfenaminsaure, Etersalat, etodolac, etofenamate, etoricoxib, Feclobuzon, felbinac, fenbufen, fenclofenac, fenoprofen, fentiazac, Fepradinol, Feprazon, Flobufen, floctafenine, flufenamic acid, flufenisal, Flunoxaprofen, flurbiprofen, Flurbiprofenaxetil, Furofenac, Furprofen, Glucametacin, ibufenac, ibuprofen, Indobufen, indomethacin, Indometacinfarnesil, indoprofen, Isoxepac, Isoxicam, ketoprofen, ketorolac, lobenzarit, Lonazolac, lornoxicam, Loxoprofen, lumiracoxib, meclofenamic, Meclofen, mefenamic acid, meloxicam, mesalazine, Miro Profen, Mofezolac, nabumetone, naproxen, niflumic acid, olsalazine, oxaprozin, Oxipinac, oxyphenbutazone, parecoxib, phenylbutazone, PAT059896-PCT-SEC01 -42-

[0231] Pelubiprofen, 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, Tinoridin, Tiopinac, tolfenamic acid, tolmetin, Ufenamat, valdecoxib, Ximoprofen, zaltoprofen, Zoliprofen and combinations thereof.

[0232] Suitable BTK inhibitors include for example Ibrutinib, Acalabrutinib (ACP-196), Evobrutinib; Fenebrutinib; Tirabrutinib (ONO-4059, GS-4059); Zanubrutinib (BGB-3111), Spebrutinib (CC- 292, AVL-292), Poseltinib (HM-71224, LY3337641), Vecabrutinib (SNS-062), BMS-986142; BMS986195; PRN2246; PRN1008, M7583, CT1530, BIIBO68, AC-0058TA, ARQ-531 , TAK- 020, TG1701 or a compound described in WO2015 / 079417, WO2015 / 083008,

[0233] WO20 15 / 110923, WO2014 / 173289, WO2012 / 021444, WG2013 / 081016, WO2013 / 067274, WO20 12 / 170976, WO2011 / 162515, US2017 / 119766, WO2016 / 065226, US9,688,676, WG2016 / 201280, WO2017 / 059702, US9,630,968, US2014 / 0256734, WO2017118277, WO20 14 / 039899, WO / 16 / 105531 , WO2018 / 005849, WO2013 / 185082 or in J. Med. Chem., 2016, 59(19), 9173-9200. Of particular interest, BTK inhibitors include compound of example 31 described in WO2014 / 039899, compound of the following structure: described as compound 14f in Journal of Medicinal Chemistry, 2016, 59 (19), 9173-9200; compound of example 2 described in LIS2017 / 119766, compound of example 223 described in WO2016 / 065226 which is: or compound 1 described in W02016 / 201280, compound 1 described in WO2017 / 059702, or compound 1 described in WO2017 / 118277; or a pharmaceutically acceptable salt thereof. PAT059896-PCT-SEC01 -43-

[0234] Of other particular interest, BTK inhibitors include a compound described in WO2015 / 079417, for example a compound selected from N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6- aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6- Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-fluorobenzamide; N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro- 2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (Remibrutinib); N-(3-(6-Amino-5-(2-(N- methylpropiol amido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluoro benzamide; N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)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-fluoro ethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4- cyclopropyl-2-fluoro benzamide; (S)-N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4- yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-Amino-5-(2-(N- methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclo propyl-2- fluorobenzamide and N-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5- fluoro-2-methylphenyl) -4-cyclo propyl-2-fluorobenzamide; or a pharmaceutically acceptable salt thereof.

[0235] EXAMPLES

[0236] The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof, which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and I or scope of the appended claims.

[0237] Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

[0238] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. PAT059896-PCT-SEC01 -44-

[0239] The chemical names were generated using ChemBioDraw Ultra v14 from CambridgeSoft.

[0240] Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20 - 133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. ABBREVIATIONS

[0241] AcOH Acetic acid

[0242] ASC Apoptosis-associated speck-like protein

[0243] Bn Benzyl

[0244] Boc tert-Butyloxycarbonyl

[0245] CAPS Cryopyrin-Associated Periodic Syndromes

[0246] DAMPS Danger-activated molecular patterns

[0247] DAST (Diethylamino)sulfur trifluoride

[0248] DIPEA / V-Diisopropylethylamine

[0249] DMF / V, / V-Dimethylformamide

[0250] DMSO Dimethylsulfoxide dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene

[0251] EtOAc Ethyl acetate

[0252] EtOH Ethanol

[0253] FA Formic acid h Hour(s)

[0254] HCI Hydrogen chloride

[0255] HTRF Homogeneous time resolved fluorescence

[0256] Hz / MHz Hertz I Mega Hertz

[0257] IC50 Half maximal inhibitory concentration

[0258] IL-1B Interleukin 1 beta

[0259] IR Infrared

[0260] LC-MS Liquid chromatography - mass spectrometry

[0261] LPS Lipopolysaccharides from Escherichia coli O111:B4

[0262] LRR Leucine-rich repeat

[0263] M Molar

[0264] MEK Methyl ethyl ketone; Butan-2-one

[0265] MeOH Methanol PAT059896-PCT-SEC01 -45-

[0266] MTBE Methyl tert-butyl ether min Minute mL / L Millilitre / Litre mmol Millimol

[0267] NASH Non-alcoholic steatohepatitis

[0268] NBD Nucleotide-binding site domain

[0269] NBS N-Bromosuccinimide

[0270] NLRs NOD-like receptors

[0271] NMP 1-Methylpyrrolidin-2-one

[0272] NMR Nuclear magnetic resonance

[0273] PAD Peripheral artery disease

[0274] PAMPs Pathogen activated molecular patterns

[0275] PdCI2(dppf) Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride

[0276] PMA Phorbol 12-myristate 13-acetate

[0277] PPm parts per million

[0278] RP Reverse phase

[0279] RPMI Roswell Park Memorial Institute

[0280] RT Room temperature - in Celsius

[0281] Rt Retention time

[0282] SLE systemic lupus erythematosus

[0283] TFA Trifluoroacetic acid

[0284] Tf Trifluoromethyl sulfonyl

[0285] THF Tetrahydrofuran

[0286] TMEDA N,N,N’,N’-Tetramethylethane-1 ,2-diamine

[0287] TNF-a Tumor necrosis factor-a

[0288] UPLC Ultra performance liquid chromatography

[0289] XPhos Pd G4 (SP-4-3)-[Dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,T-biphenyl]-2- yl]phosphine](methanesulfonato-KO)[2'-(methylamino-KN)[1 , 1 '- biphenyl]-2-yl-KC]palladium

[0290] ANALYTICAL DETAILS

[0291] NMR: Measurements were performed on a Bruker Ultrashield™ 400 (400 MHz) or Bruker Ascend™ (400 MHz) or Bruker cryo system (600 MHz) spectrometer using or not tetramethylsilane (TMS) as an internal standard. Chemical shifts (5) are reported in ppm downfield from TMS, spectra splitting pattern are designated as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), septet (sept), multiplet, unresolved or overlapping signals (m), broad signal (br . Deuterated solvents are given in parentheses and have a chemical shifts of PAT059896-PCT-SEC01 -46- dimethyl sulfoxide (5 2.50 ppm), methanol (5 3.31 ppm), chloroform (5 7.26 ppm), or other solvent as indicated in NMR spectral data.

[0292] LC-MS: System for Methods 1-4: Waters Acquity LIPLC with Waters SQ detector or Waters Acquity LCMS with PDA and Waters SQ detector.

[0293] Method 1

[0294] Column: CORTECS™ C18, 2.7 pm, 2.1 x 50 mm

[0295] Column Temperature: 80 °C

[0296] Eluents A: water + 0.05% FA + 3.75 mM AA, B: isopropanol + 0.05% FA

[0297] Flow Rate 1.0 mL / min

[0298] Gradient from 5 to 50% B in 1.4 min; 50% to 98% B in 0.3 min

[0299] Method 2

[0300] Column Type: ACQUITY UPLC BEH C18 1.7pm, 2.1x100 mm

[0301] Column Temperature: 80 °C

[0302] Eluents A: water + 0.05 % FA + 3.75 mM AA, B: isopropanol + 0.05 % FA

[0303] Flow: 0.4 mL / min

[0304] Gradient: from 5 to 60 % B in 8.4 min; 60 to 98 % B in 1 .0 min

[0305] Method 3

[0306] Column: ACQUITY BEH C18, 1.7 pm, 2.1 x 50 mm

[0307] Column Temperature: Ambient

[0308] Eluents A: water + 0.10% FA + 2.0 mM AA, B: acetonitrile + 0.10% FA

[0309] Flow Rate 0.45 mL / min

[0310] Gradient from 2 to 90% B in 5.0 min, 90 to 95% B in 1.0 min, then 95% B for 1 .0 min

[0311] Method 4

[0312] Column: XBridge® BEH™ C18, 2.5 pm, 2.1 x 50 mm

[0313] Column Temperature: 80 °C

[0314] Eluents A: water + 5mM NH4OH, B: acetonitrile + 5mM NH4OH

[0315] Flow Rate 1.0 mL / min

[0316] Gradient from 2 to 98% B in 1.4 min

[0317] Method 5

[0318] Instrument: ThermoScientific Vanquish Flex and ThermoScientific Orbitrap Exploris 240 Column: Acguity UPLC BEH C18 (1.7pm, 2.1x100mm)

[0319] Mobile phase A: 0.1 % formic acid in water PAT059896-PCT-SEC01 -47-

[0320] Mobile phase B: 0.1 % formic acid in acetonitrile

[0321] Flow: 0.5ml / min; Autosampler temperature: 20 °C; Column temperature: 50 °C; Wavelength:

[0322] 210nm

[0323] MS: mass range m / z 50-750

[0324] Ion Source Type: ESI

[0325] Polarity: Both, Positiv Ion (V): 3500 Negativ Ion (V): 2500

[0326] Vaporizer Temp.: 350 °C

[0327] Ion Transfer Tube Temp.: 350 °C

[0328] Aux Gas (Arb): 15

[0329] Sheath Gas (Arb): 40

[0330] Gradient Program:

[0331] Mass spectrometry results are reported as the ratio of mass over charge.

[0332] PREPARATIVE METHODS

[0333] Flash Column Chromatography Systems:

[0334] System: Teledyne ISCO, CombiFlash Rf.

[0335] Columns: pre-packed RediSep Rf normal phase silica cartridges.

[0336] Samples were typically adsorbed on Isolute.

[0337] System: Biotage Isolera One

[0338] Columns: pre-packed Biotage Star silica cartridges.

[0339] Preparative HPLC System:

[0340] System: Teledyne ISCO ACCQPrep HP150

[0341] Column: Waters XBridge Prep C18 OBD

[0342] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present disclosure are either PAT059896-PCT-SEC01 -48- commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. of intermediates of Boronate intermediates

[0343] 2,2-Difluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d][1 ,3]dioxol-4-ol, Int

[0344] A01 uorobenzo[d][1 ,3]dioxol-4-ol

[0345] Diisopropylamine (7.7 mL, 55 mmol) was dissolved in anhydrous THF (20 mL) and an inert atmosphere was created. The solution was cooled to -78 °C. nBuLi in hexane (20 mL, 2.5 M, 51 mmol) was added dropwise and the solution was stirred for 30 min at -78 °C. A solution of 5-bromo-2,2-difluorobenzo[d][1 ,3]dioxole (5.6 mL, 42 mmol) in THF (100 mL) was added dropwise over 20 min, the reaction was stirred for 2 h at -78 °C. Trimethyl borate (10 mL, 93 mmol) was added dropwise over 20 min. The resulting solution was stirred for 1.5 h at -78 °C then at room temperature overnight. The reaction mixture was cooled to -45 °C and peracetic acid (22.00 mL, 39%Wt, 129.2 eq) was slowly added. The reaction mixture was stirred for 30 min then was warmed to 0 °C. the reaction mixture was slowly quenched by addition of a sodium bisulfite solution in water (100 mL, 2.00 M, 200 mmol). The reaction mixture was acidified to pH 1 with a 2M aqueous solution HCI and extracted three times with EtOAc. The combined organic layer was washed with brine three times, dried over anhydrous magnesium sulfate, and filtered. Solvent evaporation yielded a residue which was purified by column chromatography on silica gel (80 g) using cyclohexane and EtOAc (from 0% to 10%) to afford the title compound.1H NMR (400 MHz, DMSO-d6) 5 11.31 (s, 1H), 7.36 (d, 1H), 6.86 (d, 1 H). LC-MS: Method 1, Rt= 1.09 min; MS m / z 251.0 [M-H]’.

[0346] (2) 4-(Benzyloxy)-5-bromo-2,2-difluorobenzo[d][1 ,3]dioxol PAT059896-PCT-SEC01 -49-

[0347] To a stirred solution of 5-bromo-2,2-difluorobenzo[d][1 ,3]dioxol-4-ol (step 1 , Int A01 , 6.4 g, 83% Wt, 21 mmol) in DMF (75 mL) were added potassium iodide (1.7 g, 11 mmol) and cesium carbonate (21 g, 63 mmol). Benzyl bromide (3.7 mL, 31 mmol) was slowly added to the previously formed suspension, and the reaction mixture was stirred for 30 min at room temperature. The reaction mixture was poured into 500 mL water and extracted twice with 200 mL EtOAc. The combined organic layer was washed with brine three times, dried over anhydrous magnesium sulfate and filtered off. The combined organic layer was concentrated in vacuo to provide the crude product, which was purified by column chromatography on silica gel (80 g) using cyclohexane and EtOAc (from 0% to 10% gradient) to afford the title compound.1H NMR (500 MHz, DMSO-d6) 5 7.51 - 7.42 (m, 3H), 7.42 - 7.32 (m, 3H), 7.06 (d, 1 H), 5.36 (s, 2H). LC-MS: Method 1, Rt= 1.65 min; MS m / z (no mass detected).

[0348] (3) 2-(4-(Benzyloxy)-2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane

[0349] To a stirred solution of 4-(benzyloxy)-5-bromo-2,2-difluorobenzo[d][1 ,3]dioxole (step 2, Int A01 , 6.0 g, 94% Wt, 16 mmol) in THF (100 mL) under an inert atmosphere at 0 °C was slowly added a solution of iPrMgCl. LiCI in THF (19 mL, 1.3 M, 25 mmol). The reaction mixture was stirred for 30 min at 0 °C and 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (6.7 mL, 33 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirring was continued for 30 min. The reaction mixture was poured into a saturated aqueous solution NH4CI. The aqueous layer was extracted three times with CH2CI2. The combined organic layer was dried over anhydrous magnesium sulfate and filtered off. The combined organic layer was concentrated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (120 g) using cyclohexane and EtOAc (from 0% to 5% gradient) to afford the title compound.1H NMR (400 MHz, DMSO-de) 5 7.58 - 7.51 (m, 2H), 7.44 - 7.28 (m, 4H), 7.07 (d, 1 H), 5.26 (s, 2H), 1.29 (s, 12H). LC-MS: Method 1 , Rt= 1.69 min; MS m / z 391.0 [M+H]+. PAT059896-PCT-SEC01 -50-

[0350] (4) 2,2-Difluoro-5-(4,4,5, 5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzo[d][1 ,3]dioxol-4-ol , Int

[0351] A01

[0352] To a stirred solution of 2-(4-(benzyloxy)-2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane (step 3, Int A01 , 5.8 g, 75% Wt, 11 mmol) in THF (100 mL) was added palladium on charcoal (1.2 g, 10% Wt, 1.1 mmol) and the vessel was flushed with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere for 2 h at room temperature.

[0353] The reaction mixture was filtered through a pad of celite, the filter was washed with EtOAc (100 mL). The combined organic layer was concentrated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (80 g) using cyclohexane and EtOAc (from 0% to 20% gradient) to afford the title compound as a white solid.1H NMR (400 MHz, DMSO-d6) 5 9.68 (s, 1 H), 7.33 (d, 1 H), 6.87 (d, 1 H), 1.28 (s, 12H). LC-MS: Method 1 , Rt= 1 .49 min; MS m / z 299.3 [M-H]’.

[0354] Alternatively, 2,2-Difluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d][1 ,3]dioxol- 4-ol Int A01 may also be prepared according to the following route:

[0355] ( uorobenzo[d][1 ,3]dioxol-4-ol

[0356] Under a nitrogen atmosphere, tetrahydrofuran (THF, 86 mL, 10.0 eq) and 5-bromo-2,2- difluorobenzo[d][1 ,3]dioxole (8.6 g, 25 mmol) were charged into a 500 mL round-bottom flask. The reaction mixture was cooled to -50 °C to -40 °C and stirred for 1 hour. Lithium diisopropylamide (LDA, 21.7 g, 1.2 eq; 2 M in hexane, 10.8 mL) was added dropwise, and stirring was continued at -50 °C to -40 °C for an additional hour. A solution of trimethyl borate (B(OMe)3, 4.52 g, 1.2 eq) in THF (50 mL, 5.0 eq) was then added to the reaction mixture, which was stirred for another hour at the same temperature. Hydrogen peroxide (H2O2, 12.34 g, 3.0 eq; 30 wt% aqueous solution) was added dropwise over 30 minutes while maintaining the temperature between -40 °C and 0 °C. The mixture was stirred for an PAT059896-PCT-SEC01 -51- additional 1-2 hours at -5 °C to 5 °C. The reaction was quenched with sodium bisulfite (NaHSOs, 3.5 eq; 30 wt% aqueous solution), and the pH was adjusted to 3-4 with hydrochloric acid (HCI, 2 M aqueous solution). After phase separation, the aqueous layer was extracted with methyl tert-butyl ether (MTBE, 5.0 vol). The combined organic layers were concentrated and treated with saturated aqueous sodium carbonate (Na2COs, 64.5 mL,

[0357] 7.5 vol). The aqueous layer was subsequently extracted with n-heptane (43 mL, 5.0 vol). After adjusting the pH to 3-4 with hydrochloric acid (HCI, 4 M aqueous solution), the mixture was extracted with MTBE. The collected organic layer was washed with water (3.0 vol) and dried over anhydrous sodium sulfate (Na2SCU). The solution was filtered and concentrated to afford the title compound.1H NMR (400 MHz, DMSO-de) 6 11.29 (s, 1 H), 7.36 (d, 1 H), 6.86 (d, 1 H).

[0358] (2) 2,2-Difluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d][1 ,3]dioxol-4-ol , Int

[0359] A01

[0360] Under a nitrogen atmosphere, tetrahydrofuran (THF, 80 mL, 10.0 eq) and 5-bromo-2,2- difluorobenzo[d][1 ,3]dioxol-4-ol (8.0 g, 25 mmol) were charged into a 300 mL round-bottom flask and cooled to -70 °C to -60 °C. The mixture was stirred for 1 hour, and then n- butyllithium (n-BuLi, 31.62 g, 2.5 eq; 2.5 M in hexane, 12.65 mL) was added dropwise.

[0361] Stirring was continued at -70 °C to -60 °C for an additional hour. Isopropoxyboron pinacol ester (i-PrOBpin, 17.64 g, 3.0 eq) was added, and the reaction was stirred for another 3 hours at the same temperature.

[0362] The reaction mixture was warmed to 20 °C to 30 °C and then cooled to 0 °C to 10 °C before quenching with hydrochloric acid (HCI, 4 M aqueous solution, 3.5 eq). After phase separation, the organic phase was washed with 10% sodium chloride solution (NaCI, 3.0 vol) and concentrated to a residue. The residue was purified by column chromatography. The purified residue was concentrated and slurried in n-heptane (1.0 vol) at -50 °C to -40 °C. The mixture was filtered, and the solid was dried under vacuum at 30 °C to 35 °C to afford the title compound as an off-white solid.1H NMR (400 MHz, DMSO-d6) 5 9.65 (s, 1 H), 7.34 (d, 1 H), 6.87 (d, 1 H), 1.29 (s, 12H).1H NMR (400 MHz, CHCI3) 6 8.08 (s, 1 H), 7.37 (d, 1 H), 6.65 (d, 1 H), 1.38 (s, 12H); LC-MS: Method s, Rt= 5.45 min; MS m / z 299.1 [M-H]-.

[0363] Alternatively, 2,2-Difluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d][1 ,3]dioxol- 4-ol Int A01 may also be prepared according to the following route: PAT059896-PCT-SEC01 -52-

[0364] ( o[d][1 ,3]dioxol-4-ol

[0365] To a solution of 2,2-difluorobenzo[d][1 ,3]dioxole (40.0 g, 1.0 eq) in tetrahydrofuran (THF, 400 mL, 10.0 vol) was added n-butyllithium (n-BuLi, 121 mL, 1.2 eq) at -75 °C to -70 °C. The reaction mixture was stirred at this temperature for 1 hour. Subsequently, trimethyl borate (31.6 g, 1.2 eq) was added dropwise to the cooled mixture. Upon complete addition, the temperature was gradually raised to 20 °C to 30 °C, and the mixture was stirred for an additional hour. Water (120 mL, 3.0 vol) was then added to the reaction mixture, followed by hydrogen peroxide (H2O2, 57.4 g, 2.0 eq). The temperature was increased to 40 °C to 50 °C, and the mixture was stirred for another hour. Upon completion of the reaction, sodium sulfite (Na2SOs, 63.8 g, 2.0 eq) was added at 20 °C to 30 °C, followed by the addition of water (80 mL, 2.0 vol). The pH of the mixture was adjusted to 4-5 using 2 N hydrochloric acid (HCI, 250 mL). Ethyl acetate (400 mL, 10.0 vol) was added to the mixture, resulting in phase separation. The aqueous layer was further extracted with ethyl acetate (200 mL, 5.0 vol). The combined organic layers were concentrated under reduced pressure to afford the title compound as a yellow oil.1H NMR (400 MHz, CD3CN) 5 7.60 (brs, 1 H), 6.98 (dd, 1 H), 6.72 (d, 1 H), 6.71 (d, 1 H).

[0366] (2) 2,2-difluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzo[d][1 ,3]dioxole

[0367] 2,2-difluorobenzo[d][1 ,3]dioxol-4-ol (61.2 g, 1.0 eq) was dissolved in dichloromethane (DCM, 600 mL, 10.0 vol) under an inert atmosphere. Pyridinium p-toluenesulfonate (35.4 g, 0.4 eq) and dihydropyridine (DHP, 88.8 g, 3.0 eq) were added to the solution. The reaction mixture was stirred at 20 °C to 30 °C for 20 hours. Upon completion, a 5% sodium bicarbonate (NaHCOs, 600 mL) solution was added. After phase separation, the aqueous layer was extracted with dichloromethane (DCM, 600 mL, 10.0 vol). The combined organic layers were concentrated under reduced pressure and subjected to silica gel chromatography to afford the PAT059896-PCT-SEC01 -53- title compound.1H NMR (400 MHz, CDCh) 6 6.97 (dd, 1 H), 6.92 (d, 1 H), 6.74 (d, 1H), 5.57 (t, 1 H), 3.96-3.91 (m, 1 H), 3.66-3.62 (m, 1 H), 1.96-1.91 (m, 2H), 1.71-1.64 (m, 4H).

[0368] (3) 2-(2,2-difluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzo[d][1 ,3]dioxol-5-yl)-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane

[0369] 2,2-difluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzo[d][1 ,3]dioxole (65.2 g, 1.0 eq) was dissolved in tetra hydrofuran (THF, 650 mL, 10.0 vol) under an inert nitrogen atmosphere and cooled to -75 °C to -70 °C using a cooling bath. n-Butyllithium (n-BuLi, 151 .5 mL, 1 .5 eq) was added dropwise to the cooled solution, and the reaction mixture was stirred at -75 °C to -70 °C for 1 hour. Subsequently, 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (103 mL, 2.0 eq) was added to the mixture, which was then stirred at the same temperature range for an additional hour. Upon completion of the reaction, an aqueous solution of ammonium chloride (15% NH4CI, 650 mL, 10.0 vol) was added to the reaction mixture, and the temperature was adjusted to 20 °C to 30 °C. Ethyl acetate (500 mL) was then added, and the mixture was stirred for 30 minutes to facilitate phase separation. The aqueous layer was extracted twice with ethyl acetate (500 mL, 8.0 vol each extraction). The combined organic layers were concentrated under reduced pressure and subjected to crystallization by adding n-heptane at -5 °C to 0 °C. The resulting crystals were filtered, washed with n-heptane, and dried under vacuum to afford the title compound as a white solid.1H NMR (400 MHz, CDCh) 6 7.51 (d, 1 H), 6.78 (d, 1 H), 5.72 (s, 1 H), 4.14-4.07 (m, 1 H), 3.60-3.56 (m, 1 H), 2.22-2.06 (m, 2H), 1.85-1.63 (m, 4H), 1.35 (s, 12H).

[0370] (4) 2,2-Difluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d][1 ,3]dioxol-4-ol Int

[0371] A01

[0372] 2-(2,2-difluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzo[d][1 ,3]dioxol-5-yl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (20.0 g, 1.0 eq) was dissolved in methanol (MeOH, 100 mL, 5.0 vol) under stirring at 20 °C to 30 °C. p-Toluenesulfonic acid (TsOH, 0.9 g, 0.1 eq) was added to the solution, and the mixture was stirred for 30 minutes at the same temperature. Upon completion, water (30 mL, 1 .5 vol) was added dropwise to the reaction mixture for PAT059896-PCT-SEC01 -54- crystallization. The solution was stirred for an additional 30 minutes. Subsequently, water (170 mL, 8.5 vol) was added dropwise, and the mixture was stirred for another hour. The reaction mixture was then filtered and washed sequentially with a methanol-water mixture (MeOH / H2O, 1:2, 40 mL) and water (40 mL, 2.0 vol). The filtered solid was dried under vacuum to afford the title compound as a white solid.1H NMR (400 MHz, CDCL) 6 8.08 (s, 1H), 7.37 (d, 1 H), 6.65 (d, 1H), 1.38 (s, 12H); LC-MS: Method 5, Rt= 5.45 min; MS m / z 299.1 [M-H]-.

[0373] Synthesis of 1,4-dichloropyridopyridazine intermediates 1,4-dichloro-5-methoxypyrido[3,4-d]pyridazine, Int B01

[0374] (1) dimethyl 2-methoxypyridine-3,4-dicarboxylate

[0375] To an inert, stirred solution of dimethyl 2-chloropyridine-3,4-dicarboxylate (1 g, 4.36 mmol) in anhydrous toluene (8 mL), were added MeOH (8.0 mL, 198 mmol), PdCI2(dppf).DCM (0.36 mg, 0.44 mmol) and LiOtBu in THF (5.94 mL, 2.2 M, 13.07 mmol). The reaction mixture was heated up to 70 °C and stirred for 1 h. The reaction mixture was cooled down to room temperature, quenched with brine and extracted three times with DCM. The combined organic layer was dried over a phase separator and concentrated in vacuo. Purification was performed by column chromatography on silica gel using DCM and MeOH (from 0% to 30% gradient) to afford the title compound. LC-MS: Method 4, Rt= 0.68 min; MS m / z 226.2 [M+H]+.

[0376] (2) 5-methoxy-2,3-dihydropyrido[3,4-d]pyridazine-1 ,4-dione

[0377] To a stirred solution of dimethyl 2-methoxypyridine-3,4-dicarboxylate (step 1 , Int B01 , 665 mg, 2.95 mmol) in MeOH (30 mL) was added hydrazine monohydrate (1.15 mL, 11.81 mmol) at room temperature. The reaction mixture was heated up to 70 °C and stirred for 4 h. After this time, the reaction mixture was concentrated to dryness. The residue was triturated in PAT059896-PCT-SEC01 -55-

[0378] DCM, filtered and the solid was dried under vacuum to obtain a yellow solid, which was used without further purification. LC-MS: Method 4, Rt= 0.19 min; MS m / z 194.1 [M+H]+.

[0379] (3) 1,4-dichloro-5-methoxypyrido[3,4-d]pyridazine, Int B01

[0380] To a stirred solution of 5-methoxy-2,3-dihydropyrido[3,4-d]pyridazine-1, 4-dione (step 2, Int B01 , 578 mg, 3.0 mmol) in phosphorus oxychloride (15 mL, 160.9 mmol) was added pyridine (2.42 mL, 29.9 mmol) at room temperature. The reaction mixture was heated up to 50 °C and stirred for 17 h. After this time, the reaction mixture was cooled down to room temperature and concentrated to dryness. The residue was purified by column chromatography on silica gel using cyclohexane and ethyl acetate (gradient from 0 to 100%) to afford the title compound as a yellow powder. LC-MS: Method 1, Rt= 0.77 min; MS m / z 232.1 [M+H]+.

[0381] 1,4-dichloro-7-methoxypyrido[3,4-d]pyridazine, Int B02

[0382] (1) dimethyl 6-methoxypyridine-3,4-dicarboxylate

[0383] An autoclave was charged with a solution of methyl 5-bromo-2-methoxy-isonicotinate (15 g, 61 mmol) in MeOH (150 mL) and triethylamine (25.5 mL, 183 mmol). PdCh(dppf) (4.46 g, 6.1 mmol) was added to the solution, and the autoclave was closed. The reaction mixture was heated up to 90 °C under CO atmosphere (10 bar) for 15 h. The reaction mixture was cooled to room temperature and filtered on a pad of silica. The dark filtrate was quenched with water and extracted three times with DCM. The combined organic layer was washed with Brine, dried over a phase separator and concentrated in vacuo. The crude residue was used in the next step without further purification.1H NMR (400 MHz, DMSO-de) 5 8.72 (s, 1 H), 7.08 (s, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H). LC-MS: Method 4, Rt= 0.72 min; MS m / z 226.1 [M+H]+. PAT059896-PCT-SEC01 -56-

[0384] (2) 7-methoxy-2,3-dihydropyrido[3,4-d]pyridazine-1 ,4-dione

[0385] To a stirred solution of dimethyl 6-methoxypyridine-3,4-dicarboxylate (step 1 , Int B02, 1 g, 3.5 mmol) in EtOH (20 mL) was added hydrazine monohydrate (1.18 mL, 15.79 mmol) at room temperature. The reaction mixture was heated up to 60 °C and stirred overnight. After this time, the reaction mixture was cooled down to room temperature until a solid precipitated. The solid was filtered off, rinsed with EtOH and concentrated in vacuo to afford the title compound, which was used without further purification.1H NMR (400 MHz, DMSO-de) 5 8.98 (s, 1 H), 7.14 (s, 1 H), 3.98 (s, 3H). LC-MS: Method 1 , Rt= 0.27 min; MS m / z 194.0 [M+H]+.

[0386] (3) 1,4-dichloro-7-methoxypyrido[3,4-d]pyridazine, Int B02

[0387] To a stirred solution of 7-methoxy-2,3-dihydropyrido[3,4-d]pyridazine-1, 4-dione (step 2, Int B02, 200 mg, 0.88 mmol) in phosphorus oxychloride (0.66 mL, 7.0 mmol) was added diisopropylamine (0.15 mL, 0.88 mmol) at room temperature. The reaction mixture was heated up to 120 °C for 1 h. After this time, the reaction mixture was cooled down to room temperature and concentrated to dryness. The residue was poured into a mixture of ice and a saturated aqueous solution of NaHCOs, then extracted three times with DCM. The combined organic layer was dried over a phase separator and concentrated on vacuo to give the title compound, which was used without further purification.1H NMR (400 MHz, DMSO-de) 5 9.48 (s, 1 H), 7.42 (s, 1 H), 4.04 (s, 3H). LC-MS: Method 1 , Rt= 0.74 min; MS m / z 231.9 [M+H]+. of 1- :in-4-amine, 4-i :in-1-amine, 5- chloro-pyridopyridazin-8-amine, 8-chloro-pyridopyridazin-5-amine or 4-

[0388] -1 -amine intermediates

[0389] (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine, Int C01 and (R)-4- chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1 -amine, Int C02 PAT059896-PCT-SEC01 -57-

[0390] To a stirred solution of 1 ,4-dichloropyrido[3,4-d]pyridazine (2.7 g, 13.5 mmol) in DMSO (15 mL) were added N,N-diisopropylethylamine (3.53 mL, 20.3 mmol) and (R)-l-methylpiperidin- 3-amine (2.0 g, 17.6 mmol). The reaction mixture was heated up to 100 °C and stirred for 18 h. The reaction mixture was quenched with brine and extracted three times with ethyl acetate. The combined organic layer was washed with brine and water, then dried over a phase separator and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using DCM and MeOH (gradient from 0 to 20 %) to afford the title products as a mixture. The mixture was separated using preparative chiral SFC method (column: Chiralpak IG 30 x 250 mm, 5 .m; Modifier: 45%_ MeOH + 0.05% ammonia; Flow rate: 84 mL / min) to afford Int C02 (first eluting) and Int C01 (second eluting).

[0391] Int C01 :1H NMR (400 MHz, DMSO-d6) 5 9.78 (d, 1 H), 9.03 (d, 1 H), 7.83 (d, 1 H), 7.73 (d, 1 H), 4.37-4.28 (m, 1 H), 3.04-3.01 (m, 1 H), 2.71-2.67 (m, 1 H), 2.19 (s, 3H), 1.99-1.86 (m, 3H),

[0392] 1.77-1.70 (m, 1 H), 1.63-1.52 (m, 1 H), 1.47-1.37 (m, 1 H). LC-MS: Method 4, Rt= 0.66 min; MS m / z 278.1 [M+H]+.

[0393] Int C02:1H NMR (400 MHz, DMSO-d6) 5 9.38 (s, 1 H), 9.07 (d, 1 H), 8.33 (d, 1 H), 7.54 (d, 1 H), 4.32-4.23 (m, 1 H), 3.01-2.99 (m, 1 H), 2.70-2.67 (m, 1 H), 2.19 (s, 3H), 1.97-1.86 (m, 3H),

[0394] 1.77-1.71 (m, 1 H), 1.63-1.54 (m, 1 H), 1.46-1.36 (m, 1 H). LC-MS: Method 4, Rt= 0.67 min; MS m / z 278.2 [M+H]+.

[0395] Alternatively, (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine Int C01 may also be prepared according to the following procedure:

[0396] (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (Int C01):

[0397] Under a nitrogen atmosphere, 1 ,4-dichloropyrido[3,4-d]pyridazine (2.5 kg, 12.5 mmol, 1.00 eq), acetonitrile (25 L), sodium carbonate (3.98 kg, 37.5 mmol, 3.0 eq), and (R)-1- methylpiperidin-3-amine dihydrochloride (1.5 kg, 13.1 mmol, 1.05 eq) were charged into a reactor and heated to 70 °C to 72 °C. The mixture was stirred for 24 - 30 hours, before being cooled to 10 °C to 20 °C. The reaction mixture was filtered, and the filtrate was concentrated. The obtained residue was dissolved in ethanol (8.55 vol) and water (0.45 vol.), before hydrochloric acid (4 M ethanol solution, 10.0 vol) was added dropwise at 20 °C to 30 °C. The resulting mixture was heated to 45 °C and stirring was continued for 2 hours. The suspension was cooled to 15 °C to 20 °C, filtered, and the filter cake was dried for 16 hours at 50 °C to 52 °C. The dried filter cake was washed 3-times with methanol (3 x 1.5 vol) before being dried PAT059896-PCT-SEC01 -58- for 16 hours at 50 °C to 52 °C. The resulting solids were dissolved in dichloromethane (10 vol), treated with sodium carbonate (5.30 kg, 4.0 eq), and stirred for 2 hours at 30 °C to 40 °C. The suspension was filtered, and the filtrate was concentrated. The obtained residue was redissolved in ethyl acetate (20 vol), stirred for 1 hour at 20 °C to 25 °C, filtered, and the filtrate was concentrated to afford the title compound.1H NMR (400 MHz, DMSO-d6) 5 9.79 (d, 1 H), 9.05 (d, 1 H), 7.85 (dd, 1 H), 7.73 (d, 1 H), 4.38-4.28 (m, 1 H), 3.07-2.99 (m, 1 H), 2.75- 2.64 (m, 1 H), 2.19 (s, 3H), 2.05-1.94 (m, 1 H), 1.94-1.85 (m, 2H), 1.79-1.70 (m, 1 H), 1.66-1.51 (m, 1 H), 1.49-1.35 (m, 1 H). LC-MS: Method s, Rt = 2.44-2.46 min; MS m / z 278.11612 [M+H]+.

[0398] (R)-1-chloro-N-(1-ethylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine, Int C03 and (R)-4- chloro-N-(1-ethylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1 -amine, Int C04

[0399] To a stirred solution of 1 ,4-dichloropyrido[3,4-d]pyridazine (0.3 g, 1.5 mmol) in DMSO (5.0 mL) were added N,N-diisopropylethylamine (1.31 mL, 7.5 mmol) and (R)-1-ethylpiperidin-3- amine dihydrochloride salt (452.5 mg, 1.5 mmol). The reaction mixture was heated up to 100 °C and stirred for 3 h. The reaction mixture was quenched with brine and extracted three times with DCM. The combined organic layer was dried over a phase separator and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using cyclohexane and ethyl acetate (gradient from 0 to 100 %) to afford the title products as a mixture (Int C03 was the major isomer). LC-MS: Method 4, Rt= 0.81 min; MS m / z 292.2 [M+H]+.

[0400] (R)-1-chloro-N-(1-isopropylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine, Int C05 and

[0401] (R)-4-chloro-N-(1-isopropylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1 -amine, Int C06 PAT059896-PCT-SEC01 -59-

[0402] (1) tert-butyl (R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate and tert-butyl (R)-3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)piperidine-1-carboxylate

[0403] To a stirred solution of 1,4-dichloropyrido[3,4-d]pyridazine (500 mg, 2.5 mmol) in DMSO (5.0 mL) were added N,N-diisopropylethylamine (1.74 mL, 10.0 mmol) and tert-butyl (R)-3- aminopiperidine-1-carboxylate (751 mg, 3.75 mmol). The reaction mixture was heated up to 100 °C and stirred for 3 h. The reaction mixture was quenched with brine and extracted three times with DCM. The combined organic layer was dried over a phase separator and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using cyclohexane and ethyl acetate (gradient from 0 to 100 %) to afford the title products as a mixture. LC-MS: Method 1 , Rt= 0.92 and 0.94 min; MS m / z 364.1 [M+H]+.

[0404] (2) (R)-1-chloro-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (R)-4-chloro-N- (piperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0405] To a stirred solution of tert-butyl (R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidine- 1-carboxylate and tert-butyl (R)-3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)piperidine-1- carboxylate (step 1 , Int C05 and Int C06, 850 mg, 2.27 mmol) in DCM (5 mL) was added trifluoroacetic acid (1.75 mL, 22.66 mmol). The reaction mixture was stirred at room temperature for 90 min. After this time, the reaction mixture was basified using a saturated aqueous solution of NaHCOs and extracted three times with DCM. The combined organic layer was dried over a phase separator and concentrated in vacuo to afford a mixture of the title products, which was used without further purification. LC-MS: Method 1, Rt= 0.14 and 0.21 min; MS m / z 264.0 [M+H]+.

[0406] (3) (R)-1-chloro-N-(1-isopropylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine, Int C05 and

[0407] (R)-4-chloro-N-(1-isopropylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1 -amine, Int C06 PAT059896-PCT-SEC01 -60-

[0408] To a stirred solution of (R)-1-chloro-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (R)- 4-chloro-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (step 2, Int C05 and Int C06, 1 g, 0.8 mmol) in DMF (2 mL) was added sodium hydride 90% Wt (27.6 mg, 1.04 mmol) at 0 °C. The reaction mixture was warmed up to room temperature over 30 min and isopropyl bromide (0.15 mL, 1.59 mmol) was added. The reaction mixture was stirred for 15 h at room temperature and further isopropyl bromide (0.15 mL, 1.59 mmol) was added. After additional 4 h at room temperature, the reaction mixture was quenched with water and extracted three times with DCM. The combined organic layer was dried over a phase separator and concentrated on vacuo to give the title compounds, which was used without further purification. LC-MS: Method 1 , Rt= 0.25 and 0.27 min; MS m / z 306.0 [M+H]+.

[0409] (R)-4-chloro-N-(1 -methylpiperidin-3-yl)phthalazin-1 -amine, Int C07

[0410] To a stirred solution of 1,4-dichlorophthalazine (500 mg, 2.24 mmol) in DMSO (6.0 mL) were added N,N-diisopropylethylamine (1.56 mL, 8.94 mmol) and (R)-1-methylpiperidin-3-amine (383 mg, 3.35 mmol). The reaction mixture was heated up to 100 °C and stirred for 15 h. The reaction mixture was quenched with brine and extracted three times with ethyl acetate. The combined organic layer was dried over a phase separator and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using DCM and MeOH (gradient from 0 to 10 %) to afford the title product as a yellow foam.1H NMR (400 MHz, DMSO-d6) 5 8.45-8.43 (m, 1H), 8.09-8.04 (m, 1 H), 8.02-7.96 (m, 2H), 7.25 (d, 1 H), 4.34-4.25 (m, 1H), 3.03-3.01 (m, 1 H), 2.70-2.68 (m, 1 H), 2.13 (s, 3H), 1.96-1.85 (m, 3H), 1.75-1.70 (m, 1H), 1.63-1.52 (m, 1 H), 1.47-1.37 (m, 1H). LC-MS: Method 1, Rt= 0.32 min; MS m / z 277.0 [M+H]+.

[0411] (R)-5-chloro-N-(1-methylpiperidin-3-yl)pyrido[2,3-d]pyridazin-8-amine, Int C08 and (R)-8- chloro-N-(1-methylpiperidin-3-yl)pyrido[2,3-d]pyridazin-5-amine, Int C09

[0412] To a stirred solution of 5,8-dichloropyrido[2,3-d]pyridazine (100 mg, 0.5 mmol) in DMSO (1.5 mL) were added N,N-diisopropylethylamine (0.22 mL, 1.25 mmol) and (R)-l-methylpiperidin- 3-amine (74.2 mg, 0.65 mmol). The reaction mixture was heated up to 85 °C and stirred for 3 h. The reaction mixture was quenched with ice-cold water and extracted three times with ethyl PAT059896-PCT-SEC01 -61- acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using DCM and MeOH (gradient from 0 to 10 %) to afford (R)-5-chloro-N-(1- methylpiperidin-3-yl)pyrido[2,3-d]pyridazin-8-amine, Int C08 (first eluting) and chloro-N-(1- methylpiperidin-3-yl)pyrido[2,3-d]pyridazin-5-amine, Int C09 (second eluting) as brown solids. Int C08:1H NMR (400 MHz, DMSO-d6) 5 9.21 (dd, 1 H), 8.48 (dd, 1 H), 8.06 (dd, 1 H), 7.43 (d, 1 H), 4.36-4.32 (m, 1 H), 2.70-2.66 (m, 1 H), 2.45-2.18 (m, 6H), 1.76-1.66 (m, 3H), 1.58-1.54 (m, 1 H). LC-MS: Method 3, Rt= 1.28 min; MS m / z 278.1 [M+H]+.

[0413] Int C09:1H NMR (400 MHz, DMSO-d6) 5 9.24 (dd, 1 H), 8.93 (d, 1 H), 8.01 (dd, 1 H), 7.63 (brs, 1 H), 4.40 (brs, 1 H), 3.23 (brs, 1 H), 2.90 (brs, 1 H), 2.55 (s, 3H), 2.44-2.38 (m, 2H), 2.04-1.94 (m, 1 H), 1.89-1.79 (m, 1 H), 1.73-1.44 (m, 2H). LC-MS: Method 3, Rt= 1.25 min; MS m / z 278.1 [M+H]+.

[0414] (R)-1-chloro-5-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine, Int C10

[0415] To a stirred solution of Int B01 (32 mg, 0.14 mmol) in DMSO (1.5 mL) were added N,N- diisopropylethylamine (0.15 mL, 0.83 mmol) and (R)-1-methylpiperidin-3-amine dihydrochloride salt (39 mg, 0.21 mmol). The reaction mixture was heated up to 100 °C and stirred for 2.5 h. The reaction mixture was diluted with water and lyophilized. The residue was dissolved in MeOH and adsorbed on isolute and purified by reverse phase column chromatography on C18 silica using acetonitrile, water and formic acid as additive to afford the title product, Int C10 as a yellow oil. LC-MS: Method 4, Rt= 0.94 min; MS m / z 308.0 [M+H]+.

[0416] (R)-1-chloro-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine, Int C11 and (R)-4-chloro-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1- amine, Int C12 PAT059896-PCT-SEC01 -62-

[0417] To a stirred solution of Int B02 (225 mg, 0.37 mmol) in DMSO (6.0 mL) were added N,N- diisopropylethylamine (0.26 mL, 1.49 mmol) and (R)-1-methylpiperidin-3-amine (63.7 mg, 0.56 mmol). The reaction mixture was heated up to 100 °C and stirred for 15 h. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layer was dried over a phase separator and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using DCM and MeOH (gradient from 0 to 10 %) to afford the title products as a mixture. LC-MS: Method 1 , Rt= 0.37 and 0.39 min; MS m / z 308.0 [M+H]+.

[0418] SYNTHESIS OF EXAMPLES

[0419] Example 1 : (R)-2,2-difluoro-5-(4-((1 -methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1 - yl)benzo[d][1 ,3]dioxol-4-ol

[0420] To a mixture of Int A01 (115 mg, 0.383 mmol, 1.2 eq), Int C01 (90 mg, 0.324 mmol, 1.0 eq) and XPhos Pd G4 (27.9 mg, 0.028 mmol, 0.1 eq) in THF (3.0 mL) under argon was added an aqueous solution of K3PO4 (1 mol / L, 0.972 mL, 0.972 mmol, 3.00 eq). The resulting mixture was heated at 70 °C for 18 h, cooled to room temperature and quenched with water. The aqueous layer was extracted with DCM / isopropanol 4:1 and the combined organic extracts were dried over Na2SC , filtered, and evaporated to give a dark brown foam, which was purified by column chromatography on silica gel (24 g) using MTBE and MeOH (from 0% to 100% gradient) to afford a yellow solid. The latter was triturated in EtOAc, filtered and concentrated in vacuo to give the title compound as a yellow powder.1H NMR (400 MHz, DMSO-de) 6 9.76 (d, 1 H), 8.81 (d, 1H), 7.61 (d, 1 H), 7.34 (dd, 1H), 7.14 (d, 1 H), 6.94 (d, 1 H), 4.49-4.42 (m, 1H), 3.12-3.08 (m, 1H), 2.74-2.72 (m, 1H), 2.23 (s, 3H), 2.06-1.90 (m, 3H), 1.80-1.75 (m, 1H), 1.66-1.57 (m, 1H), 1.51-1.41 (m, 1H). LC-MS: Method 2, Rt= 2.90 min; MS m / z 416.3 [M+H]+.

[0421] Alternatively, (R)-2,2-difluoro-5-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-

[0422] 1-yl)benzo[d][1,3]dioxol-4-ol may also be prepared according to the following procedure: PAT059896-PCT-SEC01 -63-

[0423] Under a nitrogen atmosphere, ethanol (8.5 L), Int C01 (0.71 kg, 2.6 mmol, 1 .0 eq), and Int A01 (0.92 kg, 3.1 mmol, 1.2 eq) were charged into a reactor and heated to 70 °C to 72 °C. XPhos Pd G4 (66 g, 0.08 mmol, 0.03 eq) followed by tripotassium phosphate (2 M aqueous solution, 7.6 mmol, 4 L) were charged keeping the internal temperature at 60 °C to 72 °C. The mixture was stirred for 12-18 hours at 70 °C to 72 °C, before being cooled to 10 °C to 15 °C. Dichloromethane (4 L) was added and the pH was adjusted to 1.5-2 with hydrochloric acid (2M aqueous solution). After phase separation, the aqueous layer was extracted with dichloromethane (5 L), and the combined organic layers were re-extracted with water (3 L). The combined aqueous layers were diluted with tert-amyl alcohol (4 L) and set to pH 11.5-12 with sodium hydroxide (6M aqueous solution) at 10 °C to 15 °C. After phase separation, the aqueous layer was extracted with tert-amyl alcohol (15 L) and the combined organic layers concentrated to a residue. The obtained residue was suspended in tetrahydrofuran (15 L) treated with a dimercaptotriazine (DMT; 1.2 kg) scavenger and stirred at 45 °C to 55 °C for 8 hours. The suspension was cooled to 20 °C to 25°C, filtered and the filtrate was concentrated. The obtained residue was then suspended in toluene (20 vol), heated to 100 °C to 110 °C, stirred for 2 h, cooled to 5 °C to 15 °C over a period of 4 hours, and filtered, to obtain a filter cake that was dried for 16 hours at 70 °C to 80 °C to afford the to afford the title compound.1H NMR (400 MHz, DMSO-d6) 5 9.78-9.74 (m, 1 H), 8.82 (d, 1 H), 7.62 (br d, 1 H), 7.34 (dd, 1 H), 7.14 (d, 1 H), 6.96 (d, 1 H), 4.50-4.40 (m, 1 H), 3.14-3.07 (m, 1 H), 2.73 (br d, 1 H), 2.23 (s, 3H), 2.04-1.88 (m, 3H), 1.83-1 .71 (m, 1 H), 1.69-1.53 (m, 1 H), 1 .52-1 .41 (m, 1 H). LC-MS: Method 5, Rt = 3.24 min; MS m / z 416.15262 [M+H]+.

[0424] The following examples were synthesized analogously to Example 1 , using the appropriate boronate intermediate (Int A) and the corresponding halo-pyridazine intermediate (Int C) respectively, applying catalyst / base conditions XPhos Pd G4, K3PO4 1 or 2M, THF (Cond A) or PdCl2(dppf).CH2Cl2, K2CO3, dioxane, water (Cond B).

[0425] When mixtures of intermediates “Int C” were used, the resulting mixtures of final products were separated using the separation methods below.

[0426] Preparative chiral SFC

[0427] Clumn: Chiralpak IB-N, 30 x 250 mm, 5 .m. Modifier A: 25%_MeOH + 0.05% ammonia. Flow rate: 86 mL / min.

[0428] Separation method B (Sep B): PAT059896-PCT-SEC01 -64-

[0429] Preparative HPLC

[0430] Column: Xbridge C18, 30 x 100 mm, 5 m. Solvent A: Water + 0.1 % TFA, Solvent B: Acetonitrile. Flow rate: 50 mL / min.

[0431] Fractions containing the desired products were neutralized with a saturated aqueous solution of NaHCOs and extracted with DCM. The combined organic layer was dried on a phase separator and concentrated in vacuo to afford the desired product.

[0432] Separation method C (Sep C):

[0433] Preparative chiral SFC Clumn: Chiralpak AD, 50 x 250 mm, 5 pm. Modifier A: 45%_MeOH + 0.05% ammonia. Flow rate: 120 mL / min. PAT059896-PCT-SEC01 -65- PAT059896-PCT-SEC01 -66- PAT059896-PCT-SEC01 -67- PAT059896-PCT-SEC01 -68-

[0434] BIOLOGICAL ASSAYS AND DATA

[0435] The activity of a compound according to the present disclosure can be assessed by the following in vitro methods. A compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, exhibits valuable pharmacological properties, e.g. properties susceptible to inhibit NLRP3 activity, e.g. as indicated in tests as provided in the next sections, and are therefore indicated for therapy related to NLRP3 inflammasome activity.

[0436] IL- 16 secretion assay:

[0437] Monocytic THP-1 cells (ATCC: TIB-202) were maintained according to providers’ instructions in RPMI media (RPMI / Hepes +10% fetal bovine serum + Sodium Pyruvate + 0.05 mM Betamercaptoethanol (1000x stock) + Pen-Strep). Cells were differentiated in bulk with 0.5 pM phorbol 12-myristate 13-acetate (PMA; Sigma # P8139) for 3 h, media was exchanged, and cells were plated at 50,000 cells per well in a 384-well flat-bottom cell culture plates (Greiner, #781986), and allowed to differentiate overnight. Compound in a 1 :3.16 serial dilution series in DMSO was added 1 :100 to the cells and incubated for 1 h. The NLRP3 inflammasome was activated with the addition of 15 pM (final concentration) Nigericin (Enzo Life Sciences, #BML- CA421-0005), and cells were incubated for 3 h. 10 pL supernatant was removed, and IL-10 levels were monitored using an HTRF (Homogeneous Time Resolved Fluorescence) assay (CisBio, #62IL1 PEC) according to manufacturers’ instructions. Viability and pyroptosis was monitored with the addition of PrestoBlue cell viability reagent (Life Technologies, #A13261) directly to the cell culture plate.

[0438] TNF-a secretion assay:

[0439] Monocytic THP-1 cells were maintained according to providers’ instructions in RPMI media as described above. Undifferentiated cells were plated at 50,000 cells per well in a 384-well flatbottom cell culture plates (Greiner, #781986), and allowed to rest overnight. Experimental compounds were prepared and added as described above. TNF-a secretion was triggered by the addition of either 1 pg / mL LPS (Sigma, #L4391) or 100 ng / mL Pam3CSK4 (Invivogen, #tlrl- pms) depending on the experiment, and cells were incubated for 3 h. 10 pL supernatant was removed, and TNF-a levels were monitored using an HTRF assay (CisBio, #62TNFPEC) according to manufacturers’ instructions. Viability was monitored as described above.

[0440] Data

[0441] IC50 values were calculated from the plot of percentage of inhibition versus the inhibitor concentration by a logistics fit according to: y = A2 + (A1 - A2) / (1 + (x / IC50)Ap) PAT059896-PCT-SEC01 -69- where y is the %-inhibition at the inhibitor concentration, x. A1 is the lowest inhibition value, i.e. 0%, and A2 the maximum inhibition value, i.e. 100%. The exponent, p, is the Hill coefficient. The curve fitting was conducted with an internally developed software suite.

[0442] NLRP3-dependent IL-ip secretion was stimulated in PMA-differentiated THP-1 cells by the addition of nigericin, and cytokines were measured in the serum after 3 h. As discussed above, activation of the NLRP3 inflammasome requires both an NF-kB-dependent priming step and the addition of a NLRP3 activator. To ensure that the inhibitors did not interfere with the priming step, Pam3CSK4-stimulated, NF-kB-dependent TNF-a secretion was monitored as a counter screen. Data for the inhibitory effect (IC50) of the compounds of the disclosure for both assays are given in the table below. Data for I L-1 p secretion was calculated as the geometric mean of at least 3 individual experiments, TNF-a data was from either one or two individual experiments.

Claims

PAT059896-PCT-SEC01 -70-CLAIMS1. A compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof,whereinR1aand R1 bare selected from H, F, Ci-C4alkyl and haloCi-C4alkyl;A1is N or CRA1;A2is N or CRA2;A3is N or CRA3;A4is N or CRA4; wherein no more than one of A1, A2, A3and A4are N;RA1, RA2, RA3and RA4are independently selected from H, Ci-C4alkyl, Ci-C4alkoxy and haloCi- C4alkyl;R2is selected from Ci-C4alkyl and Ci-C4-alkoxy-C2-C4alkyl;R3a, R3b, R3cand R3dare independently selected from H, F and Ci-C4alkyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR1aand R1 bare selected from H, F, CH3 and CF3;RA1, RA2, RA3and RA4are independently selected from H, Ci-C4alkyl, Ci-C4alkoxy and haloCi- C4alkyl;R2is selected from -CH3, -CH2CH3, -CH(CH3)2and -CH2CH2OCH3;R3a, R3b, R3cand R3dare independently selected from H, F and Ci-C4alkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR1ais H and R1bis H or CH3 or CF3; orR1ais F and R1bis H; orR1ais CH3and R1 bis H;RA1, RA2, RA3and RA4are independently selected from H and Ci-C4alkoxy;PAT059896-PCT-SEC01 -71-R2is selected from -CH3, -CH2CH3 and -CH(CHs)2;R3a, R3b, R3cand R3dare independently selected from H, F and CH3.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR1ais H;R1bis H or CH3;RA1, RA2, RA3and RA4are independently selected from H and Ci-C4alkoxy;R2is selected from CH3, -CH2CH3 and -CH(CHs)2;R3a, R3b, R3cand R3dare independently selected from H, F and CH3.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR2is CH3, R3a, R3b, R3cand R3dare H; orR2is CH3, R3bis F, R3a, R3cand R3dare H; orR2is CH3, R3dis CH3, R3a, R3band R3care H; orR2is CH3, R3cis CH3, R3a, R3band R3dare H.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IA)wherein * indicates a stereocenter with ( / ^-configuration.

7. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IB)PAT059896-PCT-SEC01 -72-wherein RA1is H or -OCH3, andRA3is H or -OCH3, and * indicates a stereocenter with ( / ^-configuration.

8. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IC)and * indicates a stereocenter with ( / ^-configuration.

9. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (ID)wherein * indicates a stereocenter with ( / ^-configuration.

10. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IE)PAT059896-PCT-SEC01 -73-wherein * indicates a stereocenter with ( / ^-configuration.11 . The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IF)wherein * indicates a stereocenter with ( / ^-configuration.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from (R)-2,2-difluoro-5-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1- yl)benzo[d][1 ,3]dioxol-4-ol;(R)-2,2-difluoro-5-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)benzo[d][1 ,3]dioxol-4-ol;(R)-5-(4-((1-ethylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2,2- difluorobenzo[d][1 ,3]dioxol-4-ol;(R)-5-(1-((1-ethylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-4-yl)-2,2- difluorobenzo[d][1 ,3]dioxol-4-ol;(R)-2,2-difluoro-5-(4-((1-isopropylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1- yl)benzo[d][1 ,3]dioxol-4-ol;(R)-2,2-difluoro-5-(1-((1-isopropylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-4- yl)benzo[d][1 ,3]dioxol-4-ol;(R)-2,2-difluoro-5-(5-((1-methylpiperidin-3-yl)amino)pyrido[2,3-d]pyridazin-8- yl)benzo[d][1 ,3]dioxol-4-ol;(R)-2,2-difluoro-5-(5-methoxy-4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1- yl)benzo[d][1 ,3]dioxol-4-ol;PAT059896-PCT-SEC01 -74-(R)-2,2-difluoro-5-(8-((1-methylpiperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5- yl)benzo[d][1,3]dioxol-4-ol; and (R)-2,2-difluoro-5-(7-methoxy-4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1- yl)benzo[d][1 ,3]dioxol-4-ol.

13. The compound according to claim 1, wherein the compound is of formula, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

15. A combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more therapeutic agents.

16. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 14, or the combination according to claim 11 , for use as a medicament.

17. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of a disease or disorder in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression, of said disease or disorder.

18. A method of treating a disease or disorder in which the NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression, of said disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof.

19. The compound for use according to claim 16 or 17, or the method of treating according to claim 18, wherein the disease or disorder is selected from inflammasome-related diseases I disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto- inflammatory diseases, for example, autoinflammatory fever syndromes (e.g cryopyrin-PAT059896-PCT-SEC01 -75- associated periodic syndrome), liver related diseases I 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 e.g acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, aseptic meningoencephalitis of autoimmune origin, migraine, brain infection, acute injury, traumatic brain disorders such as stroke and traumatic brain injury, neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, motor neuron disease, Huntington’s disease, multiple system atrophy, progressive supranuclear palsy, frontotemporal dementia, ataxia and neurodegenerative prion disease, psychiatric brain disorders such as depression, anxiety, autism, bipolar disorder and schizophrenia), cardiovascular / metabolic diseases I disorders (e.g. cardiovascular risk reduction (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 I disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis, chronic myelomonocytic leukemia (CM ML)).

20. A method of inhibiting the NLRP3 inflammasome activity in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof.

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