Therapeutic use of NLRP3 inflammasome pathway inhibitor compounds

Abstract

The present invention relates to compounds which are for use in the treatment, alleviation or prevention of obesity and / or a disease, disorder or abnormality associated therewith. In a further embodiment, the compounds are for use in reducing neuroinflammation, reducing microgliosis, and / or improving insulin sensitivity, preferably in an obese subject. In another embodiment, the compounds are for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation of IL-17A and / or IL36G. The compounds are NLRP3 inflammasome pathway inhibitors. In particular, the compounds inhibit the activation of a component of the NLRP3 inflammasome pathway. More particularly, the component of the inflammasome pathway is NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, in particular IL-1 beta and / or IL-18 levels are modulated thereby.

Description

[0001] New PCT application

[0002] AC Immune SA

[0003] Vossius Ref.: AK1880 PCT

[0004] THERAPEUTIC USE OF NLRP3 INFLAMMASOME PATHWAY INHIBITOR COMPOUNDS

[0005] FIELD OF THE INVENTION

[0006] The present invention relates to compounds which are for use in the treatment, alleviation or prevention of obesity and / or a disease, disorder or abnormality associated therewith. The compounds are NLRP3 inflammasome pathway inhibitors. In particular, the compounds inhibit the activation of a component of the NLRP3 inflammasome pathway. More particularly, the component of the inflammasome pathway is NOD-like receptor (NLR) family, pyrin domaincontaining protein 3 (NLRP3) inflammasome, in particular IL-1 beta and / or IL-18 levels are modulated thereby.

[0007] BACKGROUND OF THE INVENTION

[0008] Inflammasome protein complexes are the key components of inflammatory signalling. These complexes assemble in response to various danger signals such as molecules from infectious agents (pathogen-associated molecular patterns, PAMPs) as well as altered host molecules, products of sterile tissue damage and environmental factors (danger associated molecular patterns, DAMPs). The inflammasome family consists of NALP1-14, IPAF, and NAIP 1-6, with each family member providing specificity towards different PAMPs / DAMPs including nucleic acids, bacterial proteins, metabolites, protein aggregates and the activity of toxins (Sharma, D. & Kanneganti, T.D. The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J. Cell Biol. 213, 617-629 (2016)). Inflammasomes are typically composed of a sensor (a cytosolic pattern-recognition receptor, PRR) and an adaptor protein called apoptosis associated speck-like protein containing a caspase-recruitment domain (CARD) (ASC), and an effector such as the protease caspase-1 (Broz, P.; Dixit, V. M. Inflammasomes: Mechanism of Assembly, Regulation and Signalling. Nat. Rev. Immunol. 2016, 16, 407-420).

[0009] NLRP3 (NOD-like receptor (NLR) family, pyrin domain-containing protein 3) inflammasome is one of the best-described family members. It is a tripartite protein of the NLR family and contains an amino-terminal PYRIN (PYD) domain, a nucleotide-binding NACHT domain and a carboxyterminal leucine-rich repeat (LRR) domain. In response to various agents including aggregated proteins, crystals and altered cellular ion homeostasis, the NLRP3 sensor molecule assembles into a multi-molecular complex with apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC aka PYCARD) adaptor protein. ASC protein polymerization into a large complex (ASC speck) leads to activation of caspase-1 effector protein and subsequent cleavage of pro-IL-1 beta (P) and pro-IL18 into their active secreted forms and mediates pyroptosis (Heneka et al., 2018 Nat Rev Neurosci). IL-1 beta (P) acts through IL-1 beta (p) receptors, induces secondary pro-inflammatory signals including IL-6 and TNF alpha secretion, and attracts and activates cells of adaptive immune system at the sites of infection. NLRP3 / ASC complexes seems to be released into the extracellular environment where they can propagate inflammation.

[0010] NLRP3 inflammasome can be activated by saturated fatty acids, which are prevalent in obesity (Karasawa et al., 2018; Gianfrancesco et al., 2019). Prior studies have demonstrated that NLRP3- / - mice do not develop diet-induced obesity (Stienstra et aL, 2011 ). Furthermore, the administration of MCC950, a potent, peripherally restricted NLRP3 inhibitor, has been demonstrated to reduce weight gain in mice fed a high-fat diet (Pavillard et aL, 2017). The activation of microglia and astrocytes can predispose individuals to excessive weight gain by impairing operation of the hypothalamic energy homeostasis system (Yoo et aL, 2020; Douglass et aL, 2023; Sonnefeld et aL, 2023) potentially linked to excessive dietary saturated fatty acids into cerebrospinal fluid (Melo et aL, 2020) promoting inflammatory activation of hypothalamic microglia (Milanski et aL, 2009; Valdearcos et aL, 2014; Folick et aL, 2022). Recently, two structurally distinct (sulfonylurea) NLRP3 inhibitors (NT-0249 and NT-0796) were reported to reverse obesity in the diet-induced obesity (DIO) mouse model (Thornton et aL, 2024) although no effect on microglia has been reported.

[0011] Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition where pro-inflammatory singalling pathways related to IL-17 and IL-36 play an important pathogenic role (Kimball et al. 2023, The Lancet; Alavi et aL 2023, The Journal of Cutaneous Medicine). HS has also been strongly linked to obesity. Studies have shown that obesity exacerbates the severity and frequency of HS flare-ups due to increased mechanical stress on the skin and the pro- inflammatory state associated with excess adipose tissue (Diaz et aL, 2022 Current Dermatology Reports; Ingram et aL 2024 Hidradenitis Suppurativa from Rook’s Textbook of Dermatology 10lhEd.). The inflammatory milieu in obese individuals, characterized by elevated levels of cytokines such as TNF and IL-6, contributes to the pathogenesis of HS.

[0012] The NLRP3 inflammasome plays a crucial role in the innate immune response in HS by promoting the maturation and secretion of pro-inflammatory cytokines like IL-1 p. The peripherally restricted NLRP3 inhibitor MCC950 has been shown to reduce inflammation in HS skin explants by blocking NLRP3 activation, thereby mitigating the downstream inflammatory cascade (Moran et al, 2023 Br J Dermatol).

[0013] Over the past few years several small molecules have been shown to inhibit the NLRP3 inflammasome pathway (Baldwin, A. G., Brough, D. & Freeman, S. Inhibiting the NLRP3 inflammasome pathway: a chemical perspective. J. Med. Chem. 59, 1691-1710 (2016); reviewed in Mangan etal., Nat Rev Drug Discov. 2018 Aug;17(8):588-606). These include various chemical classes such as sulfonylurea-based compounds (glyburide, CP-456,773 (aka CRID3 and MCC950) and its derivatives); fenamate classes of non-steroidal anti-inflammatory drugs; hydroxysulfonamide analogue JC-171 ; novel boron compound series; benzimidazole-containing structure Fc11a-2; polyketide spirodalesol; acrylate and acrylamide derivatives; 3,4-methylenedioxy-P-nitrostyrene; P-sulfonyl nitrile molecule OLT1177; CY-09; BOT-4-one; and Michael acceptors. Most of these compounds have a promiscuous mode of action and limited potency.

[0014] W02016 / 131098, WO2017 / 140778 and WO2018 / 215818 refer to sulfonylurea and related compounds and their use in treating or identifying a disease or condition responsive to inhibition of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.

[0015] WO2019 / 008025, WO2019 / 008029, WO2019 / 034686, WO2019 / 034688, WO2019 / 034690, WO2019 / 034692, WO2019 / 034693, WO2019 / 034696, WO2019 / 034697, WO2019 / 068772, WO2019 / 092170, WO2019 / 092171 and WO2019 / 092172 refer to compounds (e.g. sulfonylureas, sulfonylthioureas, sulfoximine ureas and sulfoximine thioureas) useful in the treatment and prevention of medical disorders and diseases, most especially by NLRP3 inhibition.

[0016] WO2017 / 184604, WO2017 / 184623, WO2017 / 184624, WO2019 / 023145, WO2019 / 023147 and WO2019 / 079119 refer to chemical entities that are useful for treating a condition, disease, or disorder in which a decrease or increase in NLRP3 activity contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder in a subject.

[0017] WO2019 / 211463, W02020 / 021447, and WO2021 / 043966, WO2021 / 239885, WO2021 / 219784, WO2021 / 214284, WO2021 / 209552, and WO2021 / 209539 disclose compounds for inhibiting NLRP3 and / or NLRP3 inflammasome pathway.

[0018] WO2018 / 136890 refers to sulfonylurea and sulfonyl thiourea compounds and their use in treating a disease or condition responsive to modulation of cytokines such as IL-1 beta (p) and IL-18, modulation of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.

[0019] WO2018 / 225018 and WO2019 / 043610 refer to NLRP3 modulators as well as to the use of the compounds in the treatment of diseases or conditions as well as treatment of disease states mediated by NLRP3 as well as treatment of diseases or conditions in which interleukin 1 beta ( ) activity and interleukin-18 (IL-18) are implicated.

[0020] WO2018 / 015445 refers to sulfonylurea compounds which possess inflammasome inhibitory activity.

[0021] W02020 / 018975 discloses sulfonimidamide derivatives defined as inhibitors of interleukin-1 activity and NLRP3 modulators.

[0022] WO2020 / 234715 discloses pyridazine-3-yl phenol compounds defined as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome activity.

[0023] WO2021 / 193897 refers to substituted pyridazine compounds that are described as having suppressive action on NLRP3 inflammasome activity.

[0024] WO2024 / 013395, WO2023 / 278438, WO2023 / 186020, W02024 / 041460, WO2023 / 159148, WO2023 / 028534, WO2023 / 051761 , and WO2023 / 088856 describe compounds for inhibiting NLRP3 inflammasome pathway.

[0025] SUMMARY OF THE INVENTION

[0026] The present invention relates to NLRP3 inflammasome pathway inhibitor compounds which have surprisingly been found to be beneficial in the treatment, alleviation or prevention of obesity, particularly diet-induced obesity, and / or diseases, disorders or abnormalities associated therewith.

[0027] Various embodiments of the invention are described herein.

[0028] In one aspect there is provided an NLRP3 inflammasome pathway inhibitor compound of formula (I) or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; for use in the treatment, alleviation or prevention of obesity, particularly diet-induced obesity, and / or diseases, disorders or abnormalities associated therewith.

[0029] Particularly suitable NLRP3 inflammasome pathway inhibitor compounds include compounds described in WO2024 / 013395. In one aspect the inflammasome pathway inhibitor compound is or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, particularly (compound 1) or a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof. It has surprisingly been found for the first time that an NLRP3 inflammasome pathway inhibitor compound according to formula (I), particularly compound 1, has beneficial activity for the treatment, alleviation or prevention of obesity, particularly diet-induced obesity, and / or a disease, disorder or abnormality associated therewith.

[0030] Importantly, it has surprisingly been shown for the first time that an NLRP3 inflammasome pathway inhibitor compound according to formula (I), particularly compound 1, has beneficial effects for not only on reducing body weight, reducing fat mass, improving glucose metabolism, reducing total cholesterol, reducing liver fibrosis and / or reducing liver inflammation, but also on reducing microgliosis in the brain of an obese subject. This observed effect on the reduction of obesity induced neuroinflammation in the brain of an obese subject has not previously been reported with another NLRP3 inflammasome pathway inhibitor compound.

[0031] In particular, it has been surprisingly found that the NLRP3 inflammasome pathway inhibitor compound according to formula (I), particularly compound 1, has beneficial activity for reducing neuroinflammation, reducing microgliosis, reducing astrocytosis, improving insulin sensitivity, improving glucose metabolism, reducing body weight, reducing fat mass, reducing insulin resistance, reducing fasting glucose, reducing total cholesterol, reducing inflammation, reducing liver fibrosis and / or reducing liver inflammation in vivo.

[0032] Accordingly, in one aspect the invention relates to the use of NLRP3 inflammasome pathway inhibitor compounds according to formula (I) in reducing neuroinflammation, reducing microgliosis, reducing astrocytosis, improving insulin sensitivity, improving glucose metabolism, reducing body weight, reducing fat mass, reducing insulin resistance, reducing fasting glucose, reducing total cholesterol, reducing inflammation, reducing liver fibrosis and / or reducing liver inflammation, preferably in an obese subject.

[0033] It has surprisingly been shown for the first time that an NLRP3 inflammasome pathway inhibitor compound has beneficial effects for reducing microgliosis, reducing neuroinflammation, and improving insulin sensitivity in vivo in an obese subject.

[0034] Accordingly in another aspect the invention relates to the use of an NLRP3 inflammasome pathway inhibitor compound in reducing neuroinflammation, reducing microgliosis, and / or improving insulin sensitivity, in an obese subject.

[0035] In one aspect the invention relates to the use of an NLRP3 inflammasome pathway inhibitor compound in reducing microgliosis, in an obese subject. Furthermore, it has been found that the NLRP3 inflammasome pathway inhibitor compound according to formula (I), particularly compound 1 , has beneficial activity for modulating the IL-1 (3 downstream pathways, in particular for modulating the pathogenic cytokines IL-17A and IL-36G.

[0036] Accordingly, in one aspect the invention relates to the use of NLRP3 inflammasome pathway inhibitor compounds according to formula (I) for the treatment, alleviation or prevention of a disease, or a disorder or an abnormality which is responsive to the modulation of IL-17A and / or IL-36G levels. A number of diseases, disorders or abnormalities have been shown to be responsive to modulation of IL-17A and / or IL-36G levels, for example, a disease, disorder, or abnormality of the skin such as hidradenitis suppurativa (HS), psoriasis, generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), acute generalized exanthematous pustulosis (AGEP), PAPA (pyogenic arthritis, PG and acne), PASH (PG, acne and suppurative hidradenitis), PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis), papulopustular rosacea or acne.

[0037] In one aspect the invention relates to the use of NLRP3 inflammasome pathway inhibitor compounds according to formula (I) for the treatment, alleviation or prevention of hidradenitis suppurativa (HS), preferably in an obese patient.

[0038] In one aspect the invention relates to the use of NLRP3 inflammasome pathway inhibitor compounds according to formula (I) for the treatment, alleviation or prevention of comorbid hidradenitis suppurativa (HS) and obesity.

[0039] In a particular aspect the invention relates to the use of NLRP3 inflammasome pathway inhibitor compounds according to formula (I) for the treatment, alleviation or prevention of hidradenitis suppurativa (HS) with comorbid obesity.

[0040] In a further aspect, the present invention provides a kit comprising the NLRP3 inflammasome pathway inhibitor compound of formula (I) or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof as well as a glucagon-like peptide-1 (GLP-1) receptor agonist such as semaglutide.

[0041] BRIEF DESCRIPTION OF THE FIGURES

[0042] Figure 1. Schematic of the study timeline for study Groups 2 to 5.

[0043] Figure 2. A) Body weight (Day 0) and B) fat tissue weight (Day -5) of the five study groups after randomization of the HFD-fed mice into Groups 2-5 (respectively Obese control, semaglutide, Compound 1 low dose and high dose). Mean + SEM. Ordinary one-way ANOVA followed by Dunnett’s multiple comparisons test, only the comparison of Obese control vs each of the four other study groups is shown, p-value significance threshold: **** <0.0001 , *** <0.001 , ** <0.01 ,

[0044] * <0.05.

[0045] Figure 3. Evolution of mice body weight during the study in A) gram or B) in % change from baseline Day 0 weight. Mean ± SEM.

[0046] Figure 4. Comparison of SCD-fed and HFD-fed mice A) bone mass, B) lean mass and C) fat mass on Day -5. Mean ± SEM. Unpaired t-test. p-value significance threshold: **** <0.0001 , *** <0.001 , ** <0.01 , * <0.05.

[0047] Figure 5. A) Bone mass, B) lean mass and C) fat mass for the 5 study groups on Day -5 (Baseline = B) and Day 24 (Endpoint = E). Mean ± SEM. Two-way ANOVA followed by Tukey’s multiple comparisons test (B vs E). p-value significance threshold: **** <0.0001 , *** <0.001 , ** <0.01,

[0048] * <0.05.

[0049] Figure 6. Blood concentration of A) glucose and B) insulin for the 5 study groups on Day -3 (Baseline = B) and Day 27 (Endpoint = E) after 4h fasting period. Mean ± SEM. Two-way ANOVA followed by Dunnett’s multiple comparisons test. The comparison of Obese control vs each of the four other study groups is shown with the p-value significance threshold: **** <0.0001 , *** <0.001 , ** <0.01 , * <0.05. A significant difference in baseline vs endpoint for each of the study group is shown by # meaning p-value is at least <0.05.

[0050] Figure 7. Homeostasis Model Assessment - Insulin Resistance (HOMA-IR) index for the 5 study groups on Day 27. Mean ± SEM. Ordinary one-way ANOVA followed by Dunnett’s multiple comparisons test, only the comparison of Obese control vs each of the four other study groups is shown, p-value significance threshold: **** <0.0001 , *** <0.001 , ** < 0.01, * <0.05.

[0051] Figure 8. A) Evolution of blood glucose concentrations during the oral glucose tolerance test (OGTT) on Day 26 for the 5 study groups. Mean ± SEM. B) Quantification of the area under the curve (AUC) of the blood glucose concentrations during OGTT. Mean ± SEM. Ordinary one-way ANOVA followed by Dunnett’s multiple comparisons test, only the comparison of Obese control vs each of the four other study groups is shown, p-value significance threshold: **** <0.0001 , *** <0.001 , ** <0.01 , * <0.05.

[0052] Figure 9. Liver mass at study endpoint (Day 29) for the 5 study groups. Mean ± SEM. Ordinary one-way ANOVA followed by Dunnett’s multiple comparisons test, only the comparison of Obese control vs each of the four other study groups is shown, p-value significance threshold: **** <0.0001 , *** <0.001 , ** <0.01, * <0.05.

[0053] Figure 10. Quantification of GFAP positive cells in the A) DMH, B) VMH and C) ARC for the five study groups at study endpoint (Day 29). Mean ± SEM. Kruskal-Wallis test followed by uncorrected Dunn’s test for A) and B). Ordinary one-way ANOVA followed by uncorrected Fischer LSD for C). p-value significance threshold: **** <0.0001 , *** <0.001 , ** <0.01 , * <0.05. Figure 11. Quantification of IBA1 positive cells in the A) DMH, B) VMH and C) ARC for the five study groups at study endpoint (Day 29). Mean ± SEM. Kruskal-Wallis test followed by uncorrected Dunn’s test for A) and B). Ordinary one-way ANOVA followed by uncorrected Fischer LSD for C). p-value significance threshold: **** <0.0001 , *** <0.001 , ** <0.01 , * <0.05.

[0054] Figure 12. (A) Quantification of IL-1 p production by skin explant halves, treated with either vehicle or Compound 1. p-value = 0.0039 from two-tailed paired t-test. (B) Percent inhibition of IL-10 production by Compound 1 relative to its corresponding vehicle treated half.

[0055] Figure 13. Schematic of the study timeline for study Groups 1 to 4.

[0056] Figure 14. Evolution of mice body weight during the study in A) gram or B) in % change from baseline Day 0 weight. Mean ± SD.

[0057] Figure 15. Evolution of mice cumulative food intake during the study. Mean ± SD. Two-way ANOVA followed by Dunnett’s multiple comparisons test. The comparison on Day 28 of vehicle vs each of the three other study groups is shown with the p-value significance threshold: * <0.0001 . The comparison between Compound 1 plus semaglutide and semaglutide or Compound 1 groups is shown with the p-value significance threshold: § < 0.01 .

[0058] Figure 16. Plasma levels of total cholesterol for the 4 study groups on Day -3 (Baseline = B) and Day 71 (Endpoint = E) after 4h fasting period. Mean ± SD. Two-way ANOVA followed by Dunnett’s multiple comparisons test. The comparison of vehicle vs each of the three other study groups on Day 71 is shown with the p-value significance threshold: ** <0.01 , * <0.05. A significant difference in baseline vs endpoint for each of the study group is shown with the p-value significance threshold: # <0.05.

[0059] Figure 17. Plasma levels of A) IL-1 RA and B) GFAP for the four study groups at study endpoint (Day 29). Mean ± SD. Ordinary one-way ANOVA followed by Dunnett’s multiple comparisons test, p-value significance threshold: ** <0.01 , * <0.05.

[0060] Figure 18. Heatmap representing fold-change (Iog2 scale, mean S.E.M.) in c-Fos positive cell counts in selected brain regions compared to DIO mice vehicles control group. Dunnett’s test negative binomial generalized linear model with p-value adjustment for multiple comparisons using FDR < 0.05 was applied for statistical analysis (* at least p<0.05 vs vehicles; * at least p<0.05 vs semaglutide chronic treatment group). Statistics were reported only for exemplified regions.

[0061] DETAILED DESCRIPTION OF THE INVENTION

[0062] The present invention refers to an NLRP3 inflammasome pathway inhibitor compound of formula (I)

[0063] for use in the treatment, alleviation or prevention of obesity and / or a disease, disorder or abnormality associated therewith.

[0064] The present invention also relates to a method of treating, alleviating or preventing obesity and / or a disease, disorder or abnormality associated therewith comprising administering a therapeutically effective amount of an NLRP3 inflammasome pathway inhibitor compound of formula (I) to a subject in need thereof.

[0065] In a further aspect, the present invention relates to the use of an NLRP3 inflammasome pathway inhibitor compound of formula (I) for the manufacture of a medicament for treating, alleviating or preventing obesity and / or a disease, disorder or abnormality associated therewith.

[0066] In another aspect, the present invention relates to an NLRP3 inflammasome pathway inhibitor compound, preferably an NLRP3 inflammasome pathway inhibitor compound of formula (I), for use in reducing neuroinflammation, reducing microgliosis, and / or improving insulin sensitivity, preferably in an obese subject.

[0067] The present invention also relates to a method of reducing neuroinflammation, reducing microgliosis, and / or improving insulin sensitivity, preferably in an obese subject, comprising administering a therapeutically effective amount of an NLRP3 inflammasome pathway inhibitor compound, preferably an NLRP3 inflammasome pathway inhibitor compound of formula (I), to a subject in need thereof.

[0068] In a further aspect, the present invention relates to the use of an NLRP3 inflammasome pathway inhibitor compound, preferably an NLRP3 inflammasome pathway inhibitor compound of formula (I), for the manufacture of a medicament for reducing neuroinflammation, reducing microgliosis, and / or improving insulin sensitivity, preferably in an obese subject. In another aspect, the present invention relates to an NLRP3 inflammasome pathway inhibitor compound of formula (I) for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation of IL-17A and / or IL36G.

[0069] The present invention also relates to a method of treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation of IL-17A and / or IL36G comprising administering a therapeutically effective amount of an NLRP3 inflammasome pathway inhibitor compound of formula (I) to a subject in need thereof.

[0070] In a further aspect, the present invention relates to the use of an NLRP3 inflammasome pathway inhibitor compound of formula (I) for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation of IL-17A and / or IL36G.

[0071] Throughout the present specification the term "compound of formula (I)" is intended to cover all compounds of formula (I) as well as a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.

[0072] Zi and Z2 are each selected from N and C whereby if Z1 is N, Z2 is C, and if Z1 is C, Z2 is N, In one aspect, Z1 is N and Z2 is C. In another aspect, Z1 is C, Z2 is N.

[0073] V, X and E are each independently selected from N and CRa, wherein at least one of V, X and E is CRa;

[0074] V is selected from N and CRa. In one aspect, V is N. In a further aspect, V is CRa.

[0075] X is selected from N and CRa. In one aspect, X is N. In a further aspect, X is CRa.

[0076] E is selected from N and CRa. In one aspect, E is N. In a further aspect, E is CRa.

[0077] In a preferred aspect, V and X are CRa. In a further preferred aspect, V and X are CRa and E is

[0078] N.

[0079] Ra is independently selected from the group consisting of -H, -C-i-Csalkyl, -CF3and halo, preferably Ra is independently selected from the group consisting of -H and -Ci-Csalkyl, more preferably Ra is -H. Ro is selected from the group consisting of -H, -Ci-Csalkyl and -halo, preferably Ro is selected from the group consisting of -H and -Ci-Csalkyl, more preferably Ro is H.

[0080] Ri is selected from the group consisting of -CF3, -Ci-Csalkyl, -OCF3, -OCHF2, -CN and -halo, preferably R1 is selected from the group consisting of -CF3, -Cl, -CH3 or -CN, more preferably R1 is -CF3.

[0081] R2 is selected from the group consisting of -OH, -H, -OCF3, -OCHF2, -Ci-Csalkyl, -halo and -CF3, preferably R2 is -OH.

[0082] R3 is selected from the group consisting of -H, -Ci-Gsalkyl, -OH, -CF3 and -halo, preferably R3 is selected from the group consisting of -H, and -CrCsalkyl, more preferably R3 is -H.

[0083] R4 is selected from the group consisting of -H, -Ci-Csalkyl, -CF3and -halo, preferably R4 is selected from the group consisting of -H, and -Ci-Gsalkyl, more preferably R4 is -H.

[0084] Y is selected from NH, O, NRc or a bond, preferably Y is selected from NH and NRc, more preferably Y is NH.

[0085] Rc is Ci-C4alkyl.

[0086] RA is selected from the group consisting of a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is / are independently selected from N and O; a 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein said heteroatom(s) is / are N or O; a 5- or 6-membered aryl; a 5- or 6-membered heteroaryl, wherein heteroaryl contains one or two heteroatoms, wherein said heteroatom(s) is / are N; a Cs-Cecycloalkyl; and a Ci-Cealkyl; wherein the spiro or fused heterocycloalkyl bicyclic moiety, the heterocycloalkyl, the aryl, the heteroaryl, the Cs-Cecycloalkyl, or the C-i-Cealkyl is optionally substituted at any available position with one to three substituents which are independently selected from the group consisting of Ci-C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl, hydroxyCi-C4alkyl, halo, -OH, -CN, -NRdRe, -Ci-C4alkyl-NRdRe, and a 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms selected from N and O, wherein Rd and Re are each independently selected from the group consisting of H and Ci-C4alkyl.

[0087] Preferably RA is selected from the group consisting of

[0088] (i) a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is / are independently selected from N and O, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, hydroxyCi-C4alkyl, -OH and halo;

[0089] (ii) 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein said heteroatom(s) is / are N or O, wherein the heterocycloalkyl is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, hydroxyCi-C4alkyl, -OH, halo, -NRdRe, -Ci-C4alkyl-NRdRe, 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms selected from N and O, wherein Rd and Re are each independently selected from the group consisting of H and Ci-C4alkyl;

[0090] (iii) 5- or 6-membered aryl, wherein the aryl is optionally substituted at any available position with one or two substituents independently selected from the group consisting of Ci-C4alkyl, hydroxyCi-C4alkyl, haloCi-C4alkyl, -CN, -OH and halo;

[0091] (iv) 5- or 6-membered heteroaryl, wherein heteroaryl contains one or two heteroatoms, wherein said heteroatom(s) is / are N, wherein the heteroaryl is optionally substituted at any available position with one or two substituents independently selected from the group consisting of Ci-C4alkyl, hydroxyCi-C4alkyl, haloCi-C4alkyl, -CN, -OH and halo;

[0092] (v) Cs-Cecycloalkyl optionally substituted at any available position with one or two substituents independently selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, hydroxyCi-C4alkyl, -OH and halo; and

[0093] (vi) Ci-Cealkyl substituted at any available position with one or two substituents independently selected from the group consisting of -OH, halo, haloCi-C4alkyl, hydroxyCi-C4alkyl, and Ci-C4alkoxy.

[0094] In one aspect, RA is selected from the group consisting of

[0095] (i) a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is / are independently selected from N and O, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of Ci-C4alkyl, haloCi-Qialkyl, hydroxyCi-C4alkyl, -OH and halo.

[0096] In one aspect, RA is selected from the group consisting of

[0097] (ii) 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein said heteroatom(s) is / are N or O, wherein the heterocycloalkyl is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, hydroxyCi-C4alkyl, -OH, halo, -NRdRe, -Ci-C4alkyl-NR Re, 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms selected from N and O, wherein Rd and Re are each independently selected from the group consisting of H and Ci-C4alkyl. Examples of possible groups include

[0098] Re is independently selected from -H, -Ci-Caalkyl, -CH2-NRdRe, Ci-C4alkyl-OH, and a 4-, 5- or 6- membered heterocycloalkyl containing one heteroatom selected from N and O, preferably Re is independently selected from -H, -Ci-Csalkyl, and a 4-, 5- or 6-membered heterocycloalkyl containing one heteroatom selected from N and O. R* is one to three (preferably one or two, more preferably one) substituents which are attached at any available position and are independently selected from the group consisting of Ci-C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl, hydroxyCi-C4alkyl, halo, -OH, -CN, -NRdRe, -Ci-C4alkyl-NRdRe, and a 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms selected from N and O. In another embodiment, R* is absent.

[0099] Rd and Re are each independently selected from the group consisting of H and -Ci-Caalkyl.

[0100] Re is independently selected from -H, -Ci-Csalkyl, -CH2-NRdRe, Ci-C4alkyl-OH, and a 4-, 5- or 6- membered heterocycloalkyl containing one heteroatom selected from N and O, preferably Re is independently selected from -H, -Ci-Csalkyl, and a 4-, 5- or 6-membered heterocycloalkyl containing one heteroatom selected from N and O.

[0101] R? and Rs are each independently selected from the group consisting of H, halo and Ci-Csalkyl.

[0102] Rd and Re are each independently selected from the group consisting of H and -Ci-Caalkyl. In a preferred aspect, examples include

[0103] Rs is independently selected from -H, -Ci-Csalkyl, -CH2-NRdRe, Ci-C4alkyl-OH, and a 4-, 5- or 6- membered heterocycloalkyl containing one heteroatom selected from N and O, preferably Rs is independently selected from -H, -Ci-Csalkyl, and a 4-, 5- or 6-membered heterocycloalkyl containing one heteroatom selected from N and O.

[0104] R7and Rs are each independently selected from the group consisting of H, halo and Ci-Csalkyl.

[0105] Rd and Re are each independently selected from the group consisting of H and -Ci-Csalkyl.

[0106] Examples include In one aspect, RA is selected from the group consisting of

[0107] (iii) 5- or 6-membered aryl or heteroaryl, wherein heteroaryl contains one or two heteroatoms, wherein said heteroatom(s) is / are N, wherein the aryl or heteroaryl is optionally substituted at any available position with one or two substituents independently selected from the group consisting of Ci-C4alkyl, hydroxyCi-C4alkyl, haloCi-C4alkyl, -CN, -OH and halo.

[0108] Examples include

[0109] R* is one to three substituents (preferably one or two, more preferably one) which are attached at any available position and are independently selected from the group consisting of Ci-C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl, hydroxyCi-C4alkyl, halo, -OH, -CN, -NRdRe, -Ci-C4alkyl-NRdRe, and a 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms selected from N and O. In another embodiment, R* is absent.

[0110] In one aspect, RA is selected from the group consisting of

[0111] (iv) Cs-Cecycloalkyl optionally substituted at any available position with one or two substituents independently selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, hydroxyCi-C4alkyl, -OH and halo; and

[0112] Examples include

[0113] R* is one to three substituents (preferably one or two, more preferably one) which are attached at any available position and are independently selected from the group consisting of Ci-C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl, hydroxyCi-C4alkyl, halo, -OH, -CN, -NRdRe, -Ci-C4alkyl-NRdRe, and a 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms selected from N and O. In another embodiment, R* is absent.

[0114] A preferred example includes

[0115] R? is selected from the group consisting of H, halo and Ci-Csalkyl, preferably R7 is selected from the group consisting of Ci-Csalkyl, more preferably R7 is methyl.

[0116] In one aspect, RA is selected from the group consisting of

[0117] (v) Ci-Cealkyl substituted at any available position with one or two substituents independently selected from the group consisting of -OH, halo, haloCi-C4alkyl, hydroxyCi-C4alkyl, and Ci-C4alkoxy.

[0118] The Ci-Cealkyl can be optionally substituted by R*, wherein R* is one to three substituents (preferably one or two, more preferably one) which are attached at any available position and are independently selected from the group consisting of Ci-C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl, hydroxyCi-C4alkyl, halo, -OH, -CN, -NRdRe, -Ci-C4alkyl-NRdRe, and a 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms selected from N and O. In another embodiment, R* is absent.

[0119] Preferred examples include n is selected from 0, 1 and 2.

[0120] A preferred compound having the formula (I) is or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, preferably

[0121] (R)-2-(8-((1-methylpiperidin-3-yl)amino)imidazo[1,2-d][1,2,4]triazin-5-yl)-5-

[0122] (trifluoromethyl)phenol

[0123] Compound 1 or a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.

[0124] The compounds having the formula (I) can be used to treat, alleviate or prevent obesity and / or a disease, disorder or abnormality associated therewith. The term "disease" will be used for brevity in the following and it is understood that "diseases", "disorders" and "abnormalities" are intended to be covered by this term.

[0125] According to the definitions provided by the World Health Organisation (WHO), persons are classified as being obese or overweight. Since overweight persons also have an increased risk of metabolic complications, within the present invention the term "obesity" includes obesity and overweight. In the present invention, the definitions provided by the WHO apply (https: / / www.who.int / news-room / fact-sheets / detail / obesity-and-overweight). For adults, the WHO defines overweight and obesity as follows: overweight is a BMI greater than or equal to 25; and obesity is a BMI greater than or equal to 30.

[0126] The definitions for children depend on their age.

[0127] For children under 5 years of age

[0128] • overweight is weight-for-height greater than 2 standard deviations above WHO Child Growth Standards median; and • obesity is weight-for-height greater than 3 standard deviations above the WHO Child Growth Standards median.

[0129] For children aged between 5-19 years

[0130] • overweight is BMI-for-age greater than 1 standard deviation above the WHO Growth Reference median; and

[0131] • obesity is greater than 2 standard deviations above the WHO Growth Reference median.

[0132] In the present invention, obesity is typically diet-induced obesity.

[0133] Diseases, disorders or abnormalities associated with obesity include but are not limited to

[0134] • metabolic syndrome;

[0135] • diabetes and diabetic diseases (such as type 2 diabetes, prediabetes, insulin resistance syndrome);

[0136] • cardiovascular diseases (such as hypertension, stroke, microvascular dysfunction, cardiac dysfunction, myocardial infarction, heart failure, and atherosclerotic cardiovascular diseases (including coronary heart disease, coronary artery disease, cerebrovascular disease, peripheral artery disease, peripheral vascular disease, coronary atherosclerosis and calcification);

[0137] • diseases associated with increased blood lipid levels (such as hyperlipidemia, including hypertriglyceridemia, hyperlipoproteinemia, non-alcoholic fatty liver disease, and lipodystrophy),

[0138] • chronic inflammation associated with obesity,

[0139] • microgliosis, astrocytosis and liver fibrosis; and

[0140] • skin diseases such as hidradenitis suppurativa (HS).

[0141] Metabolic syndrome is a disorder which is typically associated with the risk of developing cardiovascular disease (such as heart disease and stroke) and type 2 diabetes. It is characterized by at least three of the following five medical conditions: abdominal obesity, high blood pressure (e.g., 130 mm Hg or more systolic pressure or 80 mm Hg or more diastolic pressure), hyperglycemia, high serum triglycerides (e.g., 200 mg / dL or more), and low serum high-density lipoprotein (HDL) (e.g., 40 mg / dl or less).

[0142] In particular, the compounds having the formula (I) are suitable for reducing neuroinflammation, reducing microgliosis, reducing astrocytosis, improving insulin sensitivity, improving glucose metabolism, reducing body weight, reducing fat mass, reducing insulin resistance, reducing fasting glucose, reducing total cholesterol, reducing inflammation, reducing liver fibrosis and / or reducing liver inflammation, preferably in an obese subject. Preferably the compounds having the formula (I) are suitable for reducing neuroinflammation, reducing microgliosis, reducing astrocytosis, improving insulin sensitivity and / or improving glucose metabolism, preferably in an obese subject. More preferably, the compounds having the formula (I) are suitable for reducing neuroinflammation, reducing microgliosis, and / or improving insulin sensitivity, in an obese subject, more particularly for reducing microgliosis, preferably in an obese subject.

[0143] In a further embodiment, the compounds having the formula (I) are suitable for improving insulin sensitivity, improving glucose metabolism, reducing body weight, reducing fat mass, reducing insulin resistance, and / or reducing fasting glucose, preferably in an obese subject, particularly they have been shown to improve insulin sensitivity.

[0144] As described herein, the compounds of the present invention may be for use in “reducing neuroinflammation”, “reducing microgliosis”, “reducing astrocytosis”, “improving insulin sensitivity”, “improving glucose metabolism”, “reducing body weight”, “reducing fat mass”, “reducing insulin resistance”, “reducing fasting glucose”, “reducing total cholesterol”, “reducing inflammation”, “reducing liver fibrosis” and / or “reducing liver inflammation”, wherein the reduction or improvement in a subject, preferably an obese subject, is relative to the status prior to the treatment with a compound of the present invention.

[0145] The compounds having the formula (I) can be used in the treatment, prevention or alleviation of a disease, or a disorder or an abnormality which is responsive to the modulation of IL-17A and / or IL-36G levels. Diseases, disorders or abnormalities responsive to the modulation of IL-17A and / or IL-36G levels include but are not limited to skin diseases such as hidradenitis suppurativa (HS), psoriasis, generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), acute generalized exanthematous pustulosis (AGEP), PAPA (pyogenic arthritis, PG and acne), PASH (PG, acne and suppurative hidradenitis), PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis), papulopustular rosacea or acne.

[0146] In one embodiment, the compounds having the formula (I) can be used to treat, alleviate or prevent hidradenitis suppurativa (HS), preferably in an obese subject. In a particular embodiment, the compounds having the formula (I) can be used to treat, alleviate or prevent hidradenitis suppurativa (HS) with comorbid obesity.

[0147] It is understood that all combinations of the various aspects and preferred embodiments are envisaged in the present invention.

[0148] PHARMACEUTICAL COMPOSITIONS

[0149] While it is possible for the compounds of the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof, to be administered alone, it is preferable to formulate them into a pharmaceutical composition in accordance with standard pharmaceutical practice. Thus, the invention also provides a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof, optionally in admixture with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0150] The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention (i.e. a compound of formula (I), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof) 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, a disorder or an abnormality, etc. In one embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject in need thereof (e.g. a patient), is effective to at least partially alleviate, prevent and / or ameliorate a disease, a disorder, or an abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway or which is responsive to the modulation, in particular decrease, of IL-1 beta and / or IL-18.

[0151] Pharmaceutically acceptable carriers, diluents, adjuvants and excipients are well known in the pharmaceutical art and are described, for example, in Remington’s Pharmaceutical Sciences, 18thEd. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy 19thEd. (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rdEd. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12thEd. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeia! Convention); Fiedler’s “Lexikon der Hilfsstoffe” 5thEd., Edition Cantor Verlag Aulendorf 2002; “The Handbook of Pharmaceutical Excipients”, 4thEd., American Pharmaceuticals Association, 2003; and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are hereby incorporated by reference.

[0152] The carriers, diluents, adjuvants and pharmaceutical excipients can be selected with regard to the intended route of administration and standard pharmaceutical practice. These compounds must be acceptable in the sense of being not deleterious to the recipient thereof.

[0153] Pharmaceutically useful excipients that may be used in the formulation of the pharmaceutical composition of the present invention may comprise, for example, vehicles, solvents (such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as glycols), edible oils (such as soybean oil, coconut oil, olive oil, safflower oil, and cottonseed oil), oily esters (such as ethyl oleate and isopropyl myristate), binders (such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), pregelatinized starch and combinations thereof), solubilizers, thickening agents, stabilizers, disintegrants (such as carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g., crospovidone, Polyplasdone® or Kollidon® XL), alginic acid, sodium alginate, guar gum, cross-linked CMC (croscarmellose sodium, e.g. Ac-Di-Sol®), carboxymethyl starch-Na (sodium starch glycolate) (e.g., Primojel® or Explotab®), preferably crosslinked PVP and / or croscarmellose sodium), glidants (such as colloidal SiO2 (e.g., Aerosil® 200), magnesium trisilicate, powdered cellulose, talc and combinations thereof), lubricating agents (such as magnesium stearate, aluminium or calcium silicate, stearic acid, hydrogenated castor oil, talc, glyceryl behenate, sodium stearate fumarate and combinations thereof), buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents, colorants, flavors, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers (such as calcium phosphate), magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatine, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting waxes, and ion exchange resins.

[0154] The carrier is not particularly limited and will depend on the route of administration as well as the form of the pharmaceutical composition (i.e., solid, liquid, etc.). Suitable carriers include, without limitation, polyols such as mannitol, sorbitol, xylitol; disaccharides such as lactose, sucrose, dextrose and maltose; polysaccharides such as maltodextrin and dextran; starches such as com starch; celluloses such as microcrystalline cellulose, sodium carboxy methylcellulose, low- substituted hydroxypropyl cellulose, hydroxyl ethyl cellulose, hydroxypropyl cellulose or mixtures thereof; cyclodextrins and inorganic agents such as dicalcium phosphate, calcium hydrogen phosphate; hydroxyapatite, tricalcium phosphate, talcum and silica. Microcrystalline cellulose, sucrose and / or lactose are preferred as carriers. Combinations thereof can also be employed. Carriers can include also protein and cell penetrating peptides which should be selected depending on the route of administration and target.

[0155] The diluent is not particularly limited and will depend on the route of administration as well as the form of the pharmaceutical composition (i.e., solid, liquid, etc.). Diluents include, for instance, water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0156] An adjuvant is an additive which has few or no pharmacological effects by themselves, but that increases the efficacy or potency of the compounds of the invention if they are administered together.

[0157] The routes for administration (delivery) of the compounds of the invention include, but are not limited to, one or more of the following routes of administration: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical, mucosal (e.g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual. The compounds of the invention are preferably administered orally.

[0158] For example, the compounds can be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

[0159] The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatine and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatine capsules. Preferred excipients in this regard include starch, cellulose, milk sugar e.g. lactose or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. If the compounds of the present invention, as disclosed herein, are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the compounds; and / or by using infusion techniques. For parenteral administration, the compounds can be used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0160] As indicated, the compounds of the present invention can be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1,1 ,2-tetrafluoroethane (HFA134AT) or 1 ,1 ,1 ,2,3,3,3-heptafluoro- propane (HFA 227), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatine) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0161] Alternatively, the compounds of the present invention, as defined herein, can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the present invention, as defined herein, may also be dermally or transdermally administered, for example, by the use of a skin patch.

[0162] They may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route. For ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum. For application topically to the skin, the compounds of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0163] Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. Preferably, the NLRP3 inhibitor compound is administered at a dose of from about 0.1mg / kg to about 50mg / kg, preferably from about 0.2mg / kg to about 20mg / kg, more preferably from about 0.3mg / kg to about 10mg / kg.

[0164] The claimed compounds, as defined herein, can be used for the treatment, alleviation or prevention of the recited conditions alone or in combination with one or more other therapeutic agent, as defined herein. In particular, the other therapeutic agent can be one used for the treatment, alleviation, or prevention of the recited diseases.

[0165] The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the compound of the invention or the other therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manners as are known for such compounds in the art.

[0166] In some embodiments the additional therapeutic agent is administered prior to, in alternation, at the same time as, or in temporal proximity, or after the treatment with the NLRP3 inflammasome pathway inhibitor compound. In some further embodiments the additional therapeutic agent is administered prior to, at the same time as, or after the treatment with the NLRP3 inflammasome pathway inhibitor compound.

[0167] The pharmaceutical compositions of the invention can be produced in a manner known per se to the skilled person as described, for example, in Remington's Pharmaceutical Sciences, 15thEd., Mack Publishing Co., New Jersey (1975).

[0168] The compounds according to the present invention, as disclosed herein, can also be provided in the form of a mixture with at least one further therapeutic agent and / or a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient. The compound and / or the further biologically active compound are preferably present in a therapeutically effective amount.

[0169] The nature of the further therapeutic agent will depend on the intended use of the mixture. The further therapeutic agent may exert its biological effect by the same or a similar mechanism as the compound according to the invention or by an unrelated mechanism of action or by a multiplicity of related and / or unrelated mechanisms of action.

[0170] In one embodiment the additional therapeutic agent targets obesity or a disease, disorder or abnormality associated therewith. Examples of suitable additional therapeutic agent include, but are not limited to, Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, tirzepatide, mazdutide, pemvidutide, AMG 133 (Amgen), Bl 456906 (Boehringer Ingelheim), retatrutide, orforglipron, survodutide, maridebart / cafraglutide, danuglipron, cagrilinitide, efinopegdutide, efpeglenatide, OPK88003 (Opko); Glucose-dependent insulinotropic polypeptide (GIP) receptor agonists; Glucagon receptor agonists; Sodium-glucose cotransporter-2 (SGLT2) inhibitors include empagliflozin, canagliflozin, and dapagliflozin; Dipeptidyl peptidase-4 inhibitors (DPP-4) include sitagliptin, saxagliptin, linagliptin, and alogliptin; Thiazolidinediones (TZDs) include rosiglitazone and pioglitazone; Insulins include insulin, insulin aspart, insulin degludec, insulin detemir, insulin glargine, insulin glulisine, insulin inhalation rapid acting, insulin isophane (NPH), insulin regular or insulin lispro.

[0171] In a preferred embodiment the additional therapeutic agent is a glucagon-like peptide-1 (GLP-1) receptor agonist.

[0172] In one embodiment the additional therapeutic agent is selected from the group consisting of semaglutide, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, tirzepatide, survodutide, retatrutide, orforglipron, mazdutide, pemvidutide, cagrilinitide, efinopegdutide, maridebart / cafraglutide, danuglipron, and retatrutide. In one preferred embodiment the additional therapeutic agent is selected from semaglutide, liraglutide, tirzepatide, pemvidutide, survodutide, cagrilinitide, efinopegdutide, orforglipron, survodutide, maridebart / cafraglutide, danuglipron, mazdutide and retatrutide. In a particular embodiment the additional therapeutic agent is selected from semaglutide, liraglutide and tirzepatide. In one embodiment the additional therapeutic agent is semaglutide.

[0173] DEFINITIONS

[0174] Within the meaning of the present application the following definitions apply unless specified otherwise, and when appropriate, terms used in the singular will also include the plural and vice versa:

[0175] "Alkyl" refers to a saturated straight or branched organic moiety consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, and (as appropriate) include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl and hexyl. The term “Ci-Cealkyl” refers to an alkyl group having 1 to 6 carbon atoms. The terms “Ci-C4alkyl”, “Ci-Caalkyl”, or “Cialkyl” are to be construed accordingly.

[0176] "Hal", "halo" or "halogen" refers to F, Cl, Br, and I. Preferably halogen is F or Cl. In one aspect, halogen is Cl. In another aspect, halogen is F.

[0177] "7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety" refers to a stable 7-, 8-, 9-, 10- or 11 -membered non-aromatic bicyclic ring radical which comprises 1 , 2 or 3 heteroatoms which are independently selected from N and O. The two rings are either connected in a spiro manner (i.e. , the two rings have one common ring atom) or are fused (i.e. , the two rings have two common ring atoms) to eachother.

[0178] "4-, 5- or 6-membered heterocycloal kyl" refers to a stable 4-, 5- or 6-membered non-aromatic monocyclic ring radical which comprises 1 or 2 heteroatoms. The heteroatom is N orO, preferably N. Examples include oxetane, azetidine, pyrrolidine, tetrahydrofuran, oxane, morpholine and piperidine.

[0179] "Aryl" refers to a homocyclic aromatic organic moiety consisting of carbon and hydrogen atoms which have 5 or 6 carbon atoms. An examples is, but is not limited to, phenyl. "Heteroaryl" refers to an aryl group as defined above in which at least one of the carbon atoms has been replaced by a heteroatom which is N. Examples of possible heteroaryl groups include pyridine, etc.

[0180] "Carbocyclyl" refers to a cyclic organic moiety consisting of carbon and hydrogen atoms. Examples of suitable carbocyclyl groups have 3 to 6 carbon atoms, preferably 3 to 5 carbon atoms. The carbocyclyl group can be unsaturated or saturated. Examples of the carbocyclyl group include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0181] "Optionally substituted" in reference to a certain group refers to said group as to optionally be substituted with one or more substituents (i.e. the substituent may be present or not).

[0182] Unless specified otherwise, the term “compound of the present invention” refers to compounds of formula (I), as disclosed herein, or sub-formulae thereof, as disclosed herein, or stereoisomers thereof, or racemic mixtures thereof, or tautomers thereof, or polymorphs thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or hydrates thereof, or solvates thereof. Compounds of the present invention having one or more optically active carbons can exist as racemates and racemic mixtures (including mixtures in all ratios), stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropisomers, and rotamers. All isomeric forms are included in the present invention. Compounds described in this invention containing olefinic double bonds include E and Z geometric isomers. Also included in this invention are all pharmaceutically acceptable salts, prodrugs, hydrates and solvates of compounds of formula (I).

[0183] Tautomers are isomers of a compound which differ only in the position of the protons and electrons. The skeleton of the compound is unchanged. Common tautomeric pairs include: ketone - enol (H-O-C=CH O=C-CH2), enamine - imine (H2N-C=N HN=C-NH).

[0184] Solvates, hydrates as well as anhydrous forms of the salt are also encompassed by the invention. The solvent included in the solvates is not particularly limited and can be any pharmaceutically acceptable solvent. Examples include water and Ci^ alcohols (such as methanol or ethanol).

[0185] "Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic acid, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington’s Pharmaceutical Sciences, 18thed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference.

[0186] The term "polymorphs" refers to the various crystalline structures of the compounds of the present invention. This may include, but is not limited to, crystal morphologies (and amorphous materials) and all crystal lattice forms. Salts of the present invention can be crystalline and may exist as more than one polymorph.

[0187] "Pharmaceutically acceptable" is defined as those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0188] As used herein, the terms “patient” or "subject” mentioned in the present invention typically refer to an animal, particularly a mammal (e.g. rabbits, rats, dogs, mice, guinea pigs, pigs), more particularly primates (e.g. humans, male or female). In certain embodiments, the subject is a human.

[0189] The terms “treat”, “treating" or "treatment" of any disease, disorder or abnormality refer to alleviating or ameliorating or modulating the disease or disorder or abnormality (i.e. , slowing or arresting the development of the disease, disorder or abnormality or at least one of the clinical symptoms thereof); or alleviating or ameliorating or modulating at least one physical parameter or biomarker associated with the disease or disorder or abnormality, including those which may not be discernible to the subject (e.g., patient). The terms “prevent”, “preventing" or “prevention” of any disease or disorder or abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway refer to the prophylactic treatment of the disease or disorder or abnormality; or delaying the onset or progression of the disease or disorder.

[0190] The term “in need of’ a treatment refers to a subject if such subject would benefit biologically, medically or in quality of life from such treatment.

[0191] “Therapeutically effective amount” means an amount of compound of the invention that is sufficient, when administered to a subject suffering from a disease, disorder, and / or abnormality to treat, reduce the incidence and / or severity of, and / or delay onset of, one or more symptoms of this disease, disorder, and / or this abnormality.

[0192] "NLRP3" as used herein refers to NOD-like receptor (NLR) family, pyrin-domain containing protein 3 component of inflammasome. Inflammasomes are intracellular supramolecular complexes comprising a sensor molecule, the adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and the effector protease caspase 1. Upon activation of the inflammasome sensor molecule, ASC self-associates into a helical fibrillary assembly resulting in formation of the so- called ASC speck or pyroptosome, which acts as a molecular platform for the activation of procaspase 1 via proximity-induced autocatalytic activation. Active caspase 1 triggers the activation and release of interleukin-1 (IL-1) family proteins and enables the non-conventional secretion of numerous cytosolic proteins. Among the pro-inflammatory mediators released upon NLRP3 activation are IL-1 beta (p), IL-18, high-mobility group protein B1 (HMGB1), leukotrienes and prostaglandins.

[0193] NLRP3 inflammasome pathway activation is an important driver of inflammation interacting with the different cytokine pathways shaping the immune response to infection and injury. Formation of some pro-inflammatory cytokines is triggered by NLRP3 inflammasome pathway activation.

[0194] The terms “inhibit”, "inhibition" or “inhibiting” refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway, or a significant decrease in the baseline activity of a biological activity or process.

[0195] As used herein, "modulation" refers to alteration, e.g., up-regulation, down-regulation, increase or decrease, preferably decrease. The definitions and preferred definitions given in the "Definition'-section apply to all of the embodiments described herein unless stated otherwise.

[0196] The compounds of formula (I) can be prepared according to any known synthetic route such as the methods disclosed in W02024 / 013395.

[0197] EXAMPLES

[0198] The disclosure is further illustrated by the following examples, which are not to be construed as limiting the scope of the specific procedures herein described. It is understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of this disclosure is intended thereby.

[0199] Example 1. Compound 1 efficacy in DIO mouse model - Study protocol

[0200] The objective of this study was to evaluate the efficacy of an NLRP3 inflammasome pathway inhibitor small molecule compound (Compound 1 , (R)-2-(8-((1-methylpiperidin-3-yl)amino)- imidazo[1 ,2-d][1 ,2,4]triazin-5-yl)-5-(trifluoromethyl)phenol, described in W02024 / 013395) in a mouse model of Diet-Induced Obesity (DIO) in C57BL / 6j mice. The study duration was 29 days and comprised 46 animals randomly divided into 5 groups as set out in Table 1 .

[0201] Table 1. Summary of the study groups

[0202] SCD: standard chow diet. HFD: high fat diet.

[0203] Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, which mimics the action of the incretin hormone GLP-1 . Semaglutide has shown efficacy in promoting weight loss in clinical trials, leading to its approval for the treatment of obesity and is used as positive control in this study. Vehicle and Compound 1 Formulation

[0204] The vehicle consisting of 0.5% sodium-Carboxymethylcellulose (CMC-Na) with 0.2% Tween 80 in water was formulated daily and stored at 4°C. The treatment formulations were freshly prepared daily in vehicle.

[0205] To reach 5 mg / kg dose (Compound 1 high dose), 10 ml / kg dosing volume was applied (0.5 mg / ml compound concentration). Compound 1 was weighed and about 1 / 3 volume ofvehicle was added, then sonicated 15 minutes, and visually inspected until a homogenous suspension was reached. Then, the remaining volume of vehicle was added, and the mixture was stirred for 10 minutes to reach a homogenous suspension. For the low dose (0.5 mg / kg), the high dose formulation was diluted 10 times in vehicle and stirred for 10 minutes to reach the final compound concentration of 0.05 mg / ml in an expected final dosing volume of 10 ml / kg. Quality control of the formulation was performed daily from a 100 pl sample after preparation and from the remaining formulation after administration.

[0206] Semaglutide preparation

[0207] A 1 mg / ml solution was prepared by solubilizing semaglutide (CAS: 910463-68-2) in saline (250 ml:2.25g) and aliquots were stored at -80°C. Semaglutide solution for subcutaneous injection was prepared daily by diluting the 1 mg / ml aliquoted solution in saline to reach a 0.01 mg / ml semaglutide concentration.

[0208] Animals

[0209] C57BL / 6j male mice were fed with standard chow diet (SCD) from birth till week 5, then the diet was switched to high fat diet (HFD) for 24 weeks (D12492, rodent diet with 60 kcal% fat; Research Diets Inc.) including the 4 weeks of study duration (Figure 1). Age-matched non-obese control C57BL / 6j male mice were kept on standard chow diet (Beijing Keao Xieli Feed Co., Ltd). Animals were group-housed (4-5 animals per cage) with bedding under controlled temperature (22 ± 2°C), noise, humidity (50 + 10%), and lighting (12 h light and 12 h dark) conditions with free access to purified water.

[0210] Experimental design

[0211] After 20 weeks on HFD (except for Group 1 Non-obese control), the mice were randomized in the treatment Groups 2-5 at study baseline (Day 0) based on their body weight measurement at baseline (Figure 2A) and fat tissue measurement by DEXA at Day -5 (Figure 2B). From Day 0 (baseline) to Day 28, the treatments were administered as set out in Table 1 (no treatment at endpoint on Day 29). A series of assays were performed before the study, at baseline (Day 0), during the study and at study endpoint (Day 29) as set out in Table 2. Table 2. Assays and measurements performed

[0212] Example 2. Effect of Compound 1 on body weight and body composition in DIO mice model

[0213] Method

[0214] All animals were group housed, and food was provided to the animals in the cage ad libitum.

[0215] Body weight was recorded daily for the entire study period. Changes in body composition were determined by Dual X-Ray Absorptiometry Analysis (DEXA) using a dedicated densitometer (InAlyzer, MEDIKORS) on Day -5 and Day 24. This system employs a fan beam X-ray source generating energies of 55 and 80 keV and a flat 140 x 210 mm or 210 x 315 mm detector with precision of 0.001g. The ratio of energy attenuation in the luminescent panel separates bone, lean tissue, and fat mass and allows to determine the lean mass, fat mass and bone mass. Mice were anesthetized by inhalation of isoflurane during testing.

[0216] Results

[0217] Body weight was recorded every day. The lean mass, fat mass and bone mass were measured by DEXA on Day -5 (five days before starting treatment on Day 0) and Day 24.

[0218] Obese control mice had a significantly higher body weight throughout the study period compared to SCD-fed Non-obese control mice (Figure 3A). However, in terms of % body weight changes from baseline weight on Day 0, there was no significant difference between Obese control mice and Non-obese control mice (Figure 3B).

[0219] Regarding the body composition on Day -5, HFD feeding (Group 2-5 at this stage) significantly increased the bone mass (Figure 4A) and fat tissue mass (Figure 4C) while it significantly decreased the lean tissue mass (Figure 4B) compared to SCD feeding (Non-obese control). The same significant differences were observed when comparing the Non-obese control and Obese control group on Day 24 (Figures 5A-C). These results confirmed the HFD-fed mice (Group 2-5 on Day -5) developed diet-induced obesity (DIO) before the start of the treatment on Day 0 and validated the induction and conservation of obese mice model throughout the study. Concerning the treated groups body weight, the treatment with the positive control semaglutide resulted in a significantly lower body weight compared to Obese control mice starting from Day 6 until study endpoint (Figure 3A) and a lower change in % body weight starting from Day 2 until study endpoint (Figure 3B).

[0220] Treatment with Compound 1 low dose resulted in significantly lower body weight from Day 10 until study endpoint (Figure 3A; except for Days 22, 23 and 26) and a lower change in % body weight starting from Day 7 until study endpoint (Figure 3B).

[0221] Treatment with Compound 1 high dose resulted in significantly lower body weight from Day 7 until study endpoint (Figure 3A) and a lower change in % body weight starting from Day 3 until study endpoint (Figure 3B).

[0222] Regarding the treated groups body composition at Day 24 (endpoint for DEXA analysis), the treatment with the positive control semaglutide significantly decreased the fat tissue mass compared to the baseline value (Day -5) (Figure 5C) and did not result in any significant difference for the bone mass nor lean tissue mass (Figures 4A-B). Endpoint fat tissue mass of semaglutide treated mice was also significantly lower compared to Obese control mice. Regarding Compound 1 , a significant fat tissue mass decrease was observed for Compound 1 high dose at endpoint (Figure 5C) compared to baseline. No significant differences were observed in the lean mass tissue and bone mass in Compound 1 treated mice.

[0223] In summary, treatment of DIO mice with semaglutide, or Compound 1 low or high dose can significantly decrease the body weight and body weight changes compared to untreated DIO mice (Obese control). The difference in body weight in treated DIO mice compared to Obese control appears to predominantly result from the decrease in fat tissue mass. These results confirm the capability of Compound 1 to decrease body weight and fat mass in a dose-dependent manner in obese animals and its suitability as a therapeutic for the treatment of obesity.

[0224] Example 3. Effect of Compound 1 on glucose and insulin homeostasis in DIO mice model

[0225] Method

[0226] For the 4h fasting tests on Day -3 and Day 27, food was removed (from 9AM to 1 PM) after morning dose of the compounds at 9AM. Blood glucose was measured using ACCU-CHEK Active Blood Glucose Meter (REF03146662, Roche) with ACCU-CHEK Active Test Strips (REF06993788001 , Roche). After blood glucose measurement, blood samples were collected via retro-orbital vein and collected into tubes pre-coated with EDTA-K2for plasma preparation. The tubes were placed on ice until processing and centrifuged within 20-30 min of collection. Plasma samples were obtained by centrifugation at 4000 rpm for 10 minutes at 4°C, collected into two tubes and then stored at -80°C. One tube plasma was used for plasma insulin analysis using the Mouse Insulin Kit (K152BZC-3) from MSD and the other for total cholesterol (TC) and triglycerides (TG) analysis using the L-Type CHO M Kit (Cat# 997-33391 / 993-33491) and L-Type Triglyceride M Kit (Cat#999-32991 / 999-33091) from FUJIFILM Wako Pure Chemical Corporation, respectively. The Homeostasis Model Assessment - Insulin Resistance (HOMA-IR) index was calculated from the fasting blood glucose and insulin concentrations using the following formula: HOMA-IR = (Fasting insulin [ U / ml]- Fasting Glucose [mg / dl]) / 22.5 (Matthews et al., 1985).

[0227] Animals fasted overnight (food removed from Day 25 7PM) before Oral Glucose Tolerance Test (OGTT) on Day 26. Basal blood glucose concentration was measured with a ~3 I blood sample obtained from a tail nick using ACCU-CHEK Active Test Strips (REF06993788001 , Roche) and an ACCU-CHEK Active Blood Glucose Meter (REF03146662, Roche) at -8.30AM (T = -150min) on Day 26. Compound treatment was administered at ~9AM (T = -120min). The OGTT consisted of an oral gavage of 2g of glucose per kg of body weight with an oral injection volume of 10 ml / kg body weight at ~11AM (T = 0). Blood sampling and glucose measurements were repeated at T = 15, 30, 60, 90, 120 min after glucose gavage.

[0228] Results

[0229] Monitoring glucose and insulin homeostasis are essential for understanding metabolic health, particularly in the context of diabetes type 2 and obesity characterized by a dramatic dysregulation of glucose metabolism and insulin sensitivity.

[0230] Blood glucose and insulin concentrations were measured on Day -3 (three days before starting compound treatment on Day 0) and Day 27 following a 4h fasting period. On Day -3, HFD-fed mice (Group 2-5 at this stage) presented significantly higher blood glucose and insulin levels compared to the SCD-fed Non-obese control mice (data not shown). Similar results were observed on Day 27 between Obese control and Non-obese control group (Figure 6A-B). These results confirmed the HFD-fed mice (Group 2-5 on Day -3) had an altered glucose and fat metabolism before the start of the treatment on Day 0, which confirms the induction and conservation of the DIO mice model throughout the study.

[0231] Regarding the treated groups, the mice treated with semaglutide had significantly lower blood glucose and insulin levels compared to Obese control mice on Day 71 (Figures 6A-B). When comparing baseline (Day -3) and endpoint (Day 27) levels, semaglutide treated mice showed significantly lower blood glucose (Figure 6A).

[0232] Regarding Compound 1 , low and high dose treated mice had a significantly lower blood glucose level compared to Obese control mice on Day 27 (Figure 6A). When comparing baseline (Day -3) and endpoint (Day 27) levels, Compound 1 treated mice showed significantly lower blood glucose levels (Figure 6A).

[0233] The Homeostasis Model Assessment - Insulin Resistance (HOMA-IR) index was calculated from the fasting blood glucose and insulin concentrations measured on Day 27. The HOMA-IR was significantly lower for the semaglutide and Compound 1 treated groups compared to the Obese control group (Figure 7). These results confirm the capability of Compound 1 to decrease HOMA- IR in a dose-dependent manner in obese animals.

[0234] An oral glucose tolerance test (OGTT) was performed on Day 26. Compared to the Obese control group, treatment with semaglutide led to a significant reduction in blood glucose concentrations for up to 120 min (Figure 8A) while treatment with Compound 1 low and high dose resulted in a significant reduction in blood glucose concentrations from 30 to 120 min (Figure 8A). All the treated groups (semaglutide and Compound 1) showed a significant reduction in the blood glucose concentrations area under the curve (AUC; Figure 8B), suggesting an enhanced glucose tolerance compared to the Obese control.

[0235] Compound 1 showed significant improvement in basal glycemia and in insulin sensitivity compared to the Obese control group (HFD) and improved first-phase insulin response with glycaemic peak reached within 15 min demonstrating that it can restore normal glucose metabolism, reducing the risk of prolonged hyperglycemia and its associated complications. This supports its potential as a therapeutic agent for addressing impaired glucose regulation and insulin resistance, key factors in metabolic diseases like obesity and type 2 diabetes.

[0236] Example 4. Effect of Compound 1 on liver and CNS

[0237] Method

[0238] On Day 29, animals were euthanized after blood collection by carbon dioxide inhalation then perfused intracardially with ice-cold saline. Liver mass was recorded before collection.

[0239] Collected brains were rinsed briefly in ice cold deionized water and split into left and right hemispheres including the brain stem. The right brain was weighed and fixed in 10% NBF for histology IHC analysis of IBA1 (ionized calcium binding adaptor molecule 1 ) and GFAP (glial fibrillary acidic protein) in hypothalamus. The left cortex and leftover left brain were weighed and collected into tubes, frozen on dry ice and stored at -80°C.

[0240] For the IHC, sagittal brain sections (using the lateral stereotaxic coordinate of 0.2-0.3mm from the midline) embedded in paraffin were cut with a microtome to the thickness of 10 pm. For GFAP staining, a heat-induced citrate (pH 6.0) antigen unmasking was performed, while for IBA1 staining, a heat-induced EDTA antigen unmasking was performed. Sections of both staining were then immersed in 3% hydrogen peroxide solution for 5 min. To avoid non-specific staining, the sections were incubated in blocking serum for 15 min at room temperature, followed by anti-GFAP primary antibody (1 :800 for 1 h) or anti-IBA1 antibody (1 :3000 for 1 h). Then, secondary goat polyclonal antibody conjugated to horseradish peroxidase (HRP; Jackson ImmunoResearch) was added. Stained sections were scanned with a Leica Aperio GT450 Scanner. Images were analyzed with HALO Al. GFAP-positive or IBA1 -positive cells of the dorsomedial hypothalamic nucleus (DMH), ventromedial nucleus of the hypothalamus (VMH) and arcuate nucleus (ARC) were counted using “Nuclei Seg” HALO Al module.

[0241] Results

[0242] Animals were euthanized on Day 29, their liver collected to be weighed, and their brain collected to perform GFAP (a marker of astrocyte and astrocyte activation) and IBA1 (a marker of microglia and microglia activation) IHC stainings.

[0243] Regarding the livers mass, HFD-fed mice Obese control had significantly increased liver mass compared to SCD-fed mice Non-obese control (Figure 9). Mice treated with semaglutide and Compound 1 low and high dose had significantly lower liver mass compared to Obese control (Figure 9). The reduction in liver mass in DIO mice suggests reduced liver inflammation supported by improved insulin sensitivity and glucose metabolism, and possibly reduced fibrosis and fat content - all of which are positive indicators of the Compound 1 efficacy in treating obesity-related liver pathology.

[0244] Regarding GFAP and IBA1 expression in the central nervous system, the analysis was focused on three nuclei of the hypothalamus known to be involved in food intake and energy homeostasis and that are disrupted in obese mice. As expected, the Obese control group presented an increased number of GFAP and IBA1 positive cells in the DMH, VMH and ARC compared to the Non-obese control group (Figure 10A-C and 11A-C, respectively) confirming the phenotype of DIO mice and reflecting the neuroinflammatory response associated with excessive nutrient intake and obesity. Treatment with semaglutide and Compound 1 low and high dose reduced the number of GFAP and IBA1 positive cells in the DMH, VMH and ARC compared to the Obese control group. These results show that Compound 1 reduces astrocytosis and microgliosis in the hypothalamus of DIO mice and thus reduce neuroinflammation.

[0245] Example 5: Effect of Compound 1 on Hidradenitis Suppurativa (HS)

[0246] Method

[0247] Biopsies from nine Hurley stage II or III patients were obtained and separated into two halves. To assess the functional efficacy compound 1 in HS, HS patient skin explants were cultured using a Transwell system in the presence of compound 1 at 500, 100, 10, or 1 nM or vehicle (9 explants per treatment group), diluted DMSO control, as described in Vossen et al. 2020 J Invest Dermat. Media were collected and processed for cytokine and chemokine production using LegendPlex bead-based immunoassay or enzyme-linked immunosorbent assay.

[0248] To assess inhibition of IL-17A, IL-36G, IL-6, CXCL1 , CXCL2, and CXCL5 compound treatments were performed with up to 500 nM of Compound 1 , and percent inhibition was calculated in relation to each respective vehicle control treated explant. Cytokines IL-10, IL-17A, IL-6, CXCL1 , CXCL2, and CXCL5 were measured by LegendPlex bead-based immunoassay and IL-36G was measured by enzyme-linked immunosorbent assay.

[0249] Results

[0250] Compound 1 abrogated IL-10 production in treated explants compared to their vehicle treated control counterparts. A dose-dependent response inhibition in IL-10 production was observed relative to its corresponding control (Figure 12).

[0251] Table 3. Percent inhibition of IL-17A, IL-36G, IL-6, CXCL1, CXCL2, and CXCL5. Two-tailed ratio paired t-test of compound vs vehicle. * p < 0.05, ** p < 0.01.

[0252] As seen from Table 3, IL36G, IL-17A, IL-6, CXCL1 , CXCL2, and CXCL5 were inhibited by Compound 1. These results demonstrate that Compound 1 inhibits IL-10 release and inhibits IL- 10 downstream pathways including pathogenic cytokines IL-17A and IL-36G, and multiple neutrophil chemokines, in HS patient skin explants. This supports the potential of Compound 1 as a therapeutic agent for diseases, disorders or abnormalities modulated by IL-10, IL-17A and / or IL-36G, such as HS.

[0253] Example 6. Compound 1 efficacy in DIO mouse model - Study protocol

[0254] The objective of this study was to evaluate the efficacy of Compound 1 in DIO mice alone or in combination with semaglutide. The study duration was 29 days and comprised 38 animals randomized into 4 groups as set out in Table 4. Table 4. Summary of the study groups

[0255] HFD: high fat diet.

[0256] *One mouse was excluded from the study due to severe body weight loss and thus considered as an outlier.

[0257] Vehicle and Compound 1 Formulation

[0258] The vehicle consisting of 0.5% sodium-carboxymethylcellulose (CMC-Na) with 0.2% Tween 80 in water was formulated daily and stored at 4°C. The treatment formulations were freshly prepared daily in vehicle.

[0259] To reach 5 mg / kg dose, 10 ml / kg dosing volume was applied (0.5 mg / ml compound concentration). Compound 1 was weighed and about 1 / 3 volume of vehicle was added, then sonicated 15 minutes, and visually inspected until a homogenous suspension was reached. Then, the remaining volume of vehicle was added, and the mixture was stirred for 10 minutes to reach a homogenous suspension. Quality control of the formulation was performed daily from a 100 pl sample after preparation and from the remaining formulation after administration.

[0260] Semaglutide preparation

[0261] A 1 mg / ml solution was prepared by solubilizing semaglutide (CAS: 910463-68-2) in saline (250 ml : 2.25g) and aliquots were stored at -80°C. Semaglutide solution for subcutaneous injection was prepared daily by diluting the 1 mg / ml aliquoted solution in saline to reach a 0.001 mg / ml semaglutide concentration.

[0262] Animals

[0263] C57BL / 6j male mice were fed with standard chow diet (SCD) from birth until week 5, then the diet was switched to high fat diet (HFD) for 27 weeks (D12492, rodent diet with 60 kcal% fat; Research Diets Inc.) including the 4 weeks of study duration (Figure 13). Animals were group-housed (4-5 animals per cage) with bedding under controlled temperature (22 + 2°C), noise, humidity (50 + 10%), and lighting (12 h light and 12 h dark) conditions with free access to purified water. Experimental design

[0264] After 23 weeks on HFD, the mice were randomized in the treatment groups at study baseline based on their body weight measurement (Day 0 on Figure 14A) and fat tissue measurement by DEXA at Day -5 (data not shown). From Day 0 (baseline) to Day 28, the treatments were administered as set out in Table 4 (no treatment at endpoint on Day 29). A series of assays were performed before the study, at baseline (Day 0), during the study and at study endpoint (Day 29) as set out in Table 5 and the results are presented in the following Examples.

[0265] Table 5. Assays and measurements performed

[0266] Example 7. Effect of Compound 1 on body weight and food intake in DIO mouse model

[0267] Method

[0268] All animals were group housed, and food was provided to the animals in the cage ad libitum. Body weight and food intake were recorded daily for the entire study period. Food intake was measured by cage. At 8:00 am every day (the beginning of light cycle), food pellet was weighed and provided to the animals in the cage ad libitum. At 8:00 am on the following day, the remaining food pellet was weighed again, and the differences were recorded as the total food consumption by the group of animals in 24 hours. Results were reported as cumulative grams of average food consumption per mouse (daily total food consumption / number of animals in the cage).

[0269] Statistical comparisons of body weight (Figure 14A) and body weight % change (Figure 14B) were performed by 2-way ANOVA followed by Tukey multiple comparisons test.

[0270] Results

[0271] Body weight was recorded every day. Vehicle mice increased body weight over time until Day 29 showing a correct induction and conservation of obese phenotype throughout the study.

[0272] Treatment with Compound 1 resulted in significantly lower body weight compared to vehicle mice from Day 8 until study endpoint (Figure 14A) and a lower change in % body weight starting from Day 4 until study endpoint (Figure 14B).

[0273] Treatment with the positive control semaglutide also resulted in a significantly lower body weight compared to vehicle mice (Figure 14A) and a lower change in % body weight (Figure 14B). Co-treatment with Compound 1 and semaglutide resulted in significantly lower body weight and a lower change in % body weight compared to vehicle mice from Day 1 until study endpoint (Figures 14A-B). Moreover, the co-treatment (Compound 1 and semaglutide) resulted in lower body weight (Figure 14A) and lower change in % body weight compared to each monotherapy arm (Compound 1 alone or semaglutide alone; -15.5% at day 24; p<0.001 vs. semaglutide and p<0.0001 vs Compound 1). More importantly, when compared to the baseline, co-treatment with Compound 1 and semaglutide resulted in significantly lower body weight and a lower change in % body weight compared to baseline from Day 1 until study endpoint compared to each monotherapy arm (see Table 6), showing a synergistic effect of two compounds having different mechanisms of action.

[0274] Table 6.

[0275] (1 ) Body weight; (2) bis in die, twice a day; (3) per os, oral gavage; (4) quaque die, once a day; (5) subcutaneously

[0276] Food intake was recorded daily for the entire study period. Regarding the treated groups, Compound 1 showed a significant decrease in cumulative food intake from Day 4 to Day 28 compared to vehicle group (Figure 15). Semaglutide also resulted in a significantly reduced cumulative food intake compared to vehicle group (Figure 15). Compound 1 in combination with semaglutide significantly reduced cumulative food intake across the entire study period (days 1- 28). Moreover, the co-treatment (Compound 1 and semaglutide) resulted in lower cumulative food intake compared to each monotherapy arm from Day 7 to Day 28 (Figure 15).

[0277] In summary, treatment of DIO mice with Compound 1 , alone or in combination with semaglutide, can significantly decrease food intake, body weight and body weight changes compared to untreated group. These results confirm that Compound 1 , alone or in combination with semaglutide, is a promising therapeutic for the treatment of obesity.

[0278] Example 8. Effect of Compound 1 on plasma total cholesterol in DIO mouse model

[0279] Method

[0280] For the 4h fasting tests on Day -3 and Day 27, food was removed (from 9AM to 1 PM) after morning dose of the compounds at 9AM. Blood samples were collected via retro-orbital vein and collected into tubes pre-coated with EDTA-K2 for plasma preparation. The tubes were placed on ice until processing and centrifuged within 20 to 30 min of collection. Plasma samples were obtained by centrifugation at 4000 rpm for 10 minutes at 4°C, collected into two tubes and then stored at -80°C. One tube plasma was used for total cholesterol (TC) analysis using the L-Type CHO M Kit (Cat# 997-33391 / 993-33491) from FUJIFILM Wako Pure Chemical Corporation.

[0281] Results

[0282] Measuring total cholesterol is crucial for assessing the risk of heart disease and stroke. High cholesterol can cause plaque buildup in the arteries, which increases the likelihood of these serious conditions often associated with obesity and type 2 diabetes.

[0283] Total cholesterol was measured on Day -3 (three days before starting compound treatment on Day 0) and Day 27 following a 4h fasting period. On Day -3, mice showed similar TC levels across the groups, and those levels were maintained in vehicle group until day 27 (Figure 16).

[0284] Regarding Compound 1 , treated mice had a significantly lower TC levels compared to vehicle mice on Day 27 (Figure 16), while the lowering effect of semaglutide did not reach statistical significance (Figure 16).

[0285] When comparing baseline (Day -3) and endpoint (Day 27) levels, mice treated with Compound 1 + semaglutide showed significantly lower TC levels (Figure 16). A significant reduction in TC levels was also observed when compared to vehicle group at endpoint (Day 27).

[0286] In summary, treatment of DIO mice with Compound 1 , alone or in combination with semaglutide significantly decreases TC levels, confirming that Compound 1 alone or in combination with semaglutide has potential to mitigate cardiovascular complications associated with obesity.

[0287] Example 9. Effect of Compound 1 on plasma inflammatory markers in DIO mouse model

[0288] Method

[0289] On Day 29, blood collection on live animals was performed between 8AM and 9AM via saphenous vein. The highest volume possible of blood samples were collected into tubes pre-coated with EDTA-K2 for plasma preparation. The tubes were placed on ice until processing and centrifuged within 20 to 30 min from collection. Plasma samples were obtained by centrifugation at 4000 rpm for 10 minutes at 4°C, collected into two tubes and stored at -80°C.

[0290] Results

[0291] Measuring plasma IL-1 RA (lnterleukin-1 Receptor Antagonist) and GFAP (Glial Fibrillary Acidic Protein) provides valuable insight into brain and immune system health. IL-1 RA reflects the body’s attempt to counteract inflammation, while GFAP is a marker of astrocyte injury, often elevated in cases of brain trauma or neurodegeneration. Together, they help assess neuroinflammatory conditions and monitor disease progression or response to treatment.

[0292] Plasma IL-1 RA and GFAP levels were measured on Day 29 using the R-PLEX Mouse IL-1 RA Antibody Set for the MESO QuickPlex SQ 120 (MesoScale Discovery, Rockville, MD, USA) and the Simoa® Neurology 2-Plex B Kit immunoassay for the SR-X analyser (Quanterix, Lexington, MA, USA), respectively.

[0293] Regarding IL-1 RA, a significant decrease in plasma IL-1 RA levels was observed in all treated groups compared to vehicle mice on Day 29 (Figure 17A), the effect being the most pronounced for compound 1 , alone or in combination with semaglutide.

[0294] Regarding GFAP, a decrease in plasma GFAP levels was observed in all treated groups compared to vehicle mice on Day 29 (Figure 17B).

[0295] In summary, treatment of DIO mice with Compound 1 , alone or in combination with semaglutide, decreased plasma IL-1 RA and GFAP levels compared to untreated group, confirming the capability of Compound 1 to decrease circulating inflammatory markers linked to obesity, including in the brain.

[0296] Example 10. Compound 1 effect on brain c-Fos activation in DIO mouse model

[0297] The objective of this study was to evaluate the impact of an either acute or chronic treatment with an NLRP3 inflammasome inhibitor small molecule, Compound 1 , on the modulation of neuronal activity by measuring the trascriptional factor c-Fos in the brain of a mouse model of Diet-Induced Obesity (DIO). The study duration was 10 days and comprised 32 animals randomly divided into 4 groups as set out in Table 6.

[0298] Table 7. Summary of the study groups

[0299] HFD: high fat diet. Vehicle 1 : vehicle of Compound 1 . Vehicle 2: vehicle for semaglutide

[0300] Vehicle and Compound 1 Formulation

[0301] The vehicle consisting of 0.5% sodium-Carboxymethylcellulose (CMC-Na) with 0.2% Tween 80 in water was prepared daily and stored at 4°C. The treatment formulations were freshly prepared daily in vehicle solution.

[0302] To reach 5 mg / kg dose (Compound 1 ), 10 ml / kg dosing volume was applied (0.5 mg / ml compound concentration). Compound 1 was weighed and about 1 / 3 volume of vehicle was added, then sonicated 15 minutes, and visually inspected until a homogenous suspension was reached. Then, the remaining volume of vehicle was added, and the mixture was stirred for 10 minutes to reach a homogenous suspension. Quality control of the formulation was performed daily from a 100 pl sample after preparation and from the remaining formulation after administration.

[0303] Semaglutide preparation

[0304] A 1 mg / ml solution was prepared by solubilizing semaglutide (CAS: 910463-68-2) in saline (250 ml: 2.25g) and aliquots were stored at -80°C. Semaglutide solution for subcutaneous injection was prepared daily by diluting the 1 mg / ml aliquoted solution in saline to reach a 0.01 mg / ml semaglutide concentration.

[0305] Animals

[0306] C57BL / 6j male mice were fed with standard chow diet (SCD) from birth until week 5, then the diet was switched to high fat diet (HFD) for 21 weeks (D12492, rodent diet with 60 kcal% fat; Research Diets Inc.) including the 10 days of study duration. Animals were group-housed (4-5 animals per cage) with bedding under controlled temperature (22 ± 2°C), noise, humidity (50 ± 10%), and lighting (12 h light and 12 h dark) conditions with free access to purified water. Experimental design

[0307] After 21 weeks on HFD, the mice were randomized in the treatment Groups 1-4 at study baseline (Day 0) based on their body weight. From Day 0 to Day 10, body weight was measured daily, and the treatments were administered as set out in Table 6.

[0308] Method

[0309] Measuring c-Fos staining is a powerful and essential tool for modern neuropharmacology. It provides a reliable, high-resolution, and spatially-resolved method for determining where a drug acts in the brain, which is fundamental to understanding its mechanism and ultimately, its therapeutic potential. Combining brain c-Fos immunostaining with light sheet microscopy, a whole brain map of c-Fos activity was generated in DIO mice exposed to either Compound 1 or semaglutide.

[0310] Mice were sacrificed 2 hours after the last dose (either vehicle, Compound 1 or semaglutide) after isoflurane anesthesia. After intracardiac perfusion with heparinized (15,000 IU / I) 1x phosphate buffered saline (PBS) and 10% neutral buffered formalin (NBF), the brains were carefully dissected out of the skull and immersed in the NBF after removal of the meninges. Brains were immunolabelled for c-Fos, cleared and imaged at single-cell resolution using light-sheet fluorescence microscopy. Each imaged brain sample was mapped onto mouse brain atlas, and the number of c-Fos positive cells quantified in more than 800 annotated brain regions and compared across groups. Regions with significant c-Fos staining were removed from the analysis if the number of positive cells was too low (in the range 1-5) and / or the standard error of the mean was greater than the fold change. Remaining regions underwent false discovery rate (FDR) correction. To standardize data across different experimental sessions and account for interanimal variability, all raw values were converted to z-scores. Each raw score was transformed by subtracting the mean of its respective dataset and dividing by the standard deviation.

[0311] Results

[0312] As compared to the vehicle group, Compound 1 induced a significant change in c-Fos activation in more than 170 areas in acute administration, and in more than 90 areas when given chronically over ten days. These areas are in (but not limited to) the cortex, interbrain (thalamus and hypothalamus), midbrain, and hindbrain (pons, medulla). Chronic treatment with semaglutide induced significant variations in c-Fos staining in 5 areas of the brain, mainly in the cerebellum and fiber tracts. As compared to the group treated with semaglutide, chronic treatment with Compound 1 induced a significant change in 38 areas of the brain including (but not limited to) the prefrontal cortex, hypothalamus, and amygdala.

[0313] In summary, treatment of DIO mice with Compound 1 activated multiple brain regions and neurocircuits involved in the regulation of homeostatic feeding and food reward sensitivity. The signature of c-Fos activation following an acute treatment with Compound 1 was extensively preserved following the chronic 10-days treatment showing a persistent effect. Of note, chronic treatment with Compound 1 showed a broader and stronger impact on c-Fos activation as compared to chronic semaglutide treatment the impact of which was limited to only five areas. Finally, this data proves that the effect of Compound 1 on neuronal activation is much broader than the effect of semaglutide, indicating a significant difference in the mechanism of action of the two compounds. The broader neuronal activation effect may further translate to more beneficial treatment effect by Compound 1 thus supporting its therapeutic potential for metabolic diseases.

[0314] References

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[0320] 6. Peter Thornton, Valerie Reader, Zsofia Digby, Pamela Smolak, Nicola Lindsay, David Harrison, Nick Clarke and Alan P. Watt (2024) Reversal of High Fat Diet-Induced Obesity, Systemic Inflammation, and Astrogliosis by the NLRP3 Inflammasome Inhibitors NT-0249 and NT-0796. Journal of Pharmacology and Experimental Therapeutics March 2024, 388 (3) 813- 826.

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Claims

New PCT applicationAC Immune SAVossius Ref.: AK1880 PCTCLAIMS1 . An NLRP3 inflammasome pathway inhibitor compound of formula (I)or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; whereinZi and Z2 are each selected from N and C whereby if Z1 is N, Z2is C, and if Z1 is C, Z2is N, preferably Z1 is N and Z2 is C;V, X and E are each independently selected from N and CRa; wherein at least one of V, X and E is CRa; indicates alternating single and double bonds;Ra is independently selected from the group consisting of -H, -Ci-Csalkyl, -CF3and halo;Ro is selected from the group consisting of -H, -Ci-Csalkyl and -halo;R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, -Ci-Csalkyl, -CN and -halo;R2 is selected from the group consisting of -OH, -H, -OCF3, -OCHF2, -Ci-Csalkyl, -halo and -CF3;R3 is selected from the group consisting of -H, -Ci-Csalkyl, -OH, -CF3 and -halo;R4 is selected from the group consisting of -H, -Ci-Csalkyl, -CF3 and -halo; andY is selected from NH, O, NRcOr a bond;Rc is Ci-C4alkyl; andRA is selected from the group consisting of a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is / are independently selected from N and O; a 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein said heteroatom(s) is / are Nor O; a 5- or 6-membered aryl; a 5- or 6-membered heteroaryl, wherein heteroaryl contains one or two heteroatoms, wherein said heteroatom(s) is / are N; a Ca-Cecycloalkyl; and a Ci-Cealkyl; wherein the spiro or fused heterocycloalkyl bicyclic moiety, the heterocycloalkyl, the aryl, the heteroaryl, the Cs-Cecycloalkyl, or the Ci-Cealkyl is optionally substituted at any available position with one to three substituents which are independently selected from the group consisting of Ci-C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl, hydroxyCi-C4alkyl, halo, -OH, -CN, -NRdRe, -Ci-C4alkyl-NRdRe, and a 4-, 5- or 6- membered heterocycloalkyl containing one or two heteroatoms selected from N and O, wherein Rd and Re are each independently selected from the group consisting of H and Ci-C4alkyl; for use in the treatment, alleviation or prevention of obesity, preferably diet-induced obesity, and / or a disease, disorder or abnormality associated therewith.

2. The NLRP3 inflammasome pathway inhibitor compound for use according to claim 1 , wherein RA is selected from the group consisting of(i) a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is / are independently selected from N and O, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, hydroxyCi-C4alkyl, -OH and halo;(ii) 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein said heteroatom(s) is / are N or O, wherein the heterocycloalkyl is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, hydroxyCi-C4alkyl, -OH, halo, -NRdRe, -Ci-C4alkyl-NRdRe, 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms selected from N and O, wherein Rd and Re are each independently selected from the group consisting of H and Ci-C4alkyl;(iii) 5- or 6-membered aryl, wherein the aryl is optionally substituted at any available position with one or two substituents independently selected from the group consisting of Ci-C4alkyl, hydroxyCi -C4alkyl, haloCi-C4alkyl, -CN, -OH and halo;(iv) 5- or 6-membered heteroaryl, wherein heteroaryl contains one or two heteroatoms, wherein said heteroatom(s) is / are N, wherein the heteroaryl is optionally substituted at any available position with one or two substituents independently selected from the group consisting of Ci-C4alkyl, hydroxyCi-C4alkyl, haloCi-C4alkyl, -CN, -OH and halo;(v) Cs-Cecycloalkyl optionally substituted at any available position with one or two substituents independently selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, hydroxyCi-C4alkyl, -OH and halo; and(vi) C-i-Cealkyl substituted at any available position with one or two substituents independently selected from the group consisting of -OH, halo, haloCi-C4alkyl, hydroxyCi-C4alkyl, and Ci-C4alkoxy.

3. The NLRP3 inflammasome pathway inhibitor compound for use according to claim 1 or 2, wherein the compound has the formula (la)or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; wherein Ro, Ri, R2, R3, R4, RA, Ra, Rc, Rd, Re and Y are as defined in claim 1 , and V and X are independently selected from CRa.

4. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of the preceding claims, wherein Ra is H.

5. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of the preceding claims, wherein the compound has the formula (lb)or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; wherein Ro, R1, R2, RA, RC, R , Re and Y are as defined in claim 1.

6. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of the preceding claims, wherein Ro is H, R1 is -CF3, -Cl, -CH3 or -CN and R2 is -OH.

7. The NLRP3 inflammasome pathway inhibitor compound for use according to any one ofOH the preceding claims, wherein R is selected from the group consisting ofwherein Rs is independently selected from -H, -Ci-Csalkyl, -CH2-NRdRe, Ci-C4alkyl-OH, and a 4-, 5- or 6-membered heterocycloalkyl containing one heteroatom selected from N and O; Rd and Re are each independently selected from the group consisting of H and -Ci-Csalkyl:R? and Rs are each independently selected from the group consisting of H, halo and Ci-Csalkyl; and n is selected from 0, 1 and 2.

8. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of the preceding claims, wherein RA is selected from the group consisting ofwherein n is selected from 0, 1 and 2.

9. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of5 the preceding claims, which isor a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.

10. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of the preceding claims for use in the treatment or alleviation of obesity, preferably diet- induced obesity.

11. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of claims 1 to 9 for use in reducing neuroinflammation, reducing microgliosis, reducing astrocytosis, improving insulin sensitivity, improving glucose metabolism, reducing body weight, reducing fat mass, reducing insulin resistance, reducing fasting glucose, reducing total cholesterol, reducing inflammation, reducing liver fibrosis and / or reducing liver inflammation, preferably in an obese subject.

12. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of claims 1 to 9 for use in reducing neuroinflammation, reducing microgliosis, reducing astrocytosis, improving insulin sensitivity and / or improving glucose metabolism, preferably in an obese subject.

13. An NLRP3 inflammasome pathway inhibitor compound for use in reducing neuroinflammation, reducing microgliosis, and / or improving insulin sensitivity, preferably in an obese subject.

14. The NLRP3 inflammasome pathway inhibitor compound for use according to claim 13 for use in reducing microgliosis, preferably in an obese subject.

15. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of claims 1 to 9 for use in the treatment, prevention or alleviation of hidradenitis suppurativa (HS).

16. The NLRP3 inflammasome pathway inhibitor compound for use according to claim 15 for use in the treatment, prevention or alleviation of hidradenitis suppurativa (HS) in an obese subject.

17. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of claims 1 to 9 for use in the treatment, prevention or alleviation of comorbid hidradenitis suppurativa (HS) and obesity, preferably diet-induced obesity.

18. An NLRP3 inflammasome pathway inhibitor compound of formula (I)or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; whereinZi and Z2 are each selected from N and C whereby if Z1 is N, Z2 is C, and if Z1 is C, Z2 is N, preferably Z1 is N and Z2 is C;V, X and E are each independently selected from N and CRa; wherein at least one of V, X and E is CRa; indicates alternating single and double bonds;Ra is independently selected from the group consisting of -H, -Ci-C3alkyl, -CF3 and halo;Ro is selected from the group consisting of -H, -Ci-Csalkyl and -halo;R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, -Ci-Csalkyl, -CN and -halo;R2 is selected from the group consisting of -OH, -H, -OCF3, -OCHF2, -Ci-Csalkyl, -halo and -CF3;R3 is selected from the group consisting of -H, -Ci-Csalkyl, -OH, -CF3and -halo;R4 is selected from the group consisting of -H, -Ci-Csalkyl, -CF3 and -halo; andY is selected from NH, O, NRcOr a bond;Rc is Ci-C4alkyl; andRA is selected from the group consisting of a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is / are independently selected from N and O; a 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein said heteroatom(s) is / are N or O; a 5- or 6-membered aryl; a 5- or 6-membered heteroaryl, wherein heteroaryl contains one or two heteroatoms, wherein said heteroatom(s) is / are N; a Cs-Cecycloalkyl; and a Ci-Cealkyl; wherein the spiro or fused heterocycloalkyl bicyclic moiety, the heterocycloalkyl, the aryl, the heteroaryl, the Cs-Cecycloalkyl, or the Ci-Cealkyl is optionally substituted at any available position with one to three substituents which are independently selected from the group consisting of Ci-C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl,hydroxyCi-C4alkyl, halo, -OH, -CN, -NRaRe, -Ci-C4alkyl-NRdRe, and a 4-, 5- or 6- membered heterocycloalkyl containing one or two heteroatoms selected from N and O, wherein Rd and Re are each independently selected from the group consisting of H and Ci-C4alkyl; for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation of IL-17A and / or IL36G.

19. The NLRP3 inflammasome pathway inhibitor compound for use according to claim 18, wherein RA is selected from the group consisting of(i) a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is / are independently selected from N and O, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, hydroxyCi-C4alkyl, -OH and halo;(ii) 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein said heteroatom(s) is / are N or O, wherein the heterocycloalkyl is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, hydroxyCi-C4alkyl, -OH, halo, -NRdRe, -Ci-C4alkyl-NRdRe, 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms selected from N and O, wherein Rd and Re are each independently selected from the group consisting of H and Ci-C4alkyl;(iii) 5- or 6-membered aryl, wherein the aryl is optionally substituted at any available position with one or two substituents independently selected from the group consisting of Ci-C4alkyl, hydroxyCi -C4alkyl, haloCi-C4alkyl, -CN, -OH and halo;(iv) 5- or 6-membered heteroaryl, wherein heteroaryl contains one or two heteroatoms, wherein said heteroatom(s) is / are N, wherein the heteroaryl is optionally substituted at any available position with one or two substituents independently selected from the group consisting of Ci-C4alkyl, hydroxyCi-C4alkyl, haloCi-C4alkyl, -CN, -OH and halo;(v) Cs-Cecycloalkyl optionally substituted at any available position with one or two substituents independently selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, hydroxyCi-C4alkyl, -OH and halo; and(vi) Ci-Cealkyl substituted at any available position with one or two substituents independently selected from the group consisting of -OH, halo, haloCi-C4alkyl, hydroxyCi-C4alkyl, and Ci-C4alkoxy.

20. The NLRP3 inflammasome pathway inhibitor compound for use according to claim 18 or 19, wherein the compound has the formula (la)or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; wherein Ro, Ri, R2, R3, R4, RA, Ra, Rc, Rd, Re and Y are as defined in claim 18, and V and X are independently selected from CRa.

21. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of claims 18 to 20, wherein Ra is H.

22. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of claims 18 to 21, wherein the compound has the formula (lb)or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; wherein Ro, R1, R2, RA, RC, Rd, Re and Y are as defined in claim 18.

23. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of claims 18 to 22, wherein Ro is H, R1 is -CF3, -Cl, -CH3 or -CN and R2 is -OH.

24. The NLRP3 inflammasome pathway inhibitor compound for use according to any one ofOH claims 18 to 23, wherein RA is selected from the group consistingwherein Rs is independently selected from -H, -Ci-Csalkyl, -CH2-NRdRe, Ci-C4alkyl-OH, and a 4-, 5- or 6-membered heterocycloalkyl containing one heteroatom selected from N and O;Rd and Re are each independently selected from the group consisting of H and -Ci-Caalkyl: R? and Rs are each independently selected from the group consisting of H, halo and Ci-Csalkyl; and n is selected from 0, 1 and 2.

25. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of claims 18 to 24, wherein RA is selected from the group consisting ofwherein n is selected from 0, 1 and 2.

26. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of claims 18 to 25, which isor a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.

27. A compound for use according to any one of claim 18 to 26, wherein the disease, disorder or abnormality is selected from the group consisting of hidradenitis suppurativa (HS), psoriasis, generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), acute generalized exanthematous pustulosis (AGEP), PAPA (pyogenic arthritis, PG and acne),PASH (PG, acne and suppurative hidradenitis), PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis), papulopustular rosacea and acne.

28. A compound for use according to any one of claim 18 to 27, wherein the use is in an obese subject.

29. A compound for use according to any one of claims 18 to 28 for use in the treatment, alleviation or prevention of a disease, disorder or abnormality is selected from the group consisting of hidradenitis suppurativa (HS), psoriasis, generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), acute generalized exanthematous pustulosis (AGEP), PAPA (pyogenic arthritis, PG and acne), PASH (PG, acne and suppurative hidradenitis), PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis), papulopustular rosacea and acne, together with the treatment, alleviation or prevention of comorbid obesity.

30. A method for treating or alleviating obesity, preferably diet-induced obesity, or a disease, disorder or abnormality associated therewith in a subject in need thereof, comprising administering a therapeutically effective amount of an NLRP3 inflammasome pathway inhibitor compound of formula (I)or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; whereinZi and Z2 are each selected from N and C whereby if Z1 is N, Z2 is C, and if Z1 is C, Z2 is N, preferably Z1 is N and Z2 is C;V, X and E are each independently selected from N and CRa; wherein at least one of V, X and E is CRa; indicates alternating single and double bonds;Ra is independently selected from the group consisting of -H, -Ci-Caalkyl, -CF3 and halo;Ro is selected from the group consisting of -H, -Ci-Csalkyl and -halo;R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, -CN and -halo;R2 is selected from the group consisting of -OH, -H, -OCF3, -OCHF2, -Ci-Csalkyl, -halo and -CF3;R3 is selected from the group consisting of -H, -Ci-Csalkyl, -OH, -CF3 and -halo;R4 is selected from the group consisting of -H, -Ci-Csalkyl, -CF3and -halo; andY is selected from NH, O, NRcOr a bond;Rc is Ci-C4alkyl; andRA is selected from the group consisting of a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is / are independently selected from N and O; a 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein said heteroatom(s) is / are N or O; a 5- or 6-membered aryl; a 5- or 6-membered heteroaryl, wherein heteroaryl contains one or two heteroatoms, wherein said heteroatom(s) is / are N; a Cs-Cecycloalkyl; and a Ci-Cealkyl; wherein the spiro or fused heterocycloalkyl bicyclic moiety, the heterocycloalkyl, the aryl, the heteroaryl, the Cs-Cecycloalkyl, or the Ci-Cealkyl is optionally substituted at any available position with one to three substituents which are independently selected from the group consisting of Ci-C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl, hydroxyCi-C4alkyl, halo, -OH, -CN, -NRaRe, -Ci-C4alkyl-NR<jRe, and a 4-, 5- or 6- membered heterocycloalkyl containing one or two heteroatoms selected from N and O, wherein Rd and Re are each independently selected from the group consisting of H and Ci-C4alkyl.

31. The method according to claim 30, wherein the method is for treating obesity, preferably diet-induced obesity.

32. The method according to claim 30, wherein the method is for reducing neuroinflammation, reducing microgliosis, reducing astrocytosis, improving insulin sensitivity, improving glucose metabolism, reducing body weight, reducing fat mass, reducing insulin resistance, reducing fasting glucose, reducing total cholesterol, reducing inflammation, reducing liver fibrosis and / or reducing liver inflammation, preferably an obese subject.

33. The method according to claim 30, wherein the method is for reducing neuroinflammation, reducing microgliosis, reducing astrocytosis, improving insulin sensitivity and / or improving glucose metabolism, preferably in an obese subject.

34. A method for reducing neuroinflammation, reducing microgliosis and / or improving insulin sensitivity, in a subject in need thereof, preferably in an obese subject, comprising administering a therapeutically effective amount of an NLRP3 inflammasome pathway inhibitor compound.

35. The method according to claim 34, wherein the method is for reducing microgliosis, preferably in an obese subject.

36. The method according to claim 30, wherein the method is for the treatment, prevention or alleviation of hidradenitis suppurativa (HS).

37. The method according to claim 36, wherein the subject is an obese subject.

38. The method according to claim 30, wherein the method is for the treatment, prevention or alleviation of comorbid hidradenitis suppurativa (HS) and obesity.

39. A method for treating or alleviating a disease, disorder or abnormality which is responsive to the modulation of IL-17A and / or IL36G in a subject in need thereof, comprising administering a therapeutically effective amount of an NLRP3 inflammasome pathway inhibitor compound of formula (I)or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; whereinZi and Z2 are each selected from N and C whereby if Z1 is N, Z2 is C, and if Z1 is C, Z2 is N, preferably Z1 is N and Z2is C;V, X and E are each independently selected from N and CRa; wherein at least one of V, X and E is CRa; indicates alternating single and double bonds;Ra is independently selected from the group consisting of -H, -Ci-C3alkyl, -CF3and halo;Ro is selected from the group consisting of -H, -Ci-C3alkyl and -halo;R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, -CN and -halo;R2 is selected from the group consisting of -OH, -H, -OCF3, -OCHF2, -Ci-C3alkyl, -halo and -CF3;R3 is selected from the group consisting of -H, -Ci-C3alkyl, -OH, -CF3and -halo;R4 is selected from the group consisting of -H, -Ci-C3alkyl, -CF3and -halo; andY is selected from NH, O, NRcOr a bond;Rc is Ci-C4alkyl; andRA is selected from the group consisting of a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is / are independently selected from N and O; a 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein said heteroatom(s) is / are N or O; a 5- or 6-membered aryl; a 5- or 6-membered heteroaryl, wherein heteroaryl contains one or two heteroatoms, wherein said heteroatom(s) is / are N; a C3-C6cycloalkyl; and a Ci-Cealkyl; wherein the spiro or fused heterocycloalkyl bicyclic moiety, the heterocycloalkyl, the aryl, the heteroaryl, the C3-C6cycloalkyl, or the Ci-Cealkyl is optionally substituted at any available position with one to three substituents which are independentlyselected from the group consisting of Ci-C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl, hydroxyCi-C4alkyl, halo, -OH, -CN, -NRdRe, -Ci-C4alkyl-NRdRe, and a 4-, 5- or 6- membered heterocycloalkyl containing one or two heteroatoms selected from N and O, wherein Rd and Re are each independently selected from the group consisting of H and Ci-C4alkyl.

40. The method according to claim 39, wherein the disease, disorder or abnormality is selected from the group consisting of hidradenitis suppurativa (HS), psoriasis, generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), acute generalized exanthematous pustulosis (AGEP), PAPA (pyogenic arthritis, PG and acne), PASH (PG, acne and suppurative hidradenitis), PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis), papulopustular rosacea and acne.

41. The method according to claim 40, wherein the subject is an obese subject.

42. The method according to claim 39 for use in the treatment, alleviation or prevention of a disease, disorder or abnormality is selected from the group consisting of hidradenitis suppurativa (HS), psoriasis, generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), acute generalized exanthematous pustulosis (AGEP), PAPA (pyogenic arthritis, PG and acne), PASH (PG, acne and suppurative hidradenitis), PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis), papulopustular rosacea and acne, together with treating, alleviating or preventing comorbid obesity.

43. The NLRP3 inflammasome pathway inhibitor compound for use according to any one of claims 1 to 29 or the method according to any one of claims 30 to 42, wherein the method comprises administering at least one additional therapeutic agent.

44. The NLRP3 inflammasome pathway inhibitor compound for use or the method according to claim 43, wherein the additional therapeutic agent targets obesity or a disease, disorder or abnormality associated therewith.

45. The NLRP3 inflammasome pathway inhibitor compound for use or the method according to claim 44, wherein the additional therapeutic agent is a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist, a glucagon receptor antagonist, and sodium-glucose cotransporter-2 (SGLT2) inhibitor, a Dipeptidyl peptidase-4 (DPP-4) inhibitor, a thiazolidinedone (TZD) or insulin.

46. The NLRP3 inflammasome pathway inhibitor compound for use or the method according to claim 45, wherein the additional therapeutic agent is a glucagon-like peptide-1 (GLP-1) receptor agonist.

47. The NLRP3 inflammasome pathway inhibitor compound for use or the method according to any one of claims 43 to 46, wherein the additional therapeutic agent is selected from the group consisting of semaglutide, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, tirzepatide, survodutide, retatrutide, orforglipron, mazdutide, pemvidutide, cagrilinitide, efinopegdutide, maridebart / cafraglutide, danuglipron, and retatrutide.

48. The NLRP3 inflammasome pathway inhibitor compound for use or the method according to any one of claims 43 to 47, wherein the additional therapeutic agent is semaglutide.

49. The NLRP3 inflammasome pathway inhibitor compound for use or the method according to any one of claims 43 to 48, wherein the additional therapeutic agent is administered prior to, in alternation, at the same time as, or in temporal proximity, or after the treatment with the NLRP3 inflammasome pathway inhibitor compound defined in any one of claims 1 to 9.

50. The NLRP3 inflammasome pathway inhibitor compound for use or the method according to any one of claims 1 to 49, wherein the NLRP3 inhibitor compound is administered orally.

51. The NLRP3 inflammasome pathway inhibitor compound for use or the method according to any one of claims 1 to 50, wherein the NLRP3 inhibitor compound is administered at a dose of from about 0.1mg / kg to about 50mg / kg, preferably from about 0.2mg / kg to about 20mg / kg, more preferably from about 0.3mg / kg to about 10mg / kg.

52. The NLRP3 inflammasome pathway inhibitor compound which isor a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in combination with semaglutide in the treatment, alleviation or prevention of obesity, preferably diet-induced obesity, and / or a disease, disorder or abnormality associated therewith.

53. The NLRP3 inflammasome pathway inhibitor compound which isor a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in combination with semaglutide in reducing neuroinflammation, reducing microgliosis, and / or improving insulin sensitivity, preferably in an obese subject.

54. The NLRP3 inflammasome pathway inhibitor compound which isor a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in combination with semaglutide for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation of IL-17A and / or IL36G.

55. A kit comprising the NLRP3 inflammasome pathway inhibitor compound or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof and a glucagon-like peptide-1 (GLP-1) receptor agonist and optionally instructions for use, wherein the NLRP3 inflammasome pathway inhibitor compound is a compound of formula (I)whereinZi and Z2 are each selected from N and C whereby if Z1 is N, Z2is C, and if Z1 is C, Z2isN, preferably Z1 is N and Z2is C;V, X and E are each independently selected from N and CRa; wherein at least one of V, X and E is CRa! indicates alternating single and double bonds;Ra is independently selected from the group consisting of -H, -Ci-Csalkyl, -CF3 and halo;Ro is selected from the group consisting of -H, -Ci-Csalkyl and -halo;Ri is selected from the group consisting of -CF3, -OCF3, -OCHF2, -Ci-Csalkyl, -CN and -halo;R2 is selected from the group consisting of -OH, -H, -OCF3, -OCHF2, -Ci-Csalkyl, -halo and -CF3;R3 is selected from the group consisting of -H, -Ci-Csalkyl, -OH, -CF3 and -halo;R4 is selected from the group consisting of -H, -Ci-Csalkyl, -CF3 and -halo; andY is selected from NH, O, NRcOr a bond;Rc is Ci-C4alkyl; andRA is selected from the group consisting of a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is / are independently selected from N and O; a 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein said heteroatom(s) is / are N or O; a 5- or 6-membered aryl; a 5- or 6-membered heteroaryl, wherein heteroaryl contains one or two heteroatoms, wherein said heteroatom(s) is / are N; a Cs-Cecycloalkyl; and a Ci-Cealkyl; wherein the spiro or fused heterocycloalkyl bicyclic moiety, the heterocycloalkyl, the aryl, the heteroaryl, the Cs-Cecycloalkyl, or the Ci-Cealkyl is optionally substituted at any available position with one to three substituents which are independently selected from the group consisting of Ci-C4alkyl, Ci-C4alkoxy, haloCi-C4alkyl, hydroxyCi-C4alkyl, halo, -OH, -CN, -NRdRe, -Ci-C4alkyl-NRdRe, and a 4-, 5- or 6- membered heterocycloalkyl containing one or two heteroatoms selected from N and O, wherein Rd and Re are each independently selected from the group consisting of H and Ci-C4alkyl.

56. A kit comprising an NLRP3 inflammasome pathway inhibitor compound, semaglutide and optionally instructions for use, wherein the NLRP3 inflammasome pathway inhibitor compound isor a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.

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