Compounds as NLRP3 inflammasome inhibitors and their use as pharmaceuticals

Abstract

The present invention relates to a hexahydro-s-indacene compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein A is selected from the group consisting of (A1), (A2) and (A3), R1 is a heterocyclic substituent selected from the group consisting of H, halogen, CF3, (C1-C3) alkyl, (C1-C3) alkoxy, NH2, NO2, CN, COOH, piperidine, morpholine and optionally substituted piperazine, a substituent selected from -NHCH2Ph, -N((C1-C2) alkyl)2, -NH((C2-C4) alkyl)-NH2, -COO((C1-C2) alkyl, and -NHEt; and X is -(CH2) n -, n is equal to 0 to 1; R2 is a substituent selected from NH2 and NO2; R3 is a substituent selected from the group consisting of H, alkyl(C1-C4), alkyl(C1-C4)NH2, phenyl, benzyl, and hydroxybenzyl; Y is -(CH2) n -, n is equal to 0 or 1; and R4 is a substituent selected from NH2 and NO2. The compounds of the present invention are pharmaceuticals for use in treating immunopathologies associated with NLRP3 inflammasome, such as cancer, metabolic disorders, migraine headaches, wound repair, neurodegenerative diseases and autoimmune diseases. The hexahydro-s-indacene compounds of the present invention are selective inhibitors of the activation of NLRP3 inflammasome, and as such, can reduce the production of interleukin-1β and interleukin-18 via NLRP3 in mammalian cells and tissues. JPEG2025515371000122.jpg70170

Description

[Technical field]

[0001] The present invention relates to hexahydro-s-indacene compounds, their pharma- ceutically acceptable salts, and their use as pharmaceuticals.Specifically, the present invention provides selective inhibitors of NLRP3 inflammasome activation, which can reduce NLRP3-mediated interleukin-1β (IL-1β) and interleukin-18 (IL-18) production in mammalian cells and tissues.Therefore, the compounds of the present invention can be used to treat pathologies associated with the overactivation of NLRP3 inflammasome, which leads to overproduction of IL-1β and IL-18, such as cancer, metabolic disorders, neurodegenerative diseases, autoimmune diseases, etc. [Background technology]

[0002] The NLRP3 inflammasome is a multimeric protein complex formed by Nod-like receptor family proteins containing pyrin domain 3 (NLRP3), the adaptor protein apoptosis-associated speck-like protein (ASC), and the effector protein procaspase-1. Upon activation, NLRP3 oligomerizes and interacts with ASC through its N-terminal pyrin domain (PYD). ASC then recruits and binds procaspase-1 through the shared domain CARD (caspase activation and recruitment domain), inducing the activation of caspase-1 by autolysis. Caspase-1 then induces the maturation and release of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) (S. Missiroli et al. Cell Death Dis 2018; 9:329).

[0003] NLRP3 inflammasome activation requires two steps, priming and activation, to exert its biological effects (S. Paik et al. Cell Mol Immunol 2021;18:1141). The priming step is provided by inflammatory stimuli involving Toll-like receptors (TLRs), inducing NFKB-mediated NLRP3 and pro-IL-1β expression and post-translational modifications of NLRP3. The activation step is triggered by exposure to damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), or other stimuli that promote NLRP3 inflammasome assembly and eventual release of IL-1β and IL-1 (K V. Swanson et al. Nat Rev Immunol. 2019;19:477).

[0004] The NLRP3 inflammasome has been found to be associated with several inflammatory diseases, including neurodegenerative and metabolic diseases, atherosclerosis, and cancer (K ​​V. Swanson et al. Nat Rev Immunol. 2019; 19:477). In recent years, the role of the NLRP3 inflammasome in controlling cancer has attracted attention, and studies have revealed a complex scenario in which NLRP3 acts as a double-edged sword. However, the clinical relevance of the NLRP3 inflammasome in different stages of tumorigenesis may lead to potential strategies for the development of new anticancer therapies (S. Missiroli et al. Cancers (Basel) 2021; 13:2297).

[0005] These discoveries prompted the development of potent and selective NLRP3 inhibitors, which have become widely used as pharmacological tools to elucidate the potential clinical applications of NLRP3-targeted strategies (M. Su et al. Curr Med Chem 2021; 28:569; X. Zhang et al. Eur J Med Chem 2020; 185:111822; Adam G Schwaid et al. J Med Chem 2021; 64:101-122). Among these, MCC950, N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide, is the most studied NLRP3 inhibitor (RC Coll et al. Nat Med 2015; 21:248).

[0006] MCC950 has been demonstrated to inhibit canonical and noncanonical NLRP3 activation at nanomolar concentrations in vitro with higher selectivity than AIM2, NLRC4, or NLRP1 inflammasomes. In preclinical studies, the compound showed efficacy in different in vivo models with good oral bioavailability and reached phase II clinical trials as a potential treatment for rheumatoid arthritis. However, the study was stopped after it was found that the molecule could induce elevated liver enzyme levels in serum. The reason remains unclear (MSJ Mangan et al. Nat Rev Drug Discov 2018;17:588). In cancer therapy, MCC950 has been shown to inhibit cell proliferation in chronic myeloid leukemia (S. Hamarsheh et al. Nat Commun 2020;11:1659) and pancreatic adenocarcinoma (ACK Yaw et al. J Cancer Res Clin Oncol 2020;146:2219), as well as slow tumor growth in a mouse model of head and neck squamous cell carcinoma (L. Chen et al. Cell Mol Life Sci 2018;75:2045).

[0007] Currently, treatment of NLRP3-related immunopathology is based on the inhibition of the cytokine IL-1β, which is produced by the inflammasome. The US Food and Drug Administration (FDA) has approved three biologics for the treatment of several inflammatory diseases: the monoclonal antibody canakinumab, which neutralizes IL-1β; the IL-1 receptor antagonist anakinra; and rilonacept, a receptor “bait” that binds IL-1β and IL-1α. Two other biologics, GSK1070806, an antibody against IL-18, and MABp1, an antibody against IL-1α, are in early stages of development (K V. Swanson et al. Nat Rev Immunol. 2019; 19:477).

[0008] Despite the therapeutic potential of such biologics, they have demonstrated limited efficacy in some clinical conditions and are generally characterized by high production costs.

[0009] Direct targeting of NLRP3 with small molecular weight molecules has the advantage of being a highly selective, cost-effective and less invasive approach to cytokine blockade. Indeed, inflammasome activation is essential for immune control of numerous pathogens, so a complete deficiency of IL-1β may have detrimental effects on immune defense. Many of the new therapies advancing in clinical trials are specific for NLRP3 activation and do not affect other inflammasome functions. The increasing number of patients suffering from inflammatory diseases, along with Western lifestyles and an aging population, is likely to increase the need for specific therapies against NLRP3. Thus, there is an increasing need to identify new compounds that selectively inhibit NLRP3 that can be developed as innovative therapeutic approaches in oncology and, more generally, for the treatment of immune diseases that involve the overproduction of IL-1β due to overactivation of the NLRP3 inflammasome. Summary of the Invention

[0010] The inventors have designed and identified novel small molecular weight molecules that can selectively inhibit the activation of the NLRP3 inflammasome both in live mammalian cells and in vivo animal models by reducing the associated production of IL-1β and IL-18.

[0011] Accordingly, the present invention relates to a hexahydro-s-indacene compound of formula (I) or a pharma- ceutically acceptable salt thereof: [ka] In the formula, A is [ka] is selected from the group consisting of: During the ceremony, R1 is a heterocyclic substituent selected from the group consisting of H, halogen, CF3, (C1-C3)alkyl, (C1-C3)alkoxy, NH2, NO2, CN, COOH, piperidine, morpholine, and optionally substituted piperazine, a substituent selected from -NHCH2Ph, -N((C1-C2)alkyl)2, -NH((C2-C4)alkyl)-NH2, -COO((C1-C2)alkyl, and -NHEt; X is -(CH2) n - where n is equal to 0 to 1; R2 is a substituent selected from NH2 and NO2; R3 is a substituent selected from the group consisting of H, alkyl(C1-C4), alkyl(C1-C4)NH2, phenyl, benzyl and hydroxybenzyl; Y is -(CH2) n - where n is equal to 0 or 1; and R4 is a substituent selected from NH2 and NO2.

[0012] In a first preferred embodiment, A is A1, and the present invention relates to a tetrahydroisoquinoline compound of formula (II) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony R1 is a heterocyclic substituent selected from the group consisting of H, halogen, CF3, (C1-C3)alkyl, (C1-C3)alkoxy, NH2, NO2, CN, COOH, piperidine, morpholine, and optionally substituted piperazine, a substituent selected from -NHCH2Ph, -N((C1-C2)alkyl)2, -NH((C2-C4)alkyl)-NH2, -COO((C1-C2)alkyl, and -NHEt.

[0013] In a second preferred embodiment, A is A2, and the present invention relates to a sulfonamide compound of formula (III) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, X is -(CH2) n - where n is equal to 0 to 1; R1 is a substituent selected from NH2 and NO2; R2 is a substituent selected from the group consisting of H, alkyl(C1-C4), alkyl(C1-C4)NH2, phenyl, benzyl and hydroxybenzyl.

[0014] In a third preferred embodiment, A is A3, and the present invention relates to a pyrrolidine / piperidine compound of formula (IV) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, Y is -(CH2) n - where n is equal to 0 or 1; and R4 is a substituent selected from NH2 and NO2.

[0015] The compounds of the present invention of formula (I), (II), (III) and (IV) can treat pathologies associated with NLRP3 hyperactivation, and in particular inhibit tumor growth in animal models. Thus, the present invention relates to a therapeutic approach consisting of the use of novel compounds useful in the clinical management of pathologies such as cancer, metabolic disorders, neurodegenerative diseases and autoimmune diseases.

[0016] In the present invention, when referring to compounds of formula (I), (II), (III) and (IV), it is meant to include all possible tautomers and optical isomers, such as enantiomers and / or diastereoisomers, or mixtures thereof (as racemates or in various ratios).

[0017] In another embodiment, the invention relates to a hexahydro-s-indacene compound of formula (I) or a pharma- ceutically acceptable salt thereof for use as a medicine.

[0018] In a further embodiment, the present invention relates to a hexahydro-s-indacene compound of formula (I) or a pharma- ceutically acceptable salt thereof for use as a selective inhibitor of the NLRP3 inflammasome, preferably in the treatment of pathologies associated with overactivation of NLRP3 and overproduction of interleukin-1β and interleukin-18.

[0019] The present invention provides compounds of formula (I) as modulators of NLRP3 in mammalian cells and tissues.

[0020] In the present invention, "halogen" means fluorine, chlorine, bromine and iodine. The present invention also includes pharmaceutical compositions containing one or more compounds of formula (I), (II), (III) and (IV) as an active ingredient, together with pharma- ceutically acceptable excipients and, optionally, additives and stabilizers used in pharmaceuticals. For a better understanding of the present invention, reference is now made to the accompanying drawings, in which: FIG. [Brief description of the drawings]

[0021] [Figure 1] FIG. 1 shows a synthetic scheme for the preparation of compounds of formula (II) according to Examples 1-6. (Reagents and conditions shown in the diagram: i. 4-nitrobenzenesulfonyl chloride, NaHCO3, HO, room temperature, 16h; ii. hexahydro-s-indacen-4-amine, HATU, DIPEA, DMF, 0°C to room temperature, 2-5h; iii. HPd / C, CH3COOH, EtOAc, room temperature, 16h; iv. substituted benzenesulfonyl chloride, K2CO3, HO, THF, room temperature, 2h; v. various primary or secondary amines, DMSO, 120°C, 4-16h; vi. 9d, LiOH, HO, MeOH, room temperature, 2h). [Diagram 2] Figures 2, A, B, C, D, and E report the results of Examples 7, 8, and 9. Specifically, Figure 2A reports cell viability of THP-1 cells as measured by the RealTime-Glo MT cell viability assay. Cells were treated with compound 4 at a concentration of 1 μM and monitored for 48 h; Figure 2B reports IL-1β and IL-18 production as measured by ELISA from BMDMs and THP-1 cells stimulated with lipopolysaccharide (LPS) (1 μg / mL, 2 h), treated with compound 4 (1-1,000 nM) for 30 min, and finally stimulated with ATP (5 mM, 1 h). Cytokine levels are normalized to values ​​from DMSO-treated control cells. Nonlinear regression analysis was performed; Figure 2C reports the results of Western blot analysis of NLRP3 inflammasome components in THP-1 cells before and after activation with LPS and ATP, and compound 4. Expression of NLRP3, caspase-1, pro-IL-1β, and ASC proteins was analyzed in total cell lysates and normalized to GAPDH (Figure 2D); expression of caspase-1 and released IL-1β was analyzed in the medium and normalized to Ponceau (S.) (Figure 2C). Figures 2E and 2F report IL-1β production in the supernatants of LPS-primed BMDMs treated with compound 4 and transfected with S. Typhimurium flagellin (E) or poly(dA:dT) (F). Figures 2G and 2H report the results of IL18 secretion upon NLRP-3 stimulation. [Diagram 3] Figures 3A and B report the results of Example 10. Specifically, the figures report IL-1β production, as measured by experimental ELISA, from blood (A) and peritoneal supernatants (B) of C57BL / 6 mice pretreated with compound or vehicle for 30 min and then administered LPS (1 mg / kg) by intraperitoneal injection for 4 h. Data are presented as mean ± SEM of three independent experiments. **p<0.01, ***p<0.001, ****p<0.0001. [Figure 4] Figure 4A, B, C, D, E report the results of Example 11, where C57BL / 6 mice (5 per condition) were subcutaneously inoculated with B16-F10cytLUC melanoma cells (1x106). Specifically, Figure 4A reports tumor growth kinetics at the indicated time points, Figure 4B reports ex vivo quantification of tumor volume measured with calipers 14 days after injection, Figure 4C reports representative resected tumors photographed 14 days after injection, Figure 4D reports representative images of intracellular LUC luminescence, and Figure 4E reports representative western blots and relative quantification showing levels of NLRP3, caspase-1, and ASC proteins in tumors derived from B16-F10cytLUC melanoma cells inoculated into C57BL / 6 mice. Error bars indicate SEM **p<0.01, ****p<0.0001. Figures 4F and G report the results of Examples 12 and 13, which evaluated the effect of compounds on the growth of B16-F10 tumor cells. Specifically, Figure 4F reports the growth curves of B16-F10 cells after compound treatment, and Figure 4G reports the effect of compounds on the tumor microenvironment through a co-culture model of peritoneal macrophages and B16-F10 cells. Error bars indicate SEM****p<0.0001. [Diagram 5]FIG. 5 shows a synthetic scheme for preparing the compound of formula (III) according to Examples 14, 15, and 16 (reagents and conditions shown in the diagram: i. 4-nitrobenzenesulfonyl chloride, NaHCO3, HO, room temperature, 16 h; ii. hexahydro-s-indacen-4-amine, HATU, DIPEA, DMF, 0° C. to room temperature, 2 to 5 h; iii. H2 Pd / C, CH3COOH, EtOAc, room temperature, 16 h; iv. 4N HCl in dioxane, 2 h). [Figure 6] Figures 6, A, B, C, D, E report the results of Examples 17, 18, and 19. Specifically, Figure 6A reports cell viability of THP-1 cells as measured by RealTime-Glo MT cell viability assay. Cells were treated with selected compounds (6c and 10) at a concentration of 1 μM and monitored for 48 h. Figure 6B reports IL-1β production, measured by ELISA, from BMDMs and THP-1 cells stimulated with lipopolysaccharide (LPS) (1 μg / mL, 2 h), treated with compounds (1–1,000 nM) for 30 min, and finally stimulated with ATP (5 mM, 1 h). Cytokine levels were normalized relative to values ​​from DMSO-treated control cells. Nonlinear regression analysis was performed, and Figure 6C reports the results of Western blot analysis of NLRP3 inflammasome components in THP-1 cells before and after activation with LPS and ATP, and selected compounds. Expression of NLRP3, caspase-1, pro-IL-1β, and ASC proteins was analyzed in total cell lysates and normalized to GAPDH (Figure 6D); expression of caspase-1 and released IL-1β was analyzed in culture medium and normalized to Ponceau (S.) (Figure 6C). Figures 6E and 6F report IL-1β production in the supernatants of LPS-primed BMDMs treated with compounds and transfected with S. Typhimurium flagellin (E) or poly(dA:dT) (F). Figures 6G and 6H report the results for NLRP3-stimulated secretion of IL-18 in BMDMs and THP-1 cells, respectively. Data presented as mean ± SEM from three independent experiments. *p<0.05. [Figure 7]Figures 7A and 7B report the results of Example 20. Specifically, the figures report IL-1β production measured by test ELISA from blood (part A) and peritoneal supernatants (part B) of C57BL / 6 mice pretreated with compounds 6c and 10 or vehicle for 30 min, followed by treatment with LPS (1 mg / kg) by intraperitoneal injection for 4 h. Data presented as mean ± SEM from three independent experiments. **p<0.01, ***p<0.001, ***p<0.0001. [Figure 8] Figure 8A, B, C, D, E report the results of Example 21, where C57BL / 6 mice (5 per condition) were subcutaneously inoculated with B16-F10cytLUC melanoma cells (1x106). Specifically, Figure 8A reports tumor growth kinetics at the indicated time points; Figure 8B reports ex vivo quantification of tumor volume assessed with calipers 14 days after injection; Figure 8C reports representative excised tumors imaged 14 days after injection; Figure 8D is a representative photograph of cytLUC luminescence; Figure 8E reports representative Western blots showing the amount and relative quantification of NLRP3, caspase-1, ASC and pro-IL1β protein levels in tumors from B16-F10cytLUC melanoma cells inoculated into C57BL / 6 mice. Error bars indicate SEM. **p<0.001, ***p<0.0001. Figures 8F and G report the results of Examples 22 and 23, which evaluated the effect of compounds on the proliferation of B16-F10 tumor cells. Specifically, Figure 8F reports the growth curves of B16-F10 cells after compound treatment, and Figure 8G reports the effect of compounds on the tumor microenvironment in a co-culture model of peritoneal macrophages and B16-F10 cells. Error bars indicate SEM****p<0.0001. [Figure 9]FIG. 9 shows the synthetic scheme for preparing compounds of formula (IV) according to examples 24, 25 and 26. Compounds of formula (IV) were prepared starting from α-amino acids proline (1a) or pipecolic acid (1b) by reaction with 4-nitrobenzenesulfonyl chloride in the presence of NaHCO3 to give intermediates 2a-b (FIG. 9). Subsequent amide coupling with hexahydro-s-indacen-4-amine in the presence of HATU and DIPEA gave compounds 3a-b, which were finally reduced by catalytic hydrogenation to give the corresponding aniline derivatives 4a-b. (Reagents and conditions shown in the diagram: i. 4-nitrobenzenesulfonyl chloride, NaHCO3, H2O, room temperature, 16 h; ii. hexahydro-s-indacen-4-amine, HATU, DIPEA, DMF, 0°C-room temperature, 2-5 h; iii. H2 Pd / C, CH3COOH, EtOAc, room temperature, 16 h). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Detailed Description of the Invention Accordingly, the present invention relates to a hexahydro-s-indacene compound of formula (I) or a pharma- ceutically acceptable salt thereof; [ka] In the formula, A is [ka] is selected from the group consisting of During the ceremony, R1 is a heterocyclic substituent selected from the group consisting of H, halogen, CF3, (C1-C3)alkyl, (C1-C3)alkoxy, NH2, NO2, CN, COOH, piperidine, morpholine, and optionally substituted piperazine, a substituent selected from -NHCH2Ph, -N((C1-C2)alkyl)2, -NH((C2-C4)alkyl)-NH2, -COO((C1-C2)alkyl, and -NHEt; X is -(CH2) n - where n is equal to 0 to 1; R2 is a substituent selected from NH2 and NO2; R3 is a substituent selected from the group consisting of H, alkyl(C1-C4), alkyl(C1-C4)NH2, phenyl, benzyl and hydroxybenzyl; Y is -(CH2) n - where n is equal to 0 or 1; and R4 is a substituent selected from NH2 and NO2.

[0023] In the present invention, the following terms may be used: "Compound of the invention" means a compound of formula (I) as defined above in any form, i.e. in any physical form, including any salt or non-salt form, as well as non-solid forms and solid, crystalline, amorphous, polymorphic, solvated forms including hydrates (e.g. mono-, di-, hemi-hydrates and various mixtures of these forms); · "(C1-C4) alkyl" means a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms; "(C1-C3)alkyl-NH2" means a linear or branched hydrocarbon group containing from 1 to 3 carbon atoms attached to an amino group; · "(C1-C3) alkyl" means a straight or branched chain hydrocarbon group containing from 1 to 3 carbon atoms; "(C1-C2) alkyl" means a straight chain hydrocarbon group containing from 1 to 2 carbon atoms; "(C2-C4) alkyl" means a straight or branched chain hydrocarbon group containing from 2 to 4 carbon atoms; "(C1-C3)alkoxy" means a substituent of the structure (alkyl chain)-O- having 1 to 3 carbon atoms; "Halogen" means fluorine, chlorine, bromine and iodine; ·-"optionally substituted" means that the structure may be unsubstituted or substituted with the specified substituents; "heterocyclic substituents selected from the group consisting of piperidine, morpholine and optionally substituted piperazine" means heterocyclic substituents selected from piperidine, morpholine and piperazine, the latter being optionally substituted on the nitrogen atom by a substituent, and "Compounds of formula (I), (II), (III), (IV)" include all possible tautomers and optical isomers, such as enantiomers and / or diastereoisomers or mixtures thereof (as racemates or in various ratios), and possible pharma- ceutically acceptable salts.

[0024] In a first preferred embodiment of the present invention, A is A1 and the compound of formula (I) is a tetrahydroisoquinoline compound of formula (II) or a pharma- ceutically acceptable salt thereof. [ka] During the ceremony, R1 is a heterocyclic substituent selected from the group consisting of H, halogen, CF3, (C1-C3)alkyl, (C1-C3)alkoxy, NH2, NO2, CN, COOH, piperidine, morpholine, and optionally substituted piperazine, a substituent selected from -NHCH2Ph, -N((C1-C2)alkyl)2, -NH((C2-C4)alkyl)-NH2, -COO((C1-C2)alkyl, and -NHEt.

[0025] According to the present invention, R1 is a heterocyclic substituent selected from the group consisting of H, halogen, CF3, (C1-C3)alkyl, (C1-C3)alkoxy, NH2, NO2, CN, COOH, piperidine, morpholine and optionally substituted piperazine, -NHCH2Ph, -N((C1-C2)alkyl)2, -NH((C2-C4)alkyl)-NH2, COO(C1-C2)alkyl, and -NHEt.

[0026] Preferably, R1 is NH2 or NO2. When R1 is (C1-C3)alkyl, it can be methyl, ethyl, propyl or isopropyl. When R1 is halogen it is fluorine, chlorine, bromine or iodine, preferably fluorine. When R1 is (C1-C3)alkoxy, it is preferably methoxy, ethoxy, propoxy or isopropoxy.

[0027] When R1 is a heterocyclic substituent selected from the group consisting of piperidine, morpholine and optionally substituted piperazine, it is preferably piperidine, morpholine or piperazine, the latter being optionally substituted on the nitrogen atom, preferably with methyl or tert-butoxycarbonyl. Such heterocyclic substituents are preferably [ka] is selected from the group consisting of:

[0028] When R1 is N((C1-C2)alkyl)2, it is preferably N(CH2CH3)2 or -NHCH2CH2NH 2. It is. When R1 is NH((C2-C4)alkyl)-NH2, it is preferably NHCH2CH2NH2 or NHCH2CH2CH2CH2NH2. When R1 is COO((C1-C2)alkyl), it is COOMe or COOEt. In an advantageous and preferred embodiment, R1 is NH2 or NO2.

[0029] Advantageously, the invention relates to a tetrahydroisoquinoline compound of formula (II) selected from the group consisting of: (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (3 of formula (II)) [ka]

[0030] (S)-2-((4-aminophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (4 of formula (II)) [ka]

[0031] (S)-2-((4-fluorophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (6 of formula (II)) [ka]

[0032] (S)-2-((4-(benzylamino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7a of formula (II)) [ka]

[0033] (S)-2-((4-(dimethylamino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7b of formula (II)) [ka]

[0034] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-(piperidin-1-yl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7c of formula (II)) [ka]

[0035] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-morpholinophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7d of formula (II)) [ka]

[0036] (S)-2-((4-(diethylamino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7e of formula (II)) [ka]

[0037] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-(piperazin-1-yl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7f of formula (II)) [ka]

[0038] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7g of formula (II)) [ka]

[0039] tert-Butyl (S)-4-(4-((3-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)piperazine-1-carboxylate (7h of formula (II)) [ka]

[0040] (S)-2-((4-(ethylamino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7i of formula (II)) [ka]

[0041] (S)-2-((4-((2-aminoethyl)amino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7j of formula (II)) [ka]

[0042] (S)-2-((4-((4-aminobutyl)amino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7k of formula (II)) [ka]

[0043] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (9a of formula (II)) [ka]

[0044] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (9b of formula (II)) [ka]

[0045] (S)-2-((4-cyanophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (9c of formula (II)) [ka]

[0046] (S)-Methyl 4-((3-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)benzoate (9d of formula (II)) [ka]

[0047] (S)-4-((3-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)benzoic acid (10 of formula (II)) [ka]

[0048] More preferably and advantageously, the tetrahydroisoquinoline compound of formula (II) is selected from the group consisting of: (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (3 of formula (II)) [ka]

[0049] (S)-2-((4-aminophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (4 of formula (II)) [ka]

[0050] Without being bound by any theory, the inventors believe that the basic structure of the molecule of formula (II) is active as a selective inhibitor of the NLRP3 inflammasome, precisely in the definition of R1.

[0051] In a second preferred embodiment, A is A2, and the invention relates to a sulfonamide compound of formula (III) or a pharma- ceutically acceptable salt thereof. [ka] During the ceremony, X is -(CH2) n - where n is equal to 0 to 1; R2 is a substituent selected from NH2 and NO2; R3 is a substituent selected from the group consisting of H, alkyl(C1-C4), alkyl(C1-C4)NH2, phenyl, benzyl and hydroxybenzyl.

[0052] According to the present invention, X is -(CH2) n -, where n is equal to 0 or 1. Preferably, n is equal to 0. R2 is a substituent selected from NH2 and NO2, while R3 is a substituent selected from the group consisting of H, alkyl(C1-C4), alkyl(C1-C4)NH2, phenyl, benzyl and hydroxybenzyl; When R3 is alkyl (C1-C4), it is preferably CH3, CH(CH3)2, CH2CH(CH3)2. When R3 is alkyl(C1-C4)NH2, it is preferably -(CH2)4NH2. More preferably, R3 is isopropyl, CH2CH(CH3)2, benzyl or hydroxybenzyl, and even more preferably isopropyl or p-hydroxybenzyl.

[0053] Advantageously, the invention relates to sulfonamide compounds of formula (III) selected from the group consisting of: N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)acetamide (6a of formula (III)) [ka]

[0054] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)propanamide (6b of formula (III)) [ka]

[0055] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-methyl-2-((4-nitrophenyl)sulfonamido)butanamide (6c of formula (III)) [ka]

[0056] (R)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-methyl-2-((4-nitrophenyl)sulfonamido)butanamide (6d of formula (III)) [ka]

[0057] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-4-methyl-2-((4-nitrophenyl)sulfonamido)pentanamide (6e of formula (III)) [ka]

[0058] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)-2-phenylacetamide (6f of formula (III)) [ka]

[0059] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)-3-phenylpropanamide (6g of formula (III)) [ka]

[0060] (R)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)-3-phenylpropanamide (6h of formula (III)) [ka]

[0061] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-(4-hydroxyphenyl)-2-((4-nitrophenyl)sulfonamido)propanamide (8 of formula (III)) [ka]

[0062] (S)-6-Amino-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)hexanamide (9 of formula (III)) [ka]

[0063] N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-((4-nitrophenyl)sulfonamido)propanamide (6k of formula (III)) [ka]

[0064] 2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide (7a of formula (III)) [ka]

[0065] (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)propanamide (7b of formula (III)) [ka]

[0066] (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-methylbutanamide (7c of formula (III)) [ka]

[0067] (R)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-methylbutanamide (7d of formula (III)) [ka]

[0068] (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-4-methylpentanamide (7e of formula (III)) [ka]

[0069] (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-phenylacetamide (7f of formula (III)) [ka]

[0070] (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-phenylpropanamide (7g of formula (III)) [ka]

[0071] (R)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-phenylpropanamide (7h of formula (III)) [ka]

[0072] (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-(4-hydroxyphenyl)propanamide (10 of formula (III)) [ka]

[0073] (S)-6-Amino-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)hexanamide (11 of formula (III)) [ka]

[0074] 3-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)propanamide (7k of formula (III)) [ka]

[0075] Preferably, the compound of the invention of formula (III) is selected from the group consisting of: (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-methyl-2-((4-nitrophenyl)sulfonamido)butanamide (6c of formula (III)) [ka]

[0076] (R)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)-3-phenylpropanamide (6h of formula (III)) [ka]

[0077] (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-methylbutanamide (7c of formula (III)) [ka]

[0078] (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-4-methyl-2-((4-nitrophenyl)sulfonamido)pentanamide (6e of formula (III)) [ka]

[0079] (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-(4-hydroxyphenyl)propanamide (10 of formula (III)) [ka]

[0080] More preferably and advantageously, the sulfonamide compound of formula (III) is selected from the group consisting of: (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-methyl-2-((4-nitrophenyl)sulfonamido)butanamide (6c of formula (III)) [ka]

[0081] (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-(4-hydroxyphenyl)propanamide (10 of formula (III)) [ka]

[0082] In a third preferred embodiment, A is A3, and the present invention relates to a pyrrolidine / piperidine compound of formula (IV) or a pharma- ceutically acceptable salt thereof. [ka] Y is -(CH2) n - where n is equal to 0 or 1; and R4 is a substituent selected from NH2 and NO2.

[0083] In a preferred embodiment of the invention, when Y is equal to 1, R4 is preferably NO2. In a further preferred embodiment of the invention, when Y is equal to 0, R4 is preferably NH2.

[0084] Advantageously, the invention relates to compounds of formula (IV) selected from the group consisting of: N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-((4-nitrophenyl)sulfonyl)pyrrolidine-2-carboxamide (3a of formula (IV)) [ka]

[0085] 1-((4-aminophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)piperidine-2-carboxamide (4b of formula (IV)) [ka]

[0086] N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-((4-nitrophenyl)sulfonyl)piperidine-2-carboxamide (3b of formula (IV)) [ka]

[0087] 1-((4-aminophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)pyrrolidine-2-carboxamide (4a of formula (IV)) [ka]

[0088] Preferably, the compound of the invention of formula (IV) is selected from the group consisting of: N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-((4-nitrophenyl)sulfonyl)piperidine-2-carboxamide (3b of formula (IV)) [ka]

[0089] 1-((4-aminophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)pyrrolidine-2-carboxamide (4a of formula (IV)) [ka]

[0090] The compound of formula (I) may be in the form of a pharma- ceutically acceptable salt thereof, preferably selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, acetate, succinate, oxalate, ascorbate, tartrate, gluconate, benzoate, maleate, fumarate and stearate.

[0091] The present invention also relates to the use of, for example, tritium ( 3 H), Carbon ( 14 C), iodine ( 125 The present invention also includes a compound of formula (I) labeled with at least one radioisotope, such as 1,2-dichlorophenyl ether (1,2,3,4-trifluoroethylene), or a fluorescent probe, PET (positron emission tomography), or SPECT (single photon emission computed tomography).

[0092] In another aspect, the present invention relates to a hexahydro-s-indacene compound of formula (I) or a pharma- ceutically acceptable salt thereof for use as a medicament.

[0093] In another aspect, the present invention relates to a composition comprising a hexahydro-s-indacene compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0094] For the purposes of therapeutic application, the compounds described herein may therefore be suitably formulated, either as such or in association with one or more pharma- ceutically acceptable excipients and / or carriers in suitable pharmaceutical compositions for administration to mammals, particularly humans. Compositions of the invention include those intended for oral, nasal, sublingual, and particularly parenteral (subcutaneous, intramuscular, intravenous, and intradermal) administration in the form of aqueous and non-aqueous sterile injectable preparations (solutions or suspensions).

[0095] Thus, preferably, the compositions of the present invention include pharma- ceutically acceptable carriers and excipients suitable for the ultimate desired formulation depending on the possible and desired route of administration.

[0096] The pharma- ceutically acceptable additives may be excipients, binders, dispersants, colorants, and moisturizers that are commonly used in the preparation of tablets, capsules, pills, solutions, suspensions, and emulsions for oral administration.

[0097] In another aspect, the present invention relates to a hexahydro-s-indacene compound of formula (I) or a pharma- ceutically acceptable salt thereof for use as a selective inhibitor of the NLRP3 inflammasome, preferably for the treatment of pathologies associated with overactivation of NLRP3 and overproduction of interleukin-1β and interleukin-18.

[0098] Therefore, this hexahydro-s-indacene compound is suitable for modulating NLRP3 activity in mammalian cells and tissues for the treatment of NLRP3-associated pathologies.

[0099] Considering the biological activity profile exhibited by the hexahydro-s-indacene compounds of formula (I) of the present invention, the compounds themselves, pharmaceutical compositions containing them, and any pharmaceutical formulations containing them, can be used in the treatment of pathologies and disorders or conditions associated with the need to reduce inflammatory conditions driven by overactivation of NLRP3, including, but not limited to, cancer, metabolic disorders, neurodegenerative diseases, migraine headaches, wound repair, and autoimmune diseases.

[0100] The hexahydro-s-indacene compound of formula (I) of the present invention is preferably administered in a dose range of 50 to 3000 mg per dosage unit.

[0101] The hexahydro-s-indacene compounds of the invention and compositions according to the invention can be used alone or in combination with other agents, preferably in combination therapy, in the treatment of NLRP3-associated pathologies. EXAMPLES

[0102] The present invention will now be illustrated, but not limited, by reference to examples of the preparation of compounds of formula (I) and evaluation of the therapeutic / medical efficacy of the compounds.

[0103] Experimental Section Preparation and Evaluation of Compounds of Formula (II) Compounds of formula (II) were prepared according to the scheme depicted in Figure 1. Compounds of formula (II) were obtained by reacting (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1 with the appropriate benzenesulfonyl chloride in the presence of NaHCO3 (to obtain intermediate 2) or K2CO3 (for the synthesis of compounds 5 and 8a-d), as depicted in Figure 1. Subsequent amide coupling with hexahydro-s-indacen-4-amine in the presence of HATU and DIPEA gave compounds 3, 6 and 9a-d. Compound 3 was reduced by catalytic hydrogenation to the corresponding aniline derivative 4. Compounds of formula 7a-k were synthesized from 6 by aromatic nucleophilic substitution with the appropriate amine in DMSO. Compound 10 was obtained from derivative 9d by saponification of the ester group in the presence of LiOH.

[0104] Example 1: Preparation of compound 2 of formula (II). To a solution of (S)-1,2,3,4-dehydroisoquinoline-3-carboxylic acid 1 (1.0 mmol) in water (5 mL) was added sodium bicarbonate (NaHCO3, 2.5 mmol) with vigorous stirring. Then, 4-nitrobenzenesulfonyl chloride (1.0 mmol) was added in portions over 1 h and stirred at room temperature for 16 h. The reaction mixture was then acidified to pH 2 using 1 M hydrochloric acid and the aqueous phase was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over Na2SO4 and the solvent was evaporated under reduced pressure. The remaining crude product was crystallized to give the desired product.

[0105] (S)-2-((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2) 48% yield 1H NMR (400 MHz, DMSO-d6): δ 12.97 (bs, 1H), 8.40-8.33 (m, 2H), 8.16-8.09 (m,2H), 7.15 (q, J = 3.6 Hz, 4H), 4.93 (dd, J = 6.2, 3.2 Hz, 1H), 4.66 (d, J = 15.8 Hz, 1H), 4.46 (d, J = 15.8 Hz, 1H), 3.17-3.05 (m, 2H)

[0106] Example 2: Preparation of compounds 5 and 8a-d of formula (II). To a solution of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1 (5.64 mmol, 1 equiv.) in THF (10 ml) was added HO (36 ml) and KCO (11.28 mmol, 2 equiv.). A solution of the appropriate benzenesulfonyl chloride (5.64 mmol, 1 equiv.) in THF (2 ml) was then added to the mixture. The reaction was allowed to proceed with magnetic stirring for 2 h at room temperature. The reaction mixture was acidified to pH 4-5 with 1 M hydrochloric acid and extracted with ethyl acetate (2×15 ml). After drying over NaSO, the solvent was evaporated to give a solid residue, which was purified by flash chromatography using dichloromethane and MeOH as eluent mixture.

[0107] (S)-2-((4-Fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (5). 54% yield. 1 H NMR (400 MHz, CDCl3): δ 7.86-7.78 (m, 2H), 7.20-7.00 (m, 6H), 4.95 (t, J = 4.7 Hz, 1H), 4.64 (d, J = 15.5 Hz, 1H), 4.44 (d, J = 15.5 Hz, 1H), 3.17 (d, J = 4.7 Hz, 2H).

[0108] (S)-2-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (8a) of formula (II) 30 % yield. 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.20 - 7.11 (m, 2H), 7.10 - 6.99 (m, 2H), 4.99 (t, J = 4.3 Hz, 1H), 4.69 (d, J = 15.4 Hz, 1H), 4.44 (d, J = 15.4 Hz, 1H), 3.19 (s, 2H). MS (ESI): m / z calculated value C 17 H 13 F3NO4S [MH] - 384.06; measure, 384.54.

[0109] (S)-2-((4-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (8b) of formula (II) 18 % Yield. 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.8 Hz, 2H), 7.03 - 6.97 (m, 2H), 6.94 (d, J = 4.4 Hz, 1H), 6.91 - 6.88 (m, 1H), 6.81 (d, J = 8.8 Hz, MS (ESI): m / z calculated value C 17 H 18 NO5S [M+H] + 348,08; Measurement, 348,30.

[0110] (S)-2-((4-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (8c) of formula (II) 68 % yield. 1H NMR (400 MHz, CDCl3) δ 7.95 - 7.91 (m, 2H), 7.77 - 7.73 (m, 2H), 7.22 - 7.14 (m, 2H), 7.11 - 7.03 (m, 2H), 5.00 (dd, J = 5.5, 3.9 Hz, 1H), 4.71 (d, J = 15.3 Hz, 1H), 4.44 (d, J = 15.3 Hz, 1H), 3.27 - 3.16 (m, 2H). MS (ESI): m / z calculated C 17 H 13 N2O4S [MH] - 341,07; Measurement, 341,26.

[0111] (S)-2-((4-(methoxycarbonyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (8d) of formula (II) 65 % yield. 1 H NMR (400 MHz, CDCl3) δ 8.15 - 8.11 (m, 2H), 7.92 - 7.87 (m, 2H), 7.20 - 7.11 (m, 2H), 7.09 - 7.02 (m, 2H), 5.01 (t, J = 4.7 Hz, 1H), 4.70 (d, J = 15.5 Hz, 1H), 4.47 (d, J = 15.4 Hz, 1H), 3.97 (s, 3H), 3.19 (d, J = 4.6 Hz, 2H). MS (ESI): m / z calculated value C 18 H 18 NO6S [M+H] + 376.08; measurement, 376.34.

[0112] Example 3: Preparation of compounds 3, 6, and 9a-d of formula (II). To an ice-cooled solution of 2, 5 or 8a-d (1.1 mmol) in DMF (5 mL) was added HATU (1.1 mmol) and DIPEA (1.1 mmol). Then, a solution of hexahydro-s-indacen-4-amine (1.0 mmol) in DMF (2 mL) was added dropwise. The resulting mixture was warmed to room temperature and left with stirring for 2-5 h. After removing the solvent, the crude product was dissolved in ethyl acetate (20 mL) and the organic layer was washed successively with 10% aqueous citric acid (1 × 10 mL), 35% aqueous NaHCO (1 × 10 mL), and brine (1 × 10 mL). After drying over Na2SO4, the solvent was evaporated to give a solid residue, which was triturated with diethyl ether, filtered, and the solid was recrystallized from methanol to give the desired derivative.

[0113] Compound of formula (II) 3. 84% yield. 1 H NMR (400 MHz, DMSO-d6): δ 9.47 (s, 1H), 8.39-8.31 (m, 2H), 8.16-8.08 (m, 2H), 7.21-7.12 (m, 4H), 6.90 (s, 1H), 4.79 (t, J = 5.3 Hz, 1H), 4.74-4.60 (m, 2H), 3.13 (t, J = 5.8 Hz, 2H), 2.75 (t, J = 7.3 Hz, 4H), 2.47-2.34 (m, 4H), 1.90-1.83 (m, 4H). 13 C NMR (DMSO-d6): δ 167.51, 149.60, 143.64, 142.64, 137.39, 132.24, 131.65, 128.81, 128.65, 127.90, 126.76, 126.32, 125.97, MS (ESI): m / z Calculated value C 28 H 28 N3O5S [M+H] + 518.61; Measurement, 518.60.

[0114] Compound 6 of formula (II). 78% yield. 1 H NMR (400 MHz, DMSO-d6): δ 9.40 (s, 1H), 7.94-7.83 (m, 2H), 7.39-7.28 (m, 2H), 7.18-7.06 (m, 4H), 6.89 (s, 1H), 4.65 (t, J = 5.5 Hz, 1H), 4.61-4.54 (m, 2H), 3.10-2.97 (m, 2H), 2.74 (t, J = 7.3 Hz, 4H), 2.46-2.34 (m, 4H), 1.90-1.83 (m, 4H). 13 C NMR (DMSO-d6): δ 168.46, 166.13, 143.19, 137.99, 135.08, 133.18, 132.57, 130.73, 130.63, 129.49, 128.28, 127.30, 126.82, 126.53, 118.40, 116.91, 116.68, 55.51, 45.84, 32.85, 32.76, 30.39, 25.44. MS (ESI): m / z calcd. 28 H 28 FN2O3S [M+H] + 491.60; measured value, 491.60.

[0115] Compound 9a of formula (II). 45% yield. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.2 Hz, 2H), 7.94 (s, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.23 - 7.15 (m, 2H), 7.14 - 7.09 (m, 2H), 6.96 (s, 1H), 4.68 (d, J = 14.3 Hz, 1H), 4.64 (dd, J = 6.4, 4.0 Hz, 1H), 4.32 (d, J = 14.2 Hz, 1H), 3.34 (dd, J = 15.4, 4.0 Hz, 1H), 2.83 (t, J = 7.4 Hz, 4H), 2.70 (dd, J = 15.3, 6.4 Hz, 1H), 2.60 - 2.39 (m, 4H), 2.05 - 1.92 (m, 4H). 13 C NMR (CDCl3) δ 167.79, 144.15, 140.60, 139.03, 137.74, 133.18, 131.86, 128.55, 128.49, 128.35, 127.96, 127.33, 126.66, 126.63, 126.43, 119.25, 57.41, 46.82, 33.06, 30.98, 30.49, 25.65. MS (ESI): m / z calcd. 29 H 28 F3N2O3S [M+H] + 541.17; measured value, 541.72.

[0116] Compound 9b of formula (II). 25% yield. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.84 - 7.79 (m, 2H), 7.22 - 7.11 (m, 4H), 7.01 - 6.96 (m, 2H), 6.94 (s, 1H), 4.68 (d, J = 14.0 Hz, 1H), 4.61 (dd, J = 6.2, 3.3 Hz, 1H), 4.22 (d, J = 13.9 Hz, 1H), 3.87 (s, 3H), 3.35 (dd, J = 15.2, 3.3 Hz, 1H), 2.81 (t, J = 7.3 Hz, 4H), 2.64 - 2.56 (m, 1H), 2.54 - 2.34 (m, 4H), 2.00 - 1.91 (m, 4H). 13 C NMR (CDCl3) δ 168.37, 163.68, 144.76, 144.02, 141.38, 137.75, 132.40, 133.59, 130.04, 128.47, 128.25, 127.23, 126.47, 119.06, 114.73, 57.34, 55.84, 46.80, 33.06, 31.06, 30.44, 25.65. MS (ESI): m / z calcd. 29 H 31 N2O4S [M+H] + 503.19; measured value, 503.52.

[0117] Compound 9c of formula (II). 48% yield. 1H NMR (400 MHz, CDCl3) δ 7.97 - 7.92 (m, 2H), 7.89 (s, 1H), 7.80 - 7.76 (m, 2H), 7.24 - 7.16 (m, 2H), 7.15 - 7.09 (m, 2H), 6.97 (s, 1H), 4.67 (d, J = 14.5 Hz, 1H), 4.60 (dd, J = 6.5, 4.2 Hz, 1H), 4.36 (d, J = 14.5 Hz, 1H), 3.33 (dd, J = 15.5, 4.3 Hz, 1H), 2.83 (t, J = 7.4 Hz, 4H), 2.74 (dd, J = 15.4, 6.5 Hz, 1H), 2.61 - 2.41 (m, 4H), 2.04 - 1.93 (m, 4H). 13 C NMR (CDCl3) δ 167.59, 144.19, 141.30, 137.71, 133.17, 133.02, 131.75, 128.79, 128.57, 128.43, 127.89, 127.36, 126.40, 119.31, 117.24, 117.12, 57.35, 46.80, 33.05, 30.93, 30.50, 25.65. MS (ESI): m / z calcd. 29 H 28 N3O3S [M+H] + 498.18; measured value, 498.69.

[0118] Compound 9d of formula (II). 53% yield. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.2 Hz, 2H), 7.93 (d, J = 8.2 Hz, 3H), 7.21 - 7.08 (m, 4H), 6.95 (s, 1H), 4.70 (d, J = 14.1 Hz, 1H), 4.64 (dd, J = 6.3, 3.6 Hz, 1H), 4.29 (d, J = 14.2 Hz, 1H), 3.97 (s, 3H), 3.34 (dd, J = 15.3, 3.6 Hz, 1H), 2.82 (t, J = 7.4 Hz, 4H), 2.62 (dd, J = 15.3, 6.5 Hz, 1H), 2.57 - 2.37 (m, 4H), 2.01 - 1.92 (m, 4H). 13 C NMR (CDCl3) δ 167.89, 165.52, 144.11, 140.79, 137.76, 134.68, 133.22, 131.91, 130.69, 128.56, 128.44, 127.99, 127.87, 127.33, 126.44, 119.20, 57.37, 52.91, 46.82, 33.05, 30.96, 30.47, 25.65. MS (ESI): m / z calculated value C 30 H 31 N2O5S [M+H] + 531.19; measurement, 531.65.

[0119] Example 4: Preparation of compound 4 of formula (II). The nitro derivative 3 (1 mmol) was dissolved in ethyl acetate (15 mL) and glacial acetic acid (0.5 mL). Under hydrogen atmosphere, a catalytic amount (0.1 mmol) of palladium (10% Pd basis) adsorbed on activated carbon was added. After 16 h, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and the crude product was purified by semi-preparative HPLC to give compound 4.

[0120] Compound of formula (II) 4. 82% yield. 1H NMR (400 MHz, DMSO-d6): δ 9.24 (s, 1H), 7.49-7.39 (m, 2H), 7.21-7.05 (m, 4H), 6.89 (s, 1H), 6.58-6.48 (m, 2H), 4.63-4.53 (m, 2H), 4.40 (d, J = 15.1 Hz, 1H), 3.04 (dd, J = 15.6, 4.1 Hz, 1H), 2.85 (dd, J = 15.6, 6.2 Hz, 1H), 2.74 (t, J = 7.3 Hz, 4H), 2.46-2.33 (m, 4H), 1.93-1.80 (m, 4H). 13 C NMR (DMSO-d6): δ 168.88, 153.40, 143.12, 138.03, 133.56, 132.84, 129.61, 128.26, 127.17, 126.78, 126.59, 123.27, 118.31, 113.19, 55.39, 45.70, 32.86, 32.46, 30.36, 25.46. MS (ESI): m / z calculated value C 28 H 30 N3O3S [M+H] + Measurement, 488.63.

[0121] Example 5: Preparation of compounds 7a-k of formula (II). To a solution of compound 6 (0.10 mmol, 1 equiv.) in DMSO (0.5 mL), the appropriate amine (0.51 mmol, 5 equiv.) was added and the mixture was stirred at 120 °C until the reaction was complete (4-16 h). Then, H2O (5 mL) was added and the aqueous phase was extracted with ethyl acetate (3 × 5 mL). The organic layer was washed with H2O (3 × 5 ml) and brine (10 mL). After drying over Na2SO4, the solvent was evaporated to give a residue that was purified by flash chromatography using eluent mixtures of ethyl acetate and petroleum ether or DCM / MeOH. If necessary, the compounds were further purified by semi-preparative HPLC.

[0122] Compound of formula (II) 7a. 81 % yield. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.68-7.64 (m, 2H), 7.40-7.27 (m, 5H), 7.23-7.09 (m, 4H), 6.93 (s, 1H), 6.66 (d, J = 8.6 Hz, 2H), 4.65 (d, J = 13.9 Hz, 1H), 4.60 (dd, J = 6.2, 3.1 Hz, 1H), 4.37 (s, 2H), 4.19 (d, J = 13.9 Hz, 1H), 3.35 (dd, J = 15.1, 3.2 Hz, 1H), 2.80 (t, J = 7.4 Hz, 4H), 2.60 (dd, J = 15.0, 6.2 Hz, 1H), 2.54- 2.34 (m, 4H), 1.98-1.92 (m, 4H). 13 C NMR (CDCl3) δ 168.61, 149.28, 143.98, 141.55, 141.43, 137.77, 134.76, 133.77, 132.66, 129.98, 129.06, 128.42, 128.19, 128.11, 128.00, 127.72, 127.65, 127.26, 127.16, 126.48, 125.50, 118.98, 118.90, 57.29, 46.76, 31.10, 30.43, 25.65. MS (ESI): m / z calcd. 35 H 36 N3O3S [M+H] + 578.24; measured value, 578.74.

[0123] Compound 7b of formula (II). 57% yield. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.74-7.69 (m, 2H), 7.23-7.10 (m, 4H), 6.93 (s, 1H), 6.72 - 6.67 (m, 2H), 4.67 (d, J = 13.8 Hz, 1H), 4.63 (dd, J = 6.2, 2.9 Hz, 1H), 4.18 (d, J = 13.7 Hz, 1H), 3.36 (dd, J = 15.1, 3.0 Hz, 1H), 3.06 (s, 6H), 2.80 (t, J = 7.4 Hz, 4H), 2.58 (dd, J = 14.9, 6.2 Hz, 1H), 2.53-2.32 (m, 4H), 2.00-1.90 (m, 4H). 13 C NMR (CDCl3) δ168.69, 143.94, 137.76, 133.84, 132.73, 129.70, 129.61, 128.40, 128.21, 128.07, 127.14, 126.48, 121.96, 118.94, 111.41, 65.99, 57.29, 46.76, 40.29, 33.04, 31.14, 30.41, 25.64. MS (ESI): m / z calcd. 30 H 34 N3O3S [M+H] + 516.22; measured value, 516.52.

[0124] Compound 7c of formula (II). 74% yield. 1 H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.70 (d, J = 9.0 Hz, 2H), 7.21-7.10 (m, 4H), 6.94-6.87 (m, 3H), 4.68-4.60 (m, 2H), 4.19 (d, J = 13.8 Hz, 1H), 3.39-3.31 (m, 5H), 2.80 (t, J = 7.3 Hz, 4H), 2.60 (dd, J = 15.1, 6.3 Hz, 1H), 2.54-2.32 (m, 4H), 2.00-1.89 (m, 4H), 1.72-1.65 (m, 6H).13 13C NMR (CDCl3) δ 143.98, 137.77, 137.13, 133.82, 132.68, 129.74, 128.84, 128.43, 128.20, 128.11, 127.17, 126.49, 118.97, 115.08, 114.15, 57.31, 48.88, 46.77, 33.06, 31.13, 30.43, 25.65, 25.33, 24.29. MS (ESI): m / z calculated for C 33 H 38 N3O3S [M+H] + 556.26; found, 556.73.

[0125] Compound 7d. 93% yield. 1 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.77 - 7.73 (m, 2H), 7.21 - 7.09 (m, 4H), 6.94 (d, J = 9.2 Hz, 3H), 4.67 (d, J = 13.9 Hz, 1H), 4.62 (dd, J = 6.2, 3.1 Hz, 1H), 4.20 (d, J = 13.9 Hz, 1H), 3.90 - 3.85 (m, 4H), 3.36 (dd, J = 15.1, 3.1 Hz, 1H), 3.33 - 3.28 (m, 4H), 2.80 (t, J = 7.3 Hz, 4H), 2.60 (dd, J = 15.0, 6.3 Hz, 1H), 2.54 - 2.33 (m, 4H), 1.99 - 1.90 (m, 4H). 13 13C NMR (CDCl3) δ 168.49, 154.06, 144.01, 137.76, 133.69, 132.53, 129.71, 128.45, 128.18, 128.14, 127.22, 126.48, 125.77, 119.03, 114.27, 66.49, 57.33, 47.76, 46.79, 33.05, 31.13, 30.43, 25.65. MS (ESI): m / z calculated for C 32 H 36 N3O4S [M+H] +558.23; Measured value, 558.76.

[0126] Compound 7e of formula (II). 60% yield. 1 H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.69 - 7.64 (m, 2H), 7.21 - 7.10 (m, 4H), 6.92 (s, 1H), 6.65 (d, J = 9.1 Hz, 2H), 4.69 - 4.60 (m, 2H), 4.20 (d, J = 13.7 Hz, 1H), 3.43 - 3.37 (m, 4H), 3.34 (d, J = 3.1 Hz, 1H), 2.80 (t, J = 7.4 Hz, 4H), 2.64 (dd, J = 15.0, 6.2 Hz, 1H), 2.54 - 2.34 (m, 4H), 2.00 - 1.89 (m, 4H), 1.19 (t, J = 7.1 Hz, 6H). 13 C NMR (CDCl3) δ 168.76, 151.03, 143.95, 137.76, 134.14, 133.91, 132.85, 129.99, 128.37, 128.23 128.03, 127.10, 126.49, 118.93, 110.95, 57.30, 46.75, 44.89, 33.05, 31.17, 30.43, 25.65, 12.42. MS (ESI): m / z Calculated value C 32 H 38 N3O3S [M+H] + 544.26; Measured value, 544.82.

[0127] Compound 7f of formula (II). 52% yield. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.23 - 7.10 (m, 4H), 6.95 - 6.89 (m, 3H), 4.67 (d, J = 14.0 Hz, 1H), 4.61 (dd, J = 6.2, 3.4 Hz, 1H), 4.19 (d, J = 13.8 Hz, 1H), 3.56 (s, 4H), 3.31 (s, 5H), 2.80 (t, J = 7.4 Hz, 4H), 2.65 (dd, J = 15.1, 6.0 Hz, 1H), 2.55 - 2.34 (m, 4H), 2.00 - 1.90 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 169.06, 153.10, 144.14, 137.85, 133.48, 132.45, 129.88, 128.41, 128.35, 127.86, 127.45, 127.33, 126.50, 119.30, 115.53, 57.42, 46.82, 45.14, 43.14, 33.03, 31.22, 30.40, 25.64. MS (ESI): m / z calcd. 32 H 37 N4O3S [M+H] + 557.25; measured value, 557.61.

[0128] 7g of compound of formula (II). 95% yield. 1 H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.72 (d, J = 9.0 Hz, 2H), 7.22 - 7.10 (m, 4H), 6.94 - 6.86 (m, 3H), 4.70 - 4.58 (m, 2H), 4.19 (d, J = 13.8 Hz, 1H), 3.45 - 3.30 (m, 5H), 2.80 (t, J = 7.3 Hz, 4H), 2.70 - 2.55 (m, 5H), 2.54 - 2.30 (m, 7H), 2.01 - 1.87 (m, 4H). 1313C NMR (CDCl3) δ 168.55, 154.06, 143.98, 137.77, 133.73, 132.58, 129.70, 128.75, 128.44, 128.17, 127.43, 127.19, 126.48, 119.00, 114.23, 57.33, 54.58, 47.03, 46.78, 45.94, 33.05, 31.14, 30.43, 25.65. MS (ESI): m / z calculated for C 33 H 39 N4O3S [M+H] + 571.27; found, 571.79.

[0129] Compound 7h of formula (II). 87% yield. 1 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.22 - 7.10 (m, 4H), 6.95 - 6.87 (m, 3H), 4.70 - 4.61 (m, 2H), 4.18 (d, J = 13.8 Hz, 1H), 3.66 - 3.52 (m, 4H), 3.38 - 3.28 (m, 5H), 2.80 (t, J = 7.3 Hz, 4H), 2.61 (dd, J = 15.0, 6.2 Hz, 1H), 2.50 - 2.32 (m, 4H), 1.99 - 1.90 (m, 4H), 1.49 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 168.97, 154.78, 153.95, 144.04, 137.82, 133.63, 132.57, 129.77, 128.42, 128.23, 127.95, 127.25, 126.50, 125.16, 119.15, 114.43, 114.32, 80.59, 57.32, 47.39, 46.80, 33.04, 31.19, 30.39, 28.55, 25.64. MS (ESI): m / z calculated for C 37 H 45 N4O5S [M+H] + 657.30; found, 657.75.

[0130] Compound 7i of formula (II). 48% yield. 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.71 - 7.66 (m, 2H), 7.24 - 7.13 (m, 4H), 6.94 (s, 1H), 6.64 - 6.58 (m, 2H), 4.71 - 4.65 (m, 2H), 4.11 (d, J = 13.5 Hz, 1H), 3.32 (dd, J = 15.1, 2.9 Hz, 1H), 3.27 - 3.18 (m, 2H), 2.79 (t, J = 7.5 Hz, 4H), 2.69 - 2.60 (m, 1H), 2.48 - 2.28 (m, 4H), 1.94 (p, J = 7.7 Hz, 4H), 1.29 (t, J = 7.2 Hz, 3H). 13 C NMR (CDCl3) δ 170.90, 152.31, 144.16, 138.09, 133.51, 132.84, 130.11, 128.35, 127.42, 127.25, 127.11, 126.57, 122.46, 119.60, 112.14, 57.30, 46.90, 38.16, 32.99, 31.38, 30.22, 25.61, 14.58. MS (ESI): m / z calcd. 30 H 34 N3O3S [M+H] + 516.22; measured value, 516.68.

[0131] Compound 7j of formula (II). 85% yield. 1H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H), 7.56 (d, J = 8.9 Hz, 2H), 7.19-7.07 (m, 4H), 6.89 (s, 1H), 6.62 (d, J = 8.9 Hz, 2H), 4.67-4.56 (m, 2H), 4.44-4.40 (m, 1H), 3.31-3.27 (m, 2H), 3.09-3.04 (m, 1H), 2.98-2.82 (m, 3H), 2.73 (t, J = 7.3 Hz, 4H), 2.46-2.31 (m, 4H), 1.93-1.79 (m, 4H). 13 C NMR (DMSO-d6): δ 168.79, 152.11, 143.13, 138.04, 133.44, 132.71, 129.62, 128.35, 127.17, 126.82, 126.60, 124.51, 118.34, 111.84, 55.32, 45.67, 38.19, 32.86, 32.62, 30.34, 25.45. MS (ESI): m / z calcd. 30 H 35 N4O3S [M+H] + 531.69; measured value, 531.70.

[0132] Compound 7k. 55% yield. 1 H NMR (400 MHz, Acetone-d6): δ 8.55 (s, 1H), 7.67-7.60 (m, 2H), 7.29-7.07 (m, 4H), 6.88 (s, 1H), 6.76-6.67 (m, 2H), 4.70 (d, J = 14.7 Hz, 1H), 4.63-4.61 (m, 1H), 4.38 (d, J = 14.6 Hz, 1H), 3.83 (t, J = 7.0 Hz, 2H), 3.26-3.21 (m, 3H), 2.79-2.70 (m, 5H), 2.56-2.39 (m, 5H), 2.09-2.08 (m, 2H), 2.02-1.85 (m, 5H), 1.78-1.74 (m, 2H). 13C NMR (Acetone-d6): δ 168.09, 152.87, 143.07, 137.59, 133.54, 133.28, 129.52, 127.95, 127.16, 126.55, 126.39, 122.93, MS (ESI): m / z calculated value C 32 H 39 N4O3S [M+H] + 559.75; measured value, 559.87.

[0133] Example 6: Preparation of Compound 10 To a solution of derivative 9d (0.062 mmol, 1.0 equiv.) in methanol (2.5 mL) was added a solution of LiOH (0.131 mmol, 2.1 equiv.) in HO (0.5 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was diluted with HO (1 mL) and acidified with 1 M HCl. The aqueous layer was then extracted with EtOAc (3×10 mL) and the collected organic phases were washed with brine (10 ml). After drying over NaSO, the solvent was evaporated to give a solid residue, which was purified by preparative HPLC.

[0134] Compound 10. 56 % yield. 1 H NMR (400 MHz, CDCl3): δ 8.26-8.21 (m, 2H), 8.01-7.97 (m, 3H), 7.23-7.10 (m, 4H), 6.96 (s, 1H), 4.76-4.68 (m, 2H), 4.27 (d, J = 14.1 Hz, 1H), 3.34 (dd, J = 15.3, 3.6 Hz, 1H), 2.82 (t, J = 7.4 Hz, 4H), 2.67 (dd, J = 15.4, 6.3 Hz, 1H), 2.56-2.36 (m, 4H), 2.02-1.93 (m, 4H). 13C NMR (CDCl3) δ 168.83, 168.30, 144.20, 141.30, 137.89, 133.79, 133.11, 131.95, 131.27, 128.58, 128.54, 128.04, 127.62, 127.46, 126.50, 119.48, 57.40, 46.91, 33.03, 31.15, 30.40, 25.64. MS (ESI): m / z calculated value C 29 H 29 N2O5S [M+H] + 517.17; measurement, 517.65.

[0135] Example 7: Evaluation of the inhibitory effect and selectivity of compounds of formula (II) on NLRP3-mediated release of IL-1β and IL-18 in vitro. The ability of the compound of formula (II) to reduce the release of IL-1β and IL-18 induced by the activation of NLRP3 was examined in wild-type (WT) mouse bone marrow-derived macrophages (BMDMs) that were first primed with 1 μg / ml of lipopolysaccharide (LPS) from Escherichia coli for 2 hours. The compound of formula (II) was added at a concentration of 1 μM for 30 minutes, and then the cells were stimulated with 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate triethylammonium salt (Bz-ATP) at a concentration of 100 μM. The cell culture supernatants were analyzed for IL-1β and IL-18 by enzyme-linked immunosorbent assay (ELISA). The potency of the compound of formula (II) was expressed as the percentage inhibition of IL-1β release at a concentration of 1 μM. The IL-1β release inhibition rate of compound 4 was 65.2%. Under the same experimental conditions, MCC950, used as an internal control, showed an inhibition rate of 60.1%. 50 The IC value obtained in BMDM stimulated with LPS and ATP was 19.9 nM (Figure 2B). The efficacy of compound 4 was also evaluated in human macrophages (THP-1) stimulated with LPS and ATP. The IC value obtained in THP-1 cells was 19.9 nM (Figure 2C). 50The value is 5.36 nM (Figure 2B). Thus, in both BMDM and THP-1 cells, NLRP3-stimulated IL-18 secretion was significantly reduced after treatment with compound 4 (Figures 2G and H).

[0136] Next, the selectivity of compound 4 as an NLRP3 inhibitor was evaluated with respect to NLRC4 and AIM2 inflammasomes. For NLRC4 inflammasome activation, BMDMs were treated with LPS (100 ng / ml) for 3 h. Then, the medium was removed and replaced with serum-free medium containing compound 4 (1 μM, 30 min), and finally, cells were transfected with flagellin (100 ng / ml) from S. typhimurium for 2 h. The supernatant was tested by ELISA. Compound 4 had no effect on NLRC4 inflammasome activation induced by S. typhimurium flagellin (Figure 2E), indicating its specificity in inhibiting NLRP3 inflammasomes. The effect of the same compound was examined with the non-NLR AIM2 inflammasome by transfecting BMDMs with the dsDNS analog poly(dA:dT). No reduction in IL-1β secretion was observed with the compound of formula (II) (FIG. 2F).

[0137] Example 8: Evaluation of the effect of compound 4 of formula (II) on cell viability of THP-1 cells. Cell viability was assessed in THP-1 cells using the realtime-Glo”MT cell viability assay (Promega Italia, MI). Briefly, cells were seeded (10 × 10 4Cells / well) were treated with selected compounds of formula (II) and cultured for 48 h. After treatment, cells were incubated with realtime-Glo” reagent for 10 min in an incubator according to the protocol. Luminescence was measured every 12 h using a Glomax Multi Detection System from Promega. The luminescence signal correlates with the number of metabolically active cells. Results are expressed as mean luminescence units (RLU) ± SEM. Compound 4 was not cytotoxic at the concentrations used and therefore did not affect cell viability of THP-1 cells (Figure 2A).

[0138] Example 9: Evaluation of the effect of compound 4 of formula (II) on protein expression of NLRP3 inflammasome Whole cell lysates of THP-1 cells were prepared in RIPA buffer (50 mM Tris-HCl pH 7.8, 150 mM NaCl, 1% IGEPAL CA-630, 0.5% sodium deoxycholate, 0.1% SDS, 1 mM dithiothreitol (DTT)) supplemented with protease and phosphatase inhibitors. THP-1 culture supernatants were concentrated using Pierce Protein Concentrators PES 10K MWCO (ThermoFisher) and centrifuged at 4000 × g for 15 min. A total of 20 μg of protein, or a total of 10 μl of concentrated medium, were separated by SDS-PAGE and transferred to nitrocellulose membranes for standard Western blotting. The following primary antibodies were used: NLRP3 (Adipogen, #AG-20B-0014-C100), ASC (Adipogen, #AG-20B-0014-C100), caspase-1 (Novus Biological, #14F468), IL-1β (Cell Signaling Technology, #12242), and GAPDH (Cell Signaling Technology, #2118). Isotype-matched horseradish peroxidase-conjugated secondary antibodies were used and detected by chemiluminescence (GE Image-Quant). Treatment with compound 4 did not affect the priming step of NLRP3 inflammasome activation and did not cause any changes in the expression of NLRP3, caspase-1, ASC, or pro-IL-1β in whole cell lysates (Figure 2C-D). Compound of formula (II) significantly reduced the release of IL-1β and the amount of cleaved caspase-1 in the cell supernatant (Figure 2C).

[0139] Example 10: Evaluation of the effect of compound 4 of formula (II) on LPS-induced inflammation in vivo and ex vivo. C57BL / 6 mice were treated with compound 4 of formula (II) at a concentration of 25 mg / kg or vehicle (DMSO) by intraperitoneal injection for 30 min. Mice were then treated with LPS 1 mg / kg intraperitoneally for 4 h. Mice were sacrificed and blood and peritoneal supernatants were collected. Blood was centrifuged (1000 × g for 15 min) to obtain plasma. IL-1β concentrations in plasma and peritoneal supernatants were measured by ELISA. Mice treated with compound 4 of formula (II) showed a significant reduction in IL-1β release compared to vehicle-treated mice, indicating that this compound has a strong effect of suppressing NLRP3 inflammasome activation in vivo (Figure 3).

[0140] Example 11: Evaluation of the effect of compound 4 of formula (II) on tumor growth in vivo. Procedures involving animals and their care complied with institutional guidelines and the Animal Ethics Committee approved all experimental protocols (authorization N°481 / 2017-PR and CBCC2.N.BH4 approved by the Italian Ministry of Health). A total of 1 × 10 cells were transfected with cytluc. 6 B16-F10 melanoma cells (B16-F10cytLUC) were subcutaneously inoculated into female 6-8 week-old C57BL / 6 mice. Tumor growth was monitored daily, and tumor volumes were measured every other day using a caliper with the following formula: volume = π / 6 × (a × b2), where "a" is the major diameter and "b" is the minor diameter. As soon as tumor masses were palpable, mice were randomly divided into treatment and control groups (5 mice per group). For NLRP3 inflammasome inhibition, mice were injected intraperitoneally with the selected molecules at 25 mg / Kg three times a week; control mice received an equal volume of DMSO.

[0141] Luciferase luminescence was followed with a whole-body luminometer (IVIS Lumina, Caliper-PerkinElmer). Briefly, mice were anesthetized with 2.5% isoflurane and injected intraperitoneally with 150 mg / Kg d-luciferin (Promega), and luminescence was quantified 15 min later using Living Image Software (Caliper). Mice treated with compound 4 developed significantly smaller (approximately 50% reduction) tumor masses than mice treated with vehicle (DMSO) (Figure 4A-D). Lysates of extracted tumor masses showed no change in the expression of proteins NLRP3, caspase-1, ASC and pro-IL-1β (Figure 4E).

[0142] Example 12: Proliferation of B16-F10 cancer cells after treatment with compound 4 of formula (II). B16-F10 cells were treated with selected inhibitors (1 μM) and then counted in a Barker chamber and dispensed into 5 sets of 4 wells in a 24-well plate. From the next day (day 1), one set of wells (days 2, 3, 4, and 5) was washed once with PBS and fixed with 4% formaldehyde solution for 15 min at room temperature, then kept in PBS at 4 °C. On day 5, all wells were stained with crystal violet for 20 min and the absorbance was read at 595 nm after dissolving with 10% acetic acid. Compound 4 had no direct effect on cell proliferation of B16-F10 melanoma cells (Figure 4F).

[0143] Example 13: Evaluation of the effect of compound 4 of formula (II) on the tumor microenvironment by co-culture model. Co-culture of peritoneal macrophages and B16-F10 cells was performed using a Transwell chamber (Corning, Corning, NY, USA) with 0.4 μm pores in the membrane. Peritoneal macrophages and B16-F10 cells were cultured in the lower and upper compartments of the Transwell chamber, respectively, for 48 h. Peritoneal macrophages were cultured at 2 × 10 5 The B16-F10 cells were seeded at a density of 2 × 10 cells / well, treated with LPS (1 μg / mL) for 2 hours, then treated with DMSO or compound 4 of formula (II) (1 μM) for 30 minutes, and finally stimulated with ATP for 1 hour.3 The cells were seeded at a density of 100x100x100 / mL. After 48 hours, the B16-F10 cells in the upper chamber were removed and counted using an automated cell counter (TaliTM image-based cytometer (Invitrogen)). B16-F10 cells in contact with peritoneal macrophages treated with vehicle alone proliferated more than B16-F10 cells in contact with peritoneal macrophages treated with compound 4 (Figure 4G). Compound 4 of formula (II) affected the tumor microenvironment and suppressed the activation of NLRP3 inflammasome.

[0144] Preparation and Evaluation of Compounds of Formula (III) The compounds of formula (III) of the present invention were prepared according to the scheme shown in Figure 5. The compounds of formula (III) were obtained starting from α / b amino acids 4a-k, which were reacted with 4-nitrobenzenesulfonyl chloride in the presence of NaHCO3 to give intermediates 5a-k (Figure 5). Subsequent amide coupling with hexahydro-s-indacen-4-amine in the presence of HATU and DIPEA gave compounds 6a-k. Tyrosine derivatives (6i) and lysine derivatives (6j) were treated with HCl in dioxane solution to remove the side chain protection, giving compounds 8 and 9, respectively. Compounds 6a-k were reduced by catalytic hydrogenation to the corresponding aniline derivatives 7a-k. The side chain protection of 7i-j was also removed under acidic conditions to give compounds 10 and 11, respectively.

[0145] Example 14: Preparation of compounds 5a-k of formula (III). To a solution of 4a-k (1.0 mmol) in water (5 mL) was added sodium bicarbonate (NaHCO3, 2.5 mmol) with vigorous stirring. Then 4-nitrobenzenesulfonyl chloride (1.0 mmol) was added in portions over 1 h and stirred at room temperature for 16 h. The reaction mixture was then acidified to pH 2 using 1 M hydrochloric acid and the aqueous phase was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residual crude product was crystallized to give the desired product.

[0146] ((4-nitrophenyl)sulfonyl)glycine (5a) of formula (III) 60% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.66 (bs, 1H), 8.46 (t, J = 6.1 Hz, 1H), 8.40-8.34 (m, 2H), 8.06-7.99 (m, 2H), 3.68 (d, J = 6.1 Hz, 2H). ((4-Nitrophenyl)sulfonyl)-L-alanine (5b) of formula (III). 82% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.68 (s, 1H), 8.55 (s, 1H), 8.40-8.34 (m, 2H), 8.05-7.99 (m, 2H), 3.89-3.83 (m, 1H), 1.18 (d, J = 7.2 Hz, 3H).

[0147] ((4-Nitrophenyl)sulfonyl)-L-valine (5c) of formula (III). 60% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.63 (bs, 1H), 8.43 (d, J = 9.5 Hz, 1H), 8.41-8.34 (m, 2H), 8.06-7.99 (m, 2H), 3.59 (dd, J = 9.5, 5.9 Hz, 1H), 2.02-1.90 (m, 1H), 0.80 (dd, J = 14.0, 6.8 Hz, 6H).

[0148] ((4-Nitrophenyl)sulfonyl)-D-valine (5d) of formula (III). 52% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.63 (bs, 1H), 8.45 (d, J = 9.5 Hz, 1H), 8.41 - 8.36 (m, 2H), 8.05 - 8.00 (m, 2H), 3.61 (dd, J = 9.5, 5.9 Hz, 1H), 2.05 - 1.92 (m, 1H), 0.82 (dd, J = 13.9, 6.8 Hz, 6H).

[0149] ((4-Nitrophenyl)sulfonyl)-L-leucine (5e) of formula (III). 81% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.60 (bs, 1H), 8.57 (d, J = 9.0 Hz, 1H), 8.42-8.37 (m, 2H), 8.04-8.00 (m, 2H), 3.78-3.72 (m, 1H), 1.63-1.54 (m, 1H), 1.45-1.40 (m, 2H), 0.84 (d, J = 6.6 Hz, 3H), 0.75 (d, J = 6.5 Hz, 3H).

[0150] (S)-2-((4-nitrophenyl)sulfonamido)-2-phenylacetic acid (5f) of formula (III). 74% yield. 1 H NMR (400 MHz, DMSO-d6): δ 13.03 (bs, 1H), 9.11 (d, J = 9.3 Hz, 1H), 8.29-8.21 (m, 2H), 7.96-7.89 (m, 2H), 7.26-7.18 (m, 5H), 4.98 (d, J = 9.0 Hz, 1H).

[0151] ((4-Nitrophenyl)sulfonyl)-L-phenylalanine of formula (III) (5 g). 81% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.85 (bs, 1H), 8.70 (d, J = 8.5 Hz, 1H), 8.22-8.14 (m, 2H), 7.77-7.67 (m, 2H), 7.15-7.03 (m, 5H), 3.94 (t, J = 10.0 Hz, 1H), 2.99-2.95 (m, 1H), 2.72-2.70 (m, 1H).

[0152] ((4-Nitrophenyl)sulfonyl)-D-phenylalanine (5h). 78% yield. 1H NMR (400 MHz, DMSO-d6): δ 12.82 (bs, 1H), 8.64 (d, J = 8.5 Hz, 1H), 8.20-8.11 (m, 2H), 7.75-7.67 (m, 2H), 7.18-7.05 (m, 5H), 3.97-3.89 (m, 1H), 2.99-2.95 (m, 1H), 2.72-2.70 (m, 1H).

[0153] (S)-3-(4-(tert-butoxy)phenyl)-2-((4-nitrophenyl)sulfonamido)propanoic acid (5i) of formula (III). 71% yield. 1 H NMR (400 MHz, DMSO-d6): 12.84 (bs, 1H), 8.70 (d, J = 9.1 Hz, 1H), 8.26-8.17 (m, 2H), 7.77-7.73 (m, 2H), 7.05-6.95 (m, 2H), 6.73-6.63 (m, 2H), 3.96-3.90 (m, 1H), 2.94 (dd, J = 13.8, 4.7 Hz, 1H), 2.68-2.65 (m, 1H), 1.21 (s, 9H).

[0154] N in formula (III) 6 -(tert-butoxycarbonyl)-N 2 -((4-Nitrophenyl)sulfonyl)-L-lysine (5j). 80% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.62 (bs, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.42-8.33 (m, 2H), 8.04-7.96 (m, 2H), 6.70 (t, J = 5.5 Hz, 1H), 3.73-3.68 (m, 1H), 2.80-2.75 (m, 2H), 1.65-1.41 (m, 2H), 1.34 (s, 9H), 1.26-1.22 (m, 4H).

[0155] 3-((4-Nitrophenyl)sulfonamido)propanoic acid (5k). 69% yield. 1H NMR (400 MHz, DMSO-d6): δ 12.26 (s, 1H), 8.43-8.37 (m, 2H), 8.07 (bs, 1H), 8.05-8.00 (m, 2H), 3.00-2.97 (m, 2H), 2.36 (t, J = 6.9 Hz, 2H).

[0156] Example 15: Preparation of compounds 6a-k, 8 and 9 of formula (III). To an ice-cold solution of 5a-k (1.1 mmol) in DMF (5 mL) were added HATU (1.1 mmol) and DIPEA (1.1 mmol). Then, a solution of hexahydro-s-indacen-4-amine (1.0 mmol) in DMF (2 mL) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 2-5 h. After removal of the solvent, the crude product was dissolved in ethyl acetate (20 mL) and the organic layer was washed successively with 10% aqueous citric acid (1 × 10 mL), 5% aqueous NaHCO3 (1 × 10 mL) and brine (1 × 10 mL). After drying over Na2SO4, the solvent was evaporated to give a solid residue, which was first triturated with diethyl ether, then filtered and the solid was recrystallized from methanol to give the desired derivative. Intermediates 6i and 6j were each deprotected by treatment with 4N hydrochloric acid in dioxane at room temperature. After completion of the reaction, the solvent was removed and the product was purified by semi-preparative HPLC to give unprotected compounds 8 and 9.

[0157] Compound of formula (III) 6a. 67% yield. 1 H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.53 (s, 1H), 8.48-8.36 (m, 2H), 8.14-7.99 (m, 2H), 6.91 (s, 1H), 3.79 (s, 2H), 2.77 (t, J = 7.4 Hz, 4H), 2.49-2.43 (m, 4H), 1.93-1.85 (m, 4H). 1313C NMR (DMSO-d6): δ 165.12, 149.32, 146.25, 142.71, 137.07, 128.94, 128.20, 124.25, 117.81, 44.78, 32.29, 30.11, 24.89. MS (ESI): m / z Calculated for C 20 H 22 N3O5S [M+H] + 416.47; Found, 416.33.

[0158] Compound 6b of formula (III). 77% yield. 1 1H NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 8.68 (d, J = 7.5 Hz, 1H), 8.41 (d, J = 8.7 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 6.91 (s, 1H), 4.18 - 4.07 (m, 1H), 2.76 (t, J = 7.4 Hz, 4H), 2.40 (t, J = 7.4 Hz, 4H), 1.88 - 1.84 (m, 4H), 1.30 (d, J = 6.7 Hz, 3H). 13 13C NMR (DMSO-d6): δ 169.51, 149.82, 147.42, 143.24, 137.71, 129.40, 128.63, 124.83, 118.41, 52.33, 32.82, 30.46, 25.39, 20.63. MS (ESI): m / z Calculated for C 21 H 24 N3O5S [M+H] + 430.50; Found, 430.35.

[0159] Compound 6c of formula (III). 79% yield. 11H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.45 (bs, 1H), 8.37 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 8.9 Hz, 2H), 6.87 (s, 1H), 3.80 (d, J = 6.2 Hz, 1H), 2.74 - 2.70 (m, 4H), 2.38 - 2.19 (m, 4H), 1.98 (dq, J = 13.4, 6.6 Hz, 1H), 1.89 - 1.73 (m, 4H), 0.93 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H). 13 13C NMR (DMSO-d6): δ 149.58, 143.23, 137.53, 129.46, 128.56, 124.72, 118.35, 62.16, 32.80, 31.86, 30.63, 25.35, 19.79, 18.25. MS (ESI): m / z calculated for C 23 H 28 N3O5S [M+H] + 458.55; found, 458.28.

[0160] Compound 6d of formula (III). 88% yield. 1 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.49 (d, J = 7.5 Hz, 1H), 8.43 - 8.31 (m, 2H), 8.13 - 8.01 (m, 2H), 6.87 (s, 1H), 3.85 (t, J = 6.7 Hz, 1H), 2.71 (t, J = 7.3 Hz, 4H), 2.37 - 2.17 (m, 4H), 2.05 - 1.93 (m, 1H), 1.86 - 1.72 (m, 4H), 0.95 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H). 1313C NMR (DMSO-d6): δ 168.18, 149.73, 147.66, 143.20, 137.61, 129.44, 128.68, 124.77, 118.37, 62.05, 32.79, 31.81, 30.63, 25.33, 19.74, 18.30. MS (ESI): m / z Calculated for C 23 H 28 N3O5S [M+H] + 458.55; Found, 457.70.

[0161] Compound 6e of formula (III). 78% yield. 1 1H NMR (400 MHz, DMSO-d6): δ 9.47 (s, 1H), 8.60 (s, 1H), 8.44 - 8.35 (m, 2H), 8.09 - 8.01 (m, 2H), 6.88 (s, 1H), 4.05 - 4.01 (m, 1H), 2.73 (t, J = 7.3 Hz, 4H), 2.32 (t, J = 7.4 Hz, 4H), 1.93 - 1.77 (m, 4H), 1.72 - 1.64 (m, 1H), 1.55 - 1.38 (m, 2H), 0.89 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H). 13 13C NMR (DMSO-d6): δ 169.30, 149.75, 147.61, 143.22, 137.70, 129.40, 128.62, 124.78, 118.41, 55.19, 42.81, 32.81, 30.47, 25.40, 24.49, 23.34, 21.75. MS (ESI): m / z Calculated for C 24 H 30 N3O5S [M+H] + 472.58; Found, 472.52.

[0162] Compound 6f of formula (III). 69% yield. 11H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 9.22 (d, J = 9.2 Hz, 1H), 8.32 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 6.9 Hz, 2H), 7.30 - 7.22 (m, 3H), 6.89 (s, 1H), 5.30 (d, J = 9.2 Hz, 1H), 2.72 (t, J = 7.2 Hz, 4H), 2.36 - 2.12 (m, 4H), 1.91 - 1.66 (m, 4H). 13 13C NMR (DMSO-d6): δ 166.43, 149.10, 146.72, 142.75, 137.30, 137.00, 128.53, 128.10, 127.69, 126.90, 124.04, 117.96, 59.39, 32.16, 29.72, 24.79. MS (ESI): m / z calculated for C 26 1 26 27H31N3O5S [M+H] + 492.57; found, 492.50.

[0163] Compound 6g of formula (III). 84% yield. 1 1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.82 - 8.79 (m, 1H), 8.26 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.7 Hz, 2H), 7.21 - 7.16 (m, 5H), 6.91 (s, 1H), 4.31 - 4.27 (m, 1H), 3.44 - 3.37 (m, 1H), 3.00 - 2.97 (m, 1H), 2.81 - 2.74 (m, 4H), 2.41 - 2.27 (m, 4H), 1.88 - 1.83 (m, 4H). 13C NMR (DMSO-d6): δ 168.62, 149.55, 147.48, 143.25, 137.66, 137.29, 129.82, 129.30, 128.49, 128.24, 126.81, 124.64, 118.41, 58.18, 32.83, 30.47, 25.46. MS (ESI): m / z calculated value C 27 H 28 N3O5S [M+H] + 506.60; measure, 506.50.

[0164] Compound of formula (III) 6h. 73% yield. 1 H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.80 (bs, 1H), 8.26 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.21-7.17 (m, 5H), 6.91 (s, 1H), 4.32-4.26 (m, 1H), 3.02-2.97 (m, 1H), 2.81-2.74 (m, 5H), 2.42-2.28 (m, 4H), 2.01-1.72 (m, 4H). 13 C NMR (DMSO-d6): δ 168.61, 149.55, 147.48, 143.24, 137.66, 129.82, 128.24, 126.81, 124.64, 118.41, 58.18, 32.83, 30.47, 25.46. MS (ESI): m / z calculated C 27 H 28 N3O5S [M+H] + 506.60; measure, 506.45.

[0165] (S)-3-(4-(tert-butoxy)phenyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)propanamide (6i) of formula (III). 79% yield. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.83-8.79 (m, 1H), 8.33-8.25 (m, 2H), 7.94-7.85 (m, 2H), 7.14-7.06 (m, 2H), 6.91 (s, 1H), 6.81-6.73 (m, 2H), 4.29-4.22 (m, 1H), 2.76 (t, J = 7.3 Hz, 6H), 2.42-2.29 (m, 4H), 1.91-1.78 (m, 5H), 1.24 (s, 9H). 13 C NMR (DMSO-d6): δ 168.09, 153.55, 148.97, 147.05, 142.66, 137.10, 131.15, 129.72, 128.77, 127.67, 127.08, 124.11, 123.01, 117.82, 77.39, 57.75, 38.22, 32.25, 29.92, 28.32, 24.90. MS (ESI): m / z calculated value C 31 H 36 N3O6S [M+H] + 578.70; measured value, 578.55.

[0166] Tert-butyl (S)-(6-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-((4-nitrophenyl)sulfonamido)-6-oxohexyl)carbamate (6j) of formula (III). 83% yield. 1 H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 8.60 (bs, 1H), 8.45-8.36 (m, 2H), 8.13-8.03 (m, 2H), 6.90 (s, 1H), 6.76 (t, J = 5.8 Hz, 1H), 4.06-3.88 (m, 1H), 2.87-2.82 (m, 2H), 2.75 (t, J = 7.3 Hz, 4H), 2.35 (t, J = 7.1 Hz, 4H), 1.89-1.81 (m, 4H), 1.75-1.47 (m, 2H), 1.36 (s, 9H), 1.32-1.18 (m, 4H). 1313C NMR (DMSO-d6): δ 168.42, 155.40, 149.14, 142.66, 137.06, 128.85, 128.00, 124.21, 117.81, 77.20, 57.26, 56.08, 33.16, 32.23, 29.95, 28.82, 28.14, 24.82, 22.39. MS (ESI): m / z Calculated for C 29 H 39 N4O7S [M+H] + 587.71; Found, 587.58, 531.53 [M-tBu] + , 487.57 [M-Boc] + .

[0167] Compound 6k of formula (III). Yield 89%. 1 1H NMR (400 MHz, DMSO-d6): δ 9.36 (s, 1H), 8.43 (d, J = 7.4 Hz, 2H), 8.11 - 8.06 (m, 3H), 6.93 (s, 1H), 3.12 - 3.06 (m, 2H), 2.79 (t, J = 7.5 Hz, 4H), 2.62 (t, J = 7.4 Hz, 4H), 2.48 - 2.43 (m, 2H), 1.96 - 1.92 (m, 4H). 13 13C NMR (DMSO-d6): δ 167.92, 150.01, 146.44, 143.18, 137.77, 130.07, 128.56, 125.08, 118.20, 39.66, 36.05, 32.91, 30.80, 25.51. MS (ESI): m / z Calculated for C 21 H 24 N3O5S [M+H] + 430.50; Found, 430.43.

[0168] Compound 8 of formula (III). Yield 8.71%. 11H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.71 (d, J = 9.1 Hz, 1H), 8.27 - 8.20 (m, 2H), 7.86 - 7.78 (m, 2H), 7.00 - 6.93 (m, 2H), 6.89 (s, 1H), 6.57 - 6.47 (m, 2H), 4.21 - 4.15 (m, 1H), 2.86 (dd, J = 13.7, 5.3 Hz, 1H), 2.74 (t, J = 7.3 Hz, 4H), 2.67 - 2.61 (m, 1H), 2.46 - 2.25 (m, 4H), 1.91 - 1.79 (m, 4H). 13 13C NMR (DMSO-d6): δ 168.27, 155.98, 148.85, 147.02, 142.65, 137.11, 130.14, 128.83, 127.66, 126.69, 124.00, 117.79, 114.62, 58.11, 32.27, 29.94, 24.89. MS (ESI): m / z calculated for C 27 H 28 N3O6S [M+H] + 522.60; found, 522.62.

[0169] Compound of formula (III). 9.70% yield. 1 1H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.66 (d, J = 9.1 Hz, 1H), 8.43 - 8.36 (m, 2H), 8.13 - 8.05 (m, 2H), 7.95 (s, 3H), 6.90 (s, 1H), 4.08 - 4.03 (m, 1H), 2.74 (t, J = 7.4 Hz, 6H), 2.34 (t, J = 7.4 Hz, 4H), 1.90 - 1.77 (m, 4H), 1.75 - 1.68 (m, 1H), 1.66 - 1.51 (m, 3H), 1.39 - 1.29 (m, 2H). 13C NMR (DMSO-d6): δ 168.88, 149.85, 147.52, 143.28, 137.72, 129.45, 128.75, 124.89, 118.46, 56.54, 38.91, 33.43, 32.87, 30.62, 26.77, 25.44, 22.66. MS (ESI): m / z calculated value C 24 H 31 N4O5S [M+H] + Measurement, 487.59.

[0170] Example 16: Preparation of compounds 7a-k, 10-11 of formula (III). Nitro derivatives 6a-k (1 mmol) were dissolved in ethyl acetate (15 mL) and ice-cold CH3COOH (0.5 mL). A catalytic amount (0.1 mmol) of palladium on activated carbon (10% Pd basis) was added under hydrogen atmosphere. After 16 h, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and purified by semi-preparative HPLC to give compounds 7a-k. Derivatives 7i-j were deprotected as described for 6i-j to give the final compounds 10 and 11.

[0171] Compound of formula (III) 7a. 91% yield. 1 H NMR (400 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.50-7.38 (m, 3H), 6.92 (s, 1H), 6.64-6.53 (m, 2H), 5.94 (bs, 2H), 3.51 (d, J = 6.1 Hz, 2H), 2.77 (t, J = 7.3 Hz, 4H), 2.57 (t, J = 7.4 Hz, 4H), 1.99-1.87 (m, 4H). 13 C NMR (DMSO-d6): δ 165.71, 152.55, 142.69, 137.23, 129.12, 128.54, 124.82, 117.75, 112.48, 45.14, 32.35, 30.17, 25.01. MS (ESI): m / z calculated value C 20 H 24 N3O3S [M+H] +386.49; Measured value, 386.32.

[0172] Compound of formula (III) 7b. 88% yield. 1 H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 6.91 (s, 1H), 6.56 (d, J = 8.7 Hz, 2H), 5.89 (s, 2H), 3.87 - 3.80 (m, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.54 - 2.51 (m, 4H), 1.97 - 1.89 (m, 4H), 1.17 (dd, J = 7.0, 4.0 Hz, 3H). 13 C NMR (DMSO-d6): δ 170.25, 152.98, 143.22, 137.82, 129.63, 128.90, 126.40, 118.28, 112.98, 52.18, 32.88, 30.54, 25.55, 20.37. MS (ESI): m / z Calculated value C 21 H 26 N3O3S [M + H] + 400.52; Measured value, 400.40.

[0173] Compound of formula (III) 7c. 98% yield. 1 H NMR (400 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.46 - 7.35 (m, 2H), 7.14 (d, J = 8.3 Hz, 1H), 6.90 (s, 1H), 6.57 - 6.47 (m, 2H), 5.85 (s, 2H), 3.62 (t, J = 7.1 Hz, 1H), 2.75 (t, J = 7.4 Hz, 4H), 2.48 - 2.44 (m, 4H), 1.94 - 1.87 (m, 5H), 0.90 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H). 1313C NMR (DMSO-d6): δ 168.37, 152.36, 142.62, 137.20, 129.10, 128.35, 126.08, 117.67, 112.29, 61.01, 32.30, 31.22, 30.18, 24.98, 19.22, 17.57. MS (ESI): m / z calculated value for C 23 H 30 N3O3S [M+H] + 428.57; measured value, 428.29.

[0174] Compound 7d of formula (III). Yield 87%. 1 1H NMR (400 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.45 - 7.32 (m, 2H), 7.13 (d, J = 8.9 Hz, 2H), 6.90 (s, 1H), 6.59 - 6.47 (m, 2H), 3.64 - 0.360 (m, 2H), 2.75 (t, J = 7.3 Hz, 4H), 2.47 - 2.44 (m, 4H), 1.94 - 1.87 (m, 5H), 0.90 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H). 13 13C NMR (DMSO-d6): δ 173.69, 157.59, 147.94, 142.52, 134.41, 133.67, 131.46, 123.00, 117.67, 66.33, 37.62, 36.54, 35.50, 30.30, 24.54, 22.88. MS (ESI): m / z calculated value for C 23 H 30 N3O3S [M+H] + 428.16; measured value, 428.53.

[0175] Compound (III) had a yield of 7e.73%. 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 7.48-7.38 (m, 3H), 6.92 (s, 1H), 6.60-6.50 (m, 2H), 3.82-3.76 (m, 1H), 2.78 (t, J = 7.4 Hz, 4H), 2.57-2.53 (m, 3H), 2.46-2.40 (m, 1H), 2.01-1.85 (m, 4H), 1.72-1.59 (m, 1H), 1.44-1.34 (m, 2H), 0.85 (d, J = 6.7 Hz, 3H), 0.76 (d, J = 6.5 Hz, 3H). 13 C NMR (DMSO-d6): δ 169.62, 152.32, 142.62, 137.32, 129.15, 128.34, 126.14, 117.68, 112.36, 54.55, 42.37, 32.33, 30.04, 25.03, 23.84, 22.83, 21.38. MS (ESI): m / z calcd. 24 H 32 N3O3S [M+H] + 442.60; measured value, 442.41.

[0176] Compound 7f of formula (III). Yield 72%. 1 H NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.19-8.02 (m, 1H), 7.47-7.42 (m, 4H), 7.38-7.21 (m, 3H), 6.90 (s, 1H), 6.58-6.48 (m, 2H), 5.88 (s, 2H), 5.11-5.08 (m, 1H), 2.74 (t, J = 7.3 Hz, 4H), 2.41-2.25 (m, 4H), 1.95-1.78 (m, 4H). 1313C NMR (DMSO-d6): δ 167.23, 152.36, 142.65, 138.40, 137.13, 128.81, 128.30, 127.97, 127.40, 126.88, 126.00, 125.95, 117.76, 112.27, 59.24, 32.22, 29.81, 24.96. MS (ESI): m / z calculated for C 26 H 28 N3O3S [M+H] + 462.55; found, 462.55.

[0177] Compound 7g of formula (III). 86% yield. 1 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 7.65 - 7.61 (m, 1H), 7.32 - 7.20 (m, 7H), 6.90 (s, 1H), 6.48 (d, J = 8.7 Hz, 2H), 5.86 (s, 2H), 4.09 - 4.05 (m, 1H), 2.87 - 2.83 (m, 2H), 2.78 - 2.73 (m, 4H), 2.49 - 2.40 (m, 4H), 1.91 - 1.87 (m, 4H). 13 13C NMR (DMSO-d6): δ 168.45, 152.22, 142.55, 137.19, 136.99, 129.24, 128.98, 128.16, 127.86, 126.30, 126.15, 117.61, 112.28, 57.17, 32.29, 29.95, 25.00. MS (ESI): m / z calculated for C 27 H 30 N3O3S [M+H] + 476.61; found, 476.59.

[0178] Compound 7h of formula (III). 79% yield. 11H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 7.93 (s, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.25 - 7.16 (m, 5H), 6.89 (s, 1H), 6.47 (d, J = 8.7 Hz, 2H), 5.83 (s, 2H), 4.09 (t, J = 7.3 Hz, 1H), 2.76 - 2.72 (m, 5H), 2.45 - 2.30 (m, 5H), 1.91 - 1.84 (m, 4H). 13 13C NMR (DMSO-d6): δ 168.47, 152.21, 142.54, 137.20, 129.24, 128.16, 127.86, 126.14, 117.60, 112.28, 57.21, 32.29, 29.95, 25.01. MS (ESI): m / z calculated for C 27 H 30 N3O3S [M+H] + 476.61; found, 476.27.

[0179] Compound 7k of formula (III). Yield 77%. 1 1H NMR (400 MHz, DMSO-d6): δ 10.15 (s, 1H), 8.24 (d, J = 8.7 Hz, 2H), 7.95 (t, J = 5.8 Hz, 1H), 7.74 (s, 1H), 7.45 - 7.41 (m, 2H), 6.74 (s, 2H), 3.76 - 3.70 (m, 2H), 3.60 (t, J = 7.3 Hz, 4H), 3.44 (t, J = 7.3 Hz, 4H), 3.25 (t, J = 7.4 Hz, 2H), 2.79 - 2.72 (m, 4H). 13 13C NMR (DMSO-d6): δ 167.73, 152.38, 142.57, 137.20, 129.54, 128.35, 124.93, 117.56, 112.52, 35.43, 32.33, 30.21, 24.93. MS (ESI): m / z calculated for C 21 H 26 N3O3S [M+H] +400.52; Measured value, 400.37.

[0180] Compound of formula (III) with a yield of 10.70%. 1 H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1H), 7.50 (d, J = 9.1 Hz, 1H), 7.36 - 7.28 (m, 2H), 6.98 - 6.91 (m, 2H), 6.88 (s, 1H), 6.65 - 6.57 (m, 2H), 6.53 - 6.45 (m, 2H), 4.04 - 3.98 (m, 1H), 2.76 (t, J = 7.1 Hz, 5H), 2.67 - 2.52 (m, 2H), 2.45 - 2.29 (m, 4H), 1.95 - 1.84 (m, 4H). 13 C NMR (DMSO-d6): δ 169.10, 156.37, 152.73, 143.09, 137.77, 130.73, 129.60, 128.78, 127.55, 127.06, 118.14, 115.22, 112.90, 58.04, 32.88, 30.55, 25.60. MS (ESI): m / z calculated value for C 27 H 30 N3O4S [M+H] + 492.61; Measured value, 492.68.

[0181] Compound of formula (III) with a yield of 11.91%. 1 H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 7.64 (s, 3H), 7.42 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.4 Hz, 1H), 6.92 (s, 1H), 6.55 (d, J = 8.7 Hz, 2H), 3.85 - 3.74 (m, 1H), 2.80 - 2.72 (m, 6H), 2.67 - 2.62 (m, 1H), 2.48 - 2.42 (m, 4H), 2.01 - 1.89 (m, 4H), 1.69 - 1.21 (m, 5H). 13C NMR (DMSO-d6): δ 168.91, 152.44, 142.66, 137.22, 128.99, 128.32, 127.67, 125.86, 117.77, 112.36, 55.66, 33.05, 32.31, 30.06, 28.91, 26.51, 25.02, 21.96. MS (ESI): m / z calculated value C 24 H 33 N4O3S [M+H] + 457.61; measurement, 457.40.

[0182] Example 17: Evaluation of the efficacy and selectivity of compounds of formula (III) in inhibiting NLRP3-mediated release of IL-1β in vitro. The ability of the compound of formula (III) to reduce IL-1β release induced by NLRP3 activation was examined in bone marrow-derived macrophages (BMDM) from wild-type (WT) mice that were first primed with 1 μg / ml lipopolysaccharide (LPS) from Escherichia coli for 2 h. After addition of the compound of formula (I) at a concentration of 1 μM for 30 min, the cells were stimulated with 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate triethylammonium salt (Bz-ATP) at a concentration of 100 μM for 30 min. MCC950 (N-((1,2,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide) was examined as a comparison. Cell culture supernatants were analyzed for IL-1β by ELISA. The potency of the compounds was expressed as the percentage inhibition of IL-1β release at a concentration of 1 μM, and the results are reported in Table 1.

[0183] [Table 1]

[0184] All the compounds of formula (III) were capable of inhibiting the release of IL-1β, and the preferred were compounds 6c, 6e, 7c, 6h and 10 of formula (III).

[0185] Advantageously, the inhibition rates of IL-1β release for compounds 6c and 10 of formula (III) were excellent: 59.4% for compound 6c and 58.8% for compound 10. Thus, compounds 6c and 10 showed a comparable potency to MCC950 (60.1%), one of the most potent NLRP3 inhibitors known to date, whose clinical development was discontinued due to liver toxicity issues. The ICs obtained in BMDMs stimulated with LPS, compounds and ATP were 50 The values ​​were 6.88 nm for compound 6c of formula (III) and 8.58 nm for compound 10 of formula (III) (Figure 6B). The potency of compounds 6c and 10 of formula (III) was also evaluated in human monocytes (THP-1) stimulated with LPS, compounds and ATP: the IC obtained in THP-1 cells was 50 The values ​​were 7.47 nm for compound 6c of formula (III) and 3.29 nm for compound 10 (FIG. 6B). Thus, the compounds of the present invention of formula (III) identify a new chemotype of NLRP3 inhibitors that may have the advantage of a better toxicity profile than MCC950 in future clinical trials.

[0186] Next, the selectivity of compounds 6c and 10 of formula (III) as NLRP3 inhibitors was evaluated with respect to the NLRC4 inflammasome. For activation of the NLRC4 inflammasome, BMDMs were treated with LPS (100 ng / ml) for 3 h. Then, the culture medium was removed and replaced with serum-free medium containing compound 4 of formula (III) (1 μM, 30 min), and finally the cells were transfected with flagellin (100 ng / ml) by S. typhimurium for 2 h. The supernatants were tested by ELISA. The compounds had no effect on the activation of the NLRC4 inflammasome induced by flagellin S. typhimurium (Figure 6E), indicating their specificity in inhibiting the NLRP3 inflammasome.

[0187] Example 18: Evaluation of the effect of compounds 6c and 10 of formula (III) on cell viability of THP-1 cells. Cell viability was assessed in THP-1 cells using the realtime-Glo"MT Cell Viability Assay (Promega Italia, MI). Briefly, cells were plated in 96-multiwell plates (10 × 10 4 Cells were seeded in 1000 x 1000 cells / well, treated with the selected compounds and incubated for 48 h. After treatment, cells were incubated for 10 min in an incubator with realtime-Glo reagent according to the protocol. Luminescence was measured every 12 h with a Glomax Multi Detection System Promega. The luminescence signal correlates to the number of metabolically active cells. Results represent the mean luminescence value (RLU) ± SEM. Compounds 6c and 10 of formula (III) at the concentrations used do not show cytotoxicity and therefore do not affect the cell viability of THP-1 cells (Figure 6A).

[0188] Example 19: Evaluation of the effects of compounds 6c and 10 on protein expression of the NLRP3 inflammasome Whole cell lysates of THP-1 cells were prepared in RIPA buffer (50 mM Tris-HCl pH 7.8, 150 mM NaCl, 1% IGEPAL CA-630, 0.5% sodium deoxycholate, 0.1% SDS, 1 mM dithiothreitol (DTT)) supplemented with protease and phosphatase inhibitors. Supernatants were concentrated using Pierce Protein Concentrators PES 10K MWCO (Thermo Fisher) and centrifuged at 4000 × g for 15 min. A total of 20 μg of protein or a total of 10 μl of concentrated medium was separated by SDS-PAGE and transferred to nitrocellulose membranes for standard Western blotting. The following primary antibodies were used: NLRP3 (Adipogen, #AG-20B-0014-C100), ASC (Adipogen, #AG-20B-0014-C100), CaspasI (Novus Biological, #14F468), and IL-1β (Cell Signaling Technology, #12242), GAPDH (Cell Signaling Technology, #2118) with isotype-matched horseradish peroxidase-conjugated secondary antibodies and detected by chemiluminescence (GE Image-Quant).

[0189] Treatment with these compounds did not affect the priming step of NLRP3 inflammasome activation and did not alter the expression of NLRP3, caspase-1, ASC, and pro-IL-1β in whole cell lysates (Figure 6C-D).The compounds significantly reduced the release of IL-1β and the amount of cleaved caspase-1 in the cell supernatants (Figure 6C).

[0190] Figures 6G and 6H report the results of NLRP3-stimulated secretion of IL-18 in BMDM and THP-1 cells, respectively. Data are presented as mean ± SEM from three independent experiments. *p<0.05.

[0191] Example 20: Evaluation of the effect of compounds 6c and 10 of formula (III) on LPS-induced inflammation in vivo and ex vivo. C57BL / 6 mice were treated with either inhibitors at a concentration of 25 mg / Kg or vehicle (DMSO) by intraperitoneal injection for 30 min. Afterwards, mice were administered LPS 1 mg / Kg intraperitoneally for 4 h. Mice were sacrificed and blood and peritoneal supernatants were collected. Blood was centrifuged (1000 × g, 15 min) to obtain plasma. ELISA tests were performed on plasma and peritoneal supernatants to evaluate IL-1β levels. Compound-treated mice showed a significant reduction in IL-1β release compared to vehicle-treated mice, indicating that the compounds have a strong efficacy in reducing NLRP3 inflammasome activation in vivo as well (Figure 7).

[0192] Example 21: Evaluation of the effect of compounds 6c and 10 of formula (III) on tumor growth in vivo. Procedures involving animals and their care complied with institutional guidelines and the Animal Ethics Committee approved all experimental protocols (authorization N°481 / 2017-PR and CBCC2.N.BH4 approved by the Italian Ministry of Health). A total of 1 × 10 cytluc were transfected. 6 B16-F10 melanoma cells (B16-F10cytLUC) were subcutaneously inoculated into female 6-8 week-old C57BL / 6 mice. Tumor growth was monitored daily, and tumor volumes were measured every other day using a caliper with the following formula: volume = π / 6 × (a × b2), where "a" is the major diameter and "b" is the minor diameter. As soon as tumor masses were palpable, mice were randomly divided into treatment and control groups (5 mice per group). For NLRP3 inflammasome inhibition, mice were injected intraperitoneally with the selected molecules at 25 mg / Kg three times a week; control mice received an equal volume of DMSO.

[0193] Luciferase luminescence was followed with a whole-body luminometer (IVIS Lumina, Caliper-PerkinElmer). Briefly, mice were anesthetized with 2.5% isoflurane and injected intraperitoneally with 150 mg / Kg d-luciferin (Promega), and luminescence was quantified 15 min later using Living Image Software (Caliper). Compound-treated mice developed significantly smaller (approximately 50% reduction) tumor masses than vehicle (DMSO)-treated mice (Figure 8A-D). Lysates of extracted tumor masses showed no change in the expression of proteins NLRP3, caspase-1, ASC, and pro-IL-1β (Figure 8E).

[0194] Example 22: Proliferation of B16-F10 cancer cells after treatment with compounds 6c and 10 of formula (III). B16-F10 cells were treated with selected inhibitors (1 μM) and then counted in a Barker chamber and dispensed into five sets of four wells in a 24-well plate. From the next day (day 1), one set of wells (days 2, 3, 4, and 5) was washed once with PBS and fixed with 4% formaldehyde solution for 15 min at room temperature, then kept at 4 °C in PBS. On day 5, all wells were stained with crystal violet for 20 min and absorbance was read at 595 nm after dissolving in 10% acetic acid. The compounds had no direct effect on cell proliferation of B16-F10 melanoma cells (Figure 8F).

[0195] Example 23: Evaluation of the effect of compounds 6c and 10 of formula (III) on the tumor microenvironment by a co-culture model. Co-culture of peritoneal macrophages and B16-F10 cells was performed using a Transwell chamber (Corning, Corning, NY, USA) with 0.4 μm pores in the membrane. Peritoneal macrophages and B16-F10 cells were cultured in the lower and upper compartments of the Transwell chamber, respectively, for 48 h. Peritoneal macrophages were cultured at 2 × 105The cells were seeded at a density of 2 × 10 B16-F10 cells per well, treated with LPS (1 μg / mL) for 2 hours, then treated with DMSO or the compound of formula (III) (1 μM) for 30 minutes, and finally stimulated with ATP for 1 hour. 3 Cells were seeded at a density of 100x100 / mL. After 48 hours, the B16-F10 cells in the upper chamber were removed and counted using an automated cell counter (TaliTM image-based cytometer (Invitrogen)). B16-F10 cells in contact with peritoneal macrophages treated with vehicle alone proliferated more than B16-F10 cells in contact with peritoneal macrophages treated with the compounds (Figure 8G). The compounds affected the tumor microenvironment and suppressed the activation of the NLRP3 inflammasome.

[0196] Preparation and evaluation of compounds of formula (IV) The compound of formula (IV) of the present invention was prepared according to the scheme shown in FIG.

[0197] Example 24: Preparation of compounds 2a-b of formula (IV). To a solution of 1a-b (1.0 mmol) in water (5 mL) was added sodium bicarbonate (NaHCO3, 2.5 mmol) under vigorous stirring. Then 4-nitrobenzenesulfonyl chloride (1.0 mmol) was added in portions over 1 h and stirred at room temperature for 16 h. The reaction mixture was then acidified to pH 2 using 1 M HCl and the aqueous phase was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residual crude product was crystallized to give the desired product.

[0198] ((4-Nitrophenyl)sulfonyl)proline (2a) of formula (IV). 65% yield. 1H NMR (400 MHz, DMSO-d6): δ 12.84 (bs, 1H), 8.42-8.36 (m, 2H), 8.11-8.06 (m, 2H), 4.20 (dd, J = 8.6, 3.8 Hz, 1H), 3.44-3.35 (m, 1H), 3.25-3.21 (m, 1H), 2.02-1.94 (m, 1H), 1.91-1.75 (m, 2H), 1.71-1.60 (m, 1H). 1-((4-Nitrophenyl)sulfonyl)piperidine-2-carboxylic acid (2b) of formula (IV). 55% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.97 (bs, 1H), 8.42-8.33 (m, 2H), 8.08-8.00 (m, 2H), 4.62 (d, J = 5.2 Hz, 1H), 3.75-3.71 (m, 1H), 3.20-3.09 (m, 1H), 2.07-2.00 (m, 1H), 1.62-1.58 (m, 3H), 1.30-1.18 (m, 2H).

[0199] Example 25: Preparation of compounds 3a-b of formula (IV). To an ice-cold solution of 2a-b (1.1 mmol) in DMF (5 mL) were added HATU (1.1 mmol) and DIPEA (1.1 mmol). Then, a solution of hexahydro-s-indacen-4-amine (1.0 mmol) in DMF (2 mL) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 2-5 h. After removal of the solvent, the crude product was dissolved in ethyl acetate (20 mL) and the organic layer was washed successively with 10% aqueous citric acid (1 × 10 mL), 5% aqueous NaHCO3 (1 × 10 mL) and brine (1 × 10 mL). After drying over Na2SO4, the solvent was evaporated to give a solid residue, which was first triturated with diethyl ether, then filtered and the solid was recrystallized from methanol to give the desired derivative.

[0200] Compound 3a of formula (IV). 88% yield. 11H NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 8.42 (d, J = 8.9 Hz, 2H), 8.19 - 8.07 (m, 2H), 6.95 (s, 1H), 4.26 - 4.23 (m, 1H), 3.61 - 3.49 (m, 1H), 2.80 (t, J = 7.3 Hz, 4H), 2.66 (t, J = 7.4 Hz, 4H), 2.03 - 1.84 (m, 8H), 1.72 - 1.59 (m, 1H). 13 13C NMR (DMSO-d6): δ 168.97, 149.82, 142.67, 137.61, 129.63, 129.03, 127.93, 125.40, 123.65, 118.74, 117.19, 62.16, 60.71, 32.35, 31.32, 29.97, 26.23, 24.94. MS (ESI): m / z Calcd for C 23 1 26 18H21N3O5S [M+H] + 456.54; Found, 456.41.

[0201] Compound 3b of formula (IV). 77% yield. 1 1H NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1H), 8.51 - 8.25 (m, 2H), 8.12 - 7.86 (m, 2H), 6.92 (s, 1H), 4.76 - 4.72 (m, 1H), 3.84 - 3.80 (m, 1H), 3.66 - 3.55 (m, 1H), 2.78 (t, J = 7.3 Hz, 4H), 2.60 - 2.53 (m, 4H), 2.14 - 2.10 (m, 1H), 2.01 - 1.85 (m, 4H), 1.74 - 1.62 (m, 3H), 1.40 - 1.33 (m, 2H). 13C NMR (DMSO-d6): δ 167.65, 149.36, 145.24, 142.73, 137.28, 128.87, 128.21, 124.30, 117.93, 54.40, 42.87, 32.27, 30.10, 28.85, 24.83, 24.24, 18.95. MS (ESI): m / z calculated value C 24 H 28 N3O5S [M+H] + 470.56; measurement, 470.24.

[0202] Example 26: Preparation of compounds 4a-b of formula (IV). Nitro derivatives 3a-b (1 mmol) were dissolved in ethyl acetate (15 mL) and ice-cold CH3COOH (0.5 mL). Under hydrogen atmosphere, a catalytic amount (0.1 mmol) of palladium on activated carbon (10% Pd basis) was added. After 16 h, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and the crude product was purified by semi-preparative HPLC to give compounds 4a-b of formula (IV).

[0203] Compound of formula (IV) 4a.84% yield. 1H NMR (400 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.49 (d, J = 8.7 Hz, 2H), 6.95 (s, 1H), 6.64 (d, J = 8.8 Hz, 2H), 6.05 (s, 2H), 4.02-3.99 (m, 1H), 3.47-3.39 (m, 1H), 3.14-3.04 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.3 Hz, 4H), 2.01-1.90 (m, 4H), 1.88-1.74 (m, 3H), 1.58-1.48 (m, 1H). 13 C NMR (DMSO-d6): δ 170.15, 153.69, 143.20, 138.21, 129.86, 121.74, 118.39, 113.25, 62.16, 49.62, 32.93, 31.64, 30.55, 25.55, 24.71. MS (ESI): m / z calculated value C 23H 28 N3O3S [M+H] + 426.55; measurement, 426.29.

[0204] Compound of formula (IV) 4b. Yield 71%. 1 H NMR (400 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.48-7.32 (m, 2H), 6.93 (s, 1H), 6.61-6.48 (m, 2H), 4.54 (d, J = 4.1 Hz, 1H), 3.64-3.56 (m, 1H), 3.47 (td, J = 12.7, 2.5 Hz, 1H), 2.79 (t, J = 7.3 Hz, 4H), 2.69-2.52 (m, 4H), 2.04-1.89 (m, 5H), 1.61-1.47 (m, 3H), 1.45-1.18 (m, 2H). 13 C NMR (DMSO-d6): δ 168.90, 153.03, 143.26, 137.88, 129.80, 129.16, 125.31, 118.32, 113.16, 54.69, 42.71, 32.91, 30.70, 28.33, 25.51, 24.37, 19.74. MS (ESI): m / z calculated value C 24 H 30 N3O3S [M+H] + 440.58; measurement, 440.37.

[0205] Example 27: Evaluation of the efficacy of compounds of formula (IV) in inhibiting NLRP3-mediated IL-1β release in vitro. The ability of our compounds to reduce IL-1β release induced by NLRP3 activation was examined in bone marrow-derived macrophages (BMDMs) from wild-type (WT) mice that were first primed with 1 μg / ml lipopolysaccharide (LPS) from Escherichia coli for 2 h. Compound of formula (IV) was added at a concentration of 1 μM for 30 min, followed by stimulation with 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate triethylammonium salt (Bz-ATP) at a concentration of 100 μM for 30 min. Cell culture supernatants were analyzed for IL-1β by enzyme-linked immunosorbent assay (ELISA).

[0206] For comparison, MCC950 (N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbaylmomid)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide) was used. The efficacy of the compound was expressed as the inhibition rate of IL-1β release at a concentration of 1 μM (Table 2).

[0207] [Table 2]

[0208] Compounds of formula (IV) were shown to inhibit IL-1β release with varying potency. Of these, compound 3b was the most potent, with an inhibition rate of 52.4%. This is one of the most potent NLRP3 inhibitors known to date, comparable to MCC950 (60.1%), whose clinical development has been suspended due to liver toxicity issues. Compound 4a of formula (IV) (41.6%) was slightly less potent. Thus, compounds of formula (IV) identify a new chemotype of NLRP3 inhibitors that may have a better toxicity profile than MCC950 in future clinical trials.

Claims

1. A hexahydro-s-indacene compound of formula (I) or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 wherein A is selected from the group consisting of: 【Chemistry 2】 Where: R １ is H, halogen, CF ３ , (C １ -C ３ ) alkyl, (C １ -C ３ ) Alkoxy, NH ２ , NO ２ a heterocyclic substituent selected from the group consisting of CN, COOH, piperidine, morpholine and optionally substituted piperazine, —NHCH ２ Ph, -N((C １ -C ２ ) alkyl) ２ , -NH((C ２ -C ４ ) alkyl)-NH ２ , -COO((C １ -C ２ ) alkyl, and -NHEt; X is -(CH ２ ) ｎ - with n equal to 0 to 1; R ２ NH ２ and NO ２ is a substituent selected from R ３ is H, alkyl (C １ -C ４ ), alkyl(C １ -C ４ ) N.H. ２ , a substituent selected from the group consisting of phenyl, benzyl and hydroxybenzyl; Y is -(CH ２ ) ｎ - where n is equal to 0 or 1; and R ４ NH ２ and NO ２ is a substituent selected from:

2. The hexahydro-s-indacene compound of claim 1, wherein A is A1 and the compound of formula (I) is a tetrahydroisoquinoline compound of formula (II) or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】 During the ceremony R １ is H, halogen, CF ３ , (C １ -C ３ ) alkyl, (C １ -C ３ ) Alkoxy, NH ２ , NO ２ a heterocyclic substituent selected from the group consisting of CN, COOH, piperidine, morpholine and optionally substituted piperazine, —NHCH ２ Ph, -N((C １ -C ２ ) alkyl) ２ , -NH((C ２ -C ４ ) alkyl)-NH ２ , COO (C １ -C ２ ) alkyl, and -NHEt.

3. R １ NH ２ Or NO ２ 3. The hexahydro-s-indacene compound of claim 1 or 2,

4. R １ But (C １ -C ３ 3. The hexahydro-s-indacene compound of claim 1 or claim 2, wherein when alkyl is methyl, ethyl, propyl, or isopropyl.

5. R １ A hexahydro-s-indacene compound according to claim 1 or claim 2, wherein when is halogen it is fluorine, chlorine, bromine or iodine, preferably fluorine.

6. R １ But (C １ -C ３ 3. The hexahydro-s-indacene compound of claim 1 or claim 2, wherein when alkoxy is methoxy, ethoxy, propoxy or isopropoxy.

7. R １ is a heterocyclic substituent selected from the group consisting of piperidine, morpholine and optionally substituted piperazine, is piperidine, morpholine or piperazine, the latter being optionally substituted on the nitrogen atom, preferably with methyl or tert-butoxycarbonyl.

8. The heterocyclic substituent is 【Chemistry 4】 8. The hexahydro-s-indacene compound of claim 7, selected from the group consisting of:

9. R １ N((C １ -C ２ ) alkyl) ２ When N(CH ２ CH ３ ) ２ Or -NHCH ２ CH ２ N.H. ２． 3. The hexahydro-s-indacene compound of claim 1 or 2,

10. R １ NH((C ２ -C ４ ) alkyl)-NH ２ When ２ CH ２ N.H. ２ or NHCH ２ CH ２ CH ２ CH ２ N.H. ２ 3. The hexahydro-s-indacene compound of claim 1 or 2,

11. R １ COO ((C １ -C ２ 3. The hexahydro-s-indacene compound of claim 1 or claim 2, wherein when R is 1, R is 2, R is 3, R is 4, R is 5, R is 6, R is 7, R is 8, R is 9, R is 10, R is 11, R is 12, R is 13, R is 14, R is 15, R is 16, R is 17, R is 18, R

12. The hexahydro-s-indacene compound of claim 1 or claim 2, wherein the compound of formula (I) is a tetrahydroisoquinoline compound of formula (II) selected from the group consisting of: (S)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (3 of formula (II)) 【Chemistry 5】 (S)-2-((4-aminophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (4 of formula (II)) 【Chemistry 6】 (S)-2-((4-fluorophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (6 of formula (II)) 【Chemistry 7】 (S)-2-((4-(benzylamino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7a of formula (II)) 【Chemistry 8】 (S)-2-((4-(dimethylamino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7b of formula (II)) 【Chemistry 9】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-(piperidin-1-yl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7c of formula (II)) 【Chemistry 10】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-morpholinophenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7d of formula (II)) 【Chemistry 11】 (S)-2-((4-(diethylamino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7e of formula (II)) 【Chemistry 12】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-(piperazin-1-yl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7f of formula (II)) 【Chemistry 13】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7g of formula (II)) 【Chemistry 14】 tert-Butyl (S)-4-(4-((3-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)piperazine-1-carboxylate (7h of formula (II)) 【Chemistry 15】 (S)-2-((4-(ethylamino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7i of formula (II)) 【Chemistry 16】 (S)-2-((4-((2-aminoethyl)amino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7j of formula (II)) 【Chemistry 17】 (S)-2-((4-((4-aminobutyl)amino)phenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (7k of formula (II)) 【Chemistry 18】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (9a of formula (II)) 【Chemistry 19】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (9b of formula (II)) 【Chemistry 20】 (S)-2-((4-cyanophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (9c in formula (II)) 【Chemistry 21】 (S)-Methyl 4-((3-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)benzoate (9d of formula (II)) 【Chemical 22】 (S)-4-((3-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)benzoic acid (10 of formula (II)) 【Chemistry 23】

13. The hexahydro-s-indacene compound of claim 1, wherein A is A2 and the compound of formula (I) is a sulfonamide compound of formula (III): 【Chemistry 24】 During the ceremony, X is -(CH ２ ) ｎ - with n equal to 0 to 1; R ２ NH ２ and NO ２ is a substituent selected from R ３ is H, alkyl (C １ -C ４ ), alkyl(C １ -C ４ ) N.H. ２ , phenyl, benzyl and hydroxybenzyl.

14. X is -(CH ２ ) ｎ - and n is equal to 0. The hexahydro-s-indacene compound of claim 1 or claim 13,

15. R ３ is alkyl (C １ -C ４ ) when -CH ３ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ 15. The hexahydro-s-indacene compound of any of claims 1, 13 and 14, wherein R is 0, R is 1, and R is 2.

16. R ３ is alkyl (C １ -C ４ ) N.H. ２ When -(CH ２ ) ４ N.H. ２ 15. The hexahydro-s-indacene compound of any one of claims 1, 13, and 14, wherein

17. R ３ The hexahydro-s-indacene compound of any of claims 1, 13 and 14, wherein is benzyl or hydroxy-benzyl, preferably p-hydroxy-benzyl.

18. 14. The hexahydro-s-indacene compound of claim 1 or claim 13, wherein the compound of formula (I) is a sulfonamide compound of formula (III) selected from the group consisting of: N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)acetamide (6a of formula (III)) 【Chemistry 25】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)propanamide (6b of formula (III)) 【Chemistry 26】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-methyl-2-((4-nitrophenyl)sulfonamido)butanamide (6c of formula (III)) 【Chemical 27】 (R)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-methyl-2-((4-nitrophenyl)sulfonamido)butanamide (6d of formula (III)) 【Chemistry 28】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-4-methyl-2-((4-nitrophenyl)sulfonamido)pentanamide (6e of formula (III)) 【Chemical 29】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)-2-phenylacetamide (6f of formula (III)) 【Chemistry 30】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)-3-phenylpropanamide (6g of formula (III)) 【Chemistry 31】 (R)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)-3-phenylpropanamide (6h of formula (III)) 【Chemistry 32】 (S)—N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-(4-hydroxyphenyl)-2-((4-nitrophenyl)sulfonamido)propanamide (8 of formula (III)) 【Chemical 33】 (S)-6-amino-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-((4-nitrophenyl)sulfonamido)hexanamide (9 of formula (III)) 【Chemical 34】 N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-((4-nitrophenyl)sulfonamido)propanamide (6k of formula (III)) 【Chemistry 35】 2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide (7a of formula (III)) 【Chemical Formula 36】 (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)propanamide (7b of formula (III)) 【Chemical 37】 (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-methylbutanamide (7c of formula (III)) 【Chemical 38】 (R)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-methylbutanamide (7d of formula (III)) 【Chemical 39】 (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-4-methylpentanamide (7e of formula (III)) 【Chemistry 40】 (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-2-phenylacetamide (7f of formula (III)) 【Chemistry 41】 (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-phenylpropanamide (7g of formula (III)) 【Chemistry 42】 (R)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-phenylpropanamide (7h of formula (III)) 【Chemistry 43】 (S)-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-(4-hydroxyphenyl)propanamide (10 of formula (III)) 【Chemistry 44】 (S)-6-amino-2-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)hexanamide (11 of formula (III)) 【Chemistry 45】 3-((4-aminophenyl)sulfonamido)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)propanamide (7k of formula (III)) 【Chemistry 46】

19. The hexahydro-s-indacene compound of claim 1, wherein A is A3 and is a pyrrolidine / piperidine compound of formula (IV) or a pharma- ceutically acceptable salt thereof: 【Chemistry 47】 Y is -(CH ２ ) ｎ - where n is equal to 0 or 1; and R ４ NH ２ and NO ２ is a substituent selected from:

20. When Y is equal to 1, R ４ No ２ 20. The hexahydro-s-indacene compound according to claim 1 or claim 19,

21. When Y is equal to 0, R ４ NH ２ 20. The hexahydro-s-indacene compound according to claim 1 or claim 19,

22. 20. The hexahydro-s-indacene compound of claim 1 or claim 19, wherein the compound of formula (I) is a pyrrolidine / piperidine compound of formula (IV) selected from the group consisting of: N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-((4-nitrophenyl)sulfonyl)pyrrolidine-2-carboxamide (3a of formula (IV)) 【Chemistry 48】 1-((4-aminophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)piperidine-2-carboxamide (4b of formula (IV)) 【Chemistry 49】 N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-((4-nitrophenyl)sulfonyl)piperidine-2-carboxamide (3b of formula (IV)) 【Chemistry 50】 1-((4-aminophenyl)sulfonyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)pyrrolidine-2-carboxamide (4a of formula (IV)) 【Chemistry 51】

23. A hexahydro-s-indacene compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 22 for use as a medicament.

24. A composition comprising a compound of formula (I) according to any one of claims 1 to 22 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

25. A hexahydro-s-indacene compound of formula (I) according to any one of claims 1 to 22 or a pharma- ceutically acceptable salt thereof for use as a selective inhibitor of the NLRP3 inflammasome, preferably for the treatment of pathologies associated with overactivation of NLRP3 and overproduction of interleukin-1β and interleukin-18.

26. 26. The hexahydro-s-indacene compound for use according to claim 25, wherein said pathology is selected from the group consisting of cancer, metabolic disorders, neurodegenerative diseases, migraine headaches, wound repair and autoimmune diseases.

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