NLRP3 modulators

Abstract

The present invention relates to compounds or a pharmaceutically acceptable salt or stereoisomer thereof of formula (I), wherein R1, R2, R3, R4, R5, R5a, X1, X2, X3 and R6 have the meaning as indicated in the claims and description. The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicament and in a method for treating and / or preventing of one or more diseases, disorders or conditions associated with NLRP3.

Description

NLRP3 MODULATORSBACKGROUND OF THE INVENTION

[0001] NLRP3 is a member of the nucleotide-binding domain (NBD), leucine-rich repeat (LRR)-containing (NLR) protein family that mediates innate inflammatory processes after infection or tissue injury. Upon activation it forms an inflammasome complex with ASC and caspase- 1 that leads to IL-ip and IL- 18 release and pyroptotic cell death.

[0002] Pathological functions of NLRP3 -mediated inflammation have been described in inherited diseases like cryopyrin-associated periodic syndromes (CAPS), as well as chronic inflammatory (e.g. rheumatoid arthritis), metabolic (e.g. diabetes) or neurological diseases (e.g. Alzheimer’s disease, Parkinson’s disease, multiple sclerosis).

[0003] NLRP3 is an intracellular sensor molecule that is activated in a “priming” and an “activation” step. The priming step includes the stimulation of pattern recognition receptors (PRRs) like Toll-like receptors and the activation of the nuclear factor-KB (NFKB) pathway that increases the expression of NLRP3, caspase- 1, Gasdermin D and pro-inflammatory cytokines. The NLRP3 activation step leads to formation of the active inflammasome that can be triggered by bacterial, viral and fungal infections (PAMPs; pathogen-associated molecule pattern; e.g., nigericin, DNA, RNA), sterile inflammation mediated by endogenous molecules (DAMPs; damage-associated molecule pattern; e.g. ATP, cholesterol crystals, a-synuclein, amyloid-β) and exposure to environmental irritants (Swanson et al., Nature Review Immunology, 2019, Vol 19., 477-489).

[0004] PAMPs and DAMPs cause cellular stress that is sensed by NLRP3. Many of them activate NLRP3 by causing a decrease in cytosolic potassium ions that induces conformational changes in the inactive NLRP3 protein leading to the formation of an NLRP3 complex that recruits ASC (adaptor protein apoptosis-associated speck-like protein containing a CARD). ASC binds pro-caspase- 1 which is activated within the multiprotein inflammasome complex (also called ASC speck). Active caspase- 1 cleaves the proinflammatory cytokines IL-ip and IL- 18, as well as GSDMD (Gasdermin D) which form pores within the membrane, allowing the release of mature IL-ip and IL-18, and can trigger pyroptotic cell death. During pyroptosis, the release of intracellular contents, including NLRP3 inflammasomes, high-mobility group protein Bl (HMGB1), leukotrienes and prostaglandin, amplifies the inflammatory responseand contributes to inflammatory pathology (Mangan et al., Nature Reviews Drug Discovery, 2018, Vol. 17, 588-606; Swanson et al., Nature Review Immunology, 2019, Vol 19., 477-489).

[0005] Pathological consequences of NLRP3 activation are observed in patients with inherited, autosomal dominant mutations in NLRP3 that promote NLRP3 inflammasome activation. Patients with these gain-of-function mutations develop rare systemic auto- inflammatory syndromes called cryopyrin-associated periodic syndromes (CAPS), characterized by an inflammation-related phenotype with periodic fevers, sterile urticaria, and joint inflammation. CAPS incorporate three overlapping disease entities: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem autoinflammatory syndrome (NOMID).

[0006] Pre-clinical studies with NLRP3 genetic deletions or small molecule inhibitors associate NLRP3 -mediated inflammation with plenty of peripheral and central diseases. These include chronic inflammatory diseases, including gout, rheumatoid arthritis, and inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis, metabolic diseases like atherosclerosis, diabetes, metabolic syndrome, obesity and liver steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis, and neurological diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), multiple sclerosis (MS), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), Prion disease, Traumatic Brain Injury (TBI) and stroke, as well as asthma and allergic airway inflammation, hypertension, myocardial infarction, hyperinflammation following influenza and / or severe acute respiratory syndromecoronavirus 2 (SARS CoV-2), Graft-versus-host disease, silicosis, myelodysplastic syndrome, contact hypersensitivity and joint inflammation triggered by chikungunya virus (Mangan et al., Nature Reviews Drug Discovery, 2018, Vol. 17, 588-606; Holbrook et al., Frontiers in Pharmacology, 2021, Vo.l 12, Article 643254; Coll et al., Trends in Pharmacological Science, 2022, Vol. 43, 653-668; Thornton et al., Journal of Pharmacology and Experimental Therapeutics, March 2024, 388(3) 813-826).

[0007] Several small molecules have been reported that directly or indirectly inhibit NLRP3. They have either weak potencies in the micromolar range and / or off target effects (Coll et al., Trends in Pharmacological Science, 2022, Vol. 43, 653-668). MCC950 is used in many pre-clinical studies as a tool compound with good potency and selectivity over NLRC4and NLRP1. However, high dosing in clinical studies resulted in liver toxicity (Mangan et al., Nature Reviews Drug Discovery, 2018, Vol. 17, 588-606).

[0008] The pro-inflammatory cytokine IL-ip is a potent NLRP3 -dependent effector and therefore a major target for limiting NLRP3 driven pathology. Biologies like anakinra, canakinumab and rilonacept inhibit the IL1 axis, are approved for therapeutic use in CAPS and tested in clinical trial for rheumatoid arthritis and gout. However, biologies require administration by injection, they cause inflammation at the injection site and have poor brain permeability (Mangan et al., Nature Reviews Drug Discovery, 2018, Vol. 17, 588-606).

[0009] There is a need for orally available and preferably brain-permeable NLRP3 inhibitors with improved potency and selectivity.SUMMARY OF THE INVENTION

[0010] The present application relates generally to compounds, compositions and methods for modulating the activity ofNLRP3. Also disclosed herein are compounds, compositions and methods for treating a disease, disorder, or condition which include but are not limited to (i) diseases associated with NLRP3 -mediated inflammation, including but not limited to cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem autoinflammatory syndrome (NOMID); (ii) chronic inflammatory diseases (e.g., gout, rheumatoid arthritis, inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis), (iii) metabolic diseases (e.g., atherosclerosis, diabetes, metabolic syndrome, liver steatosis, nonalcoholic steatohepatitis (NASH), and liver fibrosis); (iv) neurological diseases (e.g., Alzheimer’s disease (AD) and Parkinson’s disease (PD), multiple sclerosis (MS), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), Prion disease, Traumatic Brain Injury (TBI) and stroke); (v) diseases associated with inherited, autosomal dominant mutations in NLRP3 that promote NLRP3 inflammasome; (vi) asthma and allergic airway inflammation; (vii) hypertension; (viii) myocardial infarction; (ix) hyperinflammation following influenza and / or severe acute respiratory syndrome-coronavirus 2 (SARS CoV-2); (x) Graft-versus-host disease; (xi) silicosis; (xii) myelodysplastic syndrome; (xiii) contact hypersensitivity and joint inflammation triggered by chikungunya virus. This also includes obesity as metabolic disease.

[0011] In one aspect, the disclosure encompasses a compound of formula (I)whereinR1is CN, CH3, CF3, CHF2, OCH3, OCHF2, OCF3or halogen;R2is H, CH3, CH2CH3, CF3, CHF2, Cl, CN or cyclopropyl and R3is H or CH3, provided that not both, R2and R3, are H;R4is H, CH3, CH2CH3, CF3, CHF2, OCH3, Cl, F, C3-5cycloalkyl or unsubstituted saturated 4 to 6 membered heterocyclyl, wherein C3-5 cycloalkyl is optionally substituted with one or more F; orR3and R4are joined to form -CH2-CH2-CH2- or -CH2-O-CH2-;-X1- is -CH(R5b)- or -C(R5bl)(R5c)CH2-*, wherein the bond marked with an asterisk is attached to the nitrogen in formula (I);-X2- is -CH(R5d)- or -CH(R5dl)CH2-*, wherein the bond marked with an asterisk is attached to the nitrogen in formula (I);R5, R5a, R5bl, R5Cand R5dlare independently selected from the group consisting of H, F and R5e;R5band R5dare independently selected from the group consisting of H and R5e;Each R5eis independently selected from the group consisting of cyclopropyl and C1-4 alkyl, wherein R5eis optionally substituted with one or more substituents independently selected from the group consisting of OH and F;X3is -S(=O)2-*, -C(=O)-*, -C(=O)O-*, -C(=O)N(R6a)-*, -S(=O)2-N(R6a)-*, - S(=O)(R6a)=N-* or -S(=O)-N(R6a)-*, wherein the bond marked with an asterisk is attached to R6;R6ais H or CH3;R6is, in case X3is -S(=O)2-*, -C(=O)O-*, -C(=O)N(R6a)-*, -S(=O)2-N(R6a)-*, or - S(=O)-N(R6a)-*, selected to be C1.4 alkyl, CHF2, CF3, T1, NHCH3or N(CH3)2, wherein C1-4 alkyl is optionally substituted with OCH3or N(CH3)2; orR6is, in case X3is -C(=0)-*, selected to be C1.4 alkyl, CHF2, CF3, OC1-4 alkyl, T1, OT1, NHCH3or N(CH3)2, wherein C1-4 alkyl is optionally substituted with OCH3or N(CH3)2; orR6is, in case X3is -S(=O)(R6a)=N-*, selected to be C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more F; orR6and R5dare joined to form a bivalent group selected to be CH2 or CH2-CH2; andT1is cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, oxetanyl or tetrahydrofuranyl, wherein T1is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of F, CH3, OCH3and OH.

[0012] In another aspect for the compound of formula (I), R1is CF3, CHF2, F, Cl, OCH3, OCHF2, CH3or CN. In another aspect, R1is CN, CH3, CF3, OCH3, F or Cl, and in a further aspect R1is CF3.

[0013] In one embodiment for the compound of formula (I), R2is CH3and R3is H. In another aspect for the compound of formula (I), R4is H, CH3or CH2CH3, preferably CH3.

[0014] In another embodiment for the compound of formula (I), R1, R2and R3are selected to give formula (la)

[0015] In one aspect for the compound of formula (I), where R1, R2and R3are selected to give formula (la), R4is selected to give formula (lb) or (Ibl)

[0016] In another aspect, for the compound of formula (I), R5and R5aare H. In another aspect, X1is -CH(R5b)-. In a further aspect, R5bis H or CHs, preferably H. In yet another aspect, X2is -CH(R5d)-. In one aspect, R5dis H or joined with R6, preferably H. In another aspect, R5, R5a, X1and X2are selected to give formula (Ic)(Ic).

[0017] In one embodiment of the disclosure for the compounds described herein,R5b, R5d, X3and R6are selected to give a formula selected from the formulas (Id1) to (Id8), preferably (Id3) or (Id6):

[0018] In one embodiment of the disclosure for the compounds described herein, R6isCH3, CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, N-methylpyrrolidinyl,oxetanyl, azetidinyl, N,N-dimethylaminomethyl, methoxymethyl or methoxyethyl, preferably CH2CH3, CH(CH3)2or cyclopropyl.

[0019] In another aspect of the disclosure for the compounds described herein, the compound is: rac-2-[2-(l,l-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3-«]pyrazin-5-yl)-[1.2.4]triazolo[1,5-a ]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;3-methyl-2-[2-(2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H- [1,2,5]thiadiazolo[2,3- a]pyrazin-5-yl)-[1,2,4]triazolo[1,5-a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol;2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin- 2-yl]-l,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one;2-[2-(4-isopropylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5- yl] -3 -methyl-5 -(trifluoromethyl)phenol ;3 -methyl-2- [7-methyl-2-(2 -methyl- 1 , 1 -dioxo-3 a,4,6,7-tetrahydro-3H-[1.2.5]thiadiazolo[2,3-a]pyrazin-5-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol; l-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2- yl]piperazin- 1 -yl] ethanone;3-methyl-2-[2-[rel-(3aR)-1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3- a]pyrazin-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol;3-methyl-2-[2-[rel-(3aS)-l,l-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3- a]pyrazin-5-yl]-[1,2,4]triazolo[1,5-a ]pyrimidin-5-yl]-5-( trifluoromethyl)phenol;3-methyl-2-[2-[rel-(3aR)-2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H-[ 1.2.5]thiadiazolo[2,3- a]pyrazin-5-yl]-[1,2,4]triazolo[ l,5- ]pyrimidin-5-yl]-5- (trifluoromethyl)phenol;3-methyl-2-[2-[rel-(3aS)-2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H- [1,2,5]thiadiazolo[2,3- a]pyrazin-5-yl]-[1,2,4]triazolo[ l,5- ]pyrimidin-5-yl]-5- (trifluoromethyl)phenol; re / -(8aS)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- «]pyrimidin-2-yl]-l ,3.4,7,8,8a-hexahydropyrrolo[1,2- ]pyrazin-6-one; rel-(8aR )-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]-l,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one;3-methyl-2-[7-methyl-2-[rel-(3aR) -2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H- [1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol;3-methyl-2-[7-methyl-2-[rel-(3aS)-2-methyl- 1 ,1 -dioxo-3a,4,6,7-tetrahydro-3H- [1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol; l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[l,5- a]pyrimi di n-2-y 1 ]pi perazi n- 1 -yl] ethanone; l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[l,5- a]pyrimidin-2-yl]piperazin-l-yl]propan-l-one; cyclopropyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1.2.4]triazolo[1,5-«]pyrimidin-2-yl]piperazin-l-yl]methanone; l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[l,5- a]pyrimidin-2-yl]piperazin-l-yl]-2-methoxy-ethanone;1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[l,5-a]pyrimidin-2-yl]piperazin- 1 -yl] -3 -methoxy-propan- 1 -one;2-(dimethylamino)-l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1.2.4]triazolo[1,5-«]pyrimidin-2-yl]pi perazi n-l-yl] ethanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(35)-tetrahydrofuran-3-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(25)-tetrahydrofuran-2-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin- 1 -yl] - [(25)- 1 -methylpyrrolidin-2-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(27?)- 1 -methyl pyrrolidin-2-yl]methanone; rac-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin- 1 -yl] -( 1 -methylpyrrolidin-3 -yl)methanone;[(27?)-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimi di n-2-y I ] -2-methy l-pi perazi n- 1 -yl] - [(3R )-tetrahydrofiiran-3 -yl] methanone;[(25)-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- t / ]pyrimi di n-2-y I ] -2-methy l-pi perazi n- 1 -yl] - [(3R) -tetrahydrofuran-3 -yl] methanone;1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin- 1 -yl] -2-methyl-propan- 1 -one;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]-[rel-(3R) -1-methylpyrrolidin-3-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[rel-(3S)-l-methylpyrrolidin-3-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-(oxetan-3-yl)methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(27?)-tetrahydrofuran-2-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(3R) -tetrahydrofuran-3-yl]methanone; methyl 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[ 1 ,2,4]triazolo[ 1 ,5- a]pyrimidin-2-yl]piperazine-l -carboxylate;4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin- 2-yl] -N- methyl-piperazine-1 -carboxamide;4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin- 2-yl]-N,N -dimethyl-piperazine- 1 -carboxamide;2-[2-(4-ethylsulfonylpiperazin-l-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-3-methyl-5- (trifluoromethyl)phenol;2-[2-(4-isopropylsulfonylpiperazin-l-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3- methyl-5-(trifluoromethyl)phenol;2-[2-(4-cyclobutylsulfonylpiperazin-l-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3- methyl-5-(trifluoromethyl)phenol;2-[2-[4-(azetidin-l-ylsulfonyl)piperazin-l-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3- methyl-5-(trifluoromethyl)phenol;2-[2-(4-cyclobutylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5- yl] -3 -methyl-5 -(trifluoromethyl)phenol ;2-[2-[4-(azetidin-l-ylsulfonyl)piperazin-l-yl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]propan-l-one; methyl 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-«]pyrimidin-2-yl]piperazine-l-carboxylate; ethyl 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-l -carboxylate; cyclopropyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone; cyclobutyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[ l,5-«]pyrimidin-2-yl]piperazin-l-yl]methanone;2-[2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-3- methyl-5-(trifluoromethyl)phenol;3 -methyl-2- [2-(4-methylsulfonylpiperazin- 1 -yl)- [ 1 ,2,4]triazolo [1,5 -a]pyrimidin-5 -yl] - 5-(trifluoromethyl)phenol;4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]-N,N -dimethyl-piperazine- 1 -sulfonamide;1-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2- yl]piperazin- 1 -yl]propan- 1 -one; cyclopropyl-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]methanone;2-[2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- 3 , 5-dimethyl-phenol;1-[4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]propan-l-one; cyclopropyl-[4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1.2.4]triazolo[1,5-«]pyrimidin-2-yl]piperazin-l-yl]methanone;2-[2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5- methoxy-3-methyl-phenol;2-[2-(4-cyclobutylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5- yl]-5-methoxy-3-methyl-phenol; methyl 4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-l-carboxylate;1 - [4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[1.2.4]triazolo[1,5-«]pyrimidin-2-yl]piperazin-l-yl]propan-l-one; cyclopropyl-[4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;5-(difluoromethyl)-2-[2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-3-methyl-phenol;2-[2-(4-cyclobutylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5- yl]-5-(difluoromethyl)-3-methyl-phenol;3-methyl-2-[7-methyl-2-[4-(oxetan-3-ylsulfonyl)piperazin-l-yl]-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; or rac- -methyl-2- [7-methyl-2-(4-tetrahy drofuran-3 -ylsulfonylpiperazin- 1 -yl)-[1.2.4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol.

[0020] In another aspect of the disclosure for the compounds described herein, the compound is: methyl 4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazine-l -carboxylate;(l-fluorocyclopropyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;(l-fluorocyclobutyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;(l-fluorocyclopropyl)-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7- methyl-[ 1 ,2,4]triazolo[ 1 , 5-a]pyrimidin-2-yl]piperazin- 1 -yl]methanone;(l-fluorocyclobutyl)-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7- methyl-[ 1 ,2,4]triazolo[ 1 , 5-a]pyrimidin-2-yl]piperazin- 1 -yl]methanone;(3,3-difluorocyclobutyl)-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7- methyl-[ 1 ,2,4]triazolo[ 1 , 5-a]pyrimidin-2-yl]piperazin- 1 -yl] methanone; rac-(2,2-difluorocyclopropyl)-[4-[5-[2-hydroxy-6-methyl-4- (trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l- yl]methanone;2-[2-(4-cyclobutylsulfonylpiperazin- 1 -yl)-7-methyl-[ 1 ,2,4]triazolo[ 1 , 5-a]pyrimidin- 5 -yl] - 5 -fluoro-3 -methyl-phenol ;3 -methyl-2- [7-methyl-2- [4- [rel-(3S)-tetrahydrofuran-3 -yl]sulfonylpiperazin- 1 -yl] - [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol;3-methyl-2-[7-methyl-2-[4-[rel-(3R) -tetrahydrofuran-3-yl]sulfonylpiperazin-l-yl]- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[rel-(lS)-2,2-difluorocyclopropyl]methanone; or[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[rel-(17?)-2,2-difluorocyclopropyl]methanone.

[0021] The invention provides a compound of formula (I). The invention also provides a pharmaceutical composition comprising any of the compounds described herein. The invention also provides the use of a compound of formula (I) as medicament and (for use) in methods of treating and / or preventing of one or more diseases, disorders or conditions associated with NLRP3.

[0022] In yet another aspect, described is a method of treating and / or preventing one or more diseases and / or disorders associated with NLRP3 with a compound described herein, or a compound or composition described herein (for use) in a method of treating and / or preventing one or more diseases, disorders or conditions associated with NLRP3.

[0023] Both the foregoing summary and detailed description are exemplary and explanatory. They are intended to provide further details of the invention, but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.DETAILED DESCRIPTION OF THE INVENTION

[0024] An object of the present invention is to provide a new class of compounds as modulators of NLRP3, which may be effective in the treatment of NLRP3 related diseases and disorders and which may show improved pharmaceutically relevant properties including oral availability, brain-permeability, activity, solubility, selectivity, ADMET properties and / or reduced side effects.

[0025] Pathological functions of NLRP3-mediated inflammation have been described in inherited diseases like CAPS, as well as chronic inflammatory (e.g., rheumatoid arthritis), metabolic (e.g., diabetes) or neurological diseases (e.g., Alzheimer’s disease, Parkinson’s disease, multiple sclerosis). Also, as noted above, NLRP3 -mediated inflammation is associated with peripheral and central diseases. These include chronic inflammatory diseases, including gout, rheumatoid arthritis, and inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis, metabolic diseases like atherosclerosis, diabetes, metabolic syndrome, obesity and liver steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis, and neurological diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), multiple sclerosis (MS), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), Prion disease, Traumatic Brain Injury (TBI) and stroke, as well as asthma and allergic airway inflammation, hypertension, myocardial infarction, hyperinflammation following influenza and / or severe acute respiratory syndrome-coronavirus 2 (SARS CoV-2), Graft-versus-host disease, silicosis, myelodysplastic syndrome, contact hypersensitivity and joint inflammation triggered by chikungunya virus.

[0026] The present invention provides compounds of the present invention in free or pharmaceutically acceptable salt form or in the form of solvates, hydrates, tautomers or stereoisomers. These can be used in the treatment of diseases or disorders mentioned herein. The same applies to a pharmaceutical composition of the present invention. Accordingly, one aspect of the present invention is a pharmaceutically acceptable salt of a compound of the present invention. Another aspect of the present invention is a stereoisomer of a compound of the present invention.

[0027] Accordingly, the present invention provides a compound of formula (I):whereinR1is CN, CH3, CF3, CHF2, OCH3, OCHF2, OCF3or halogen;R2is H, CH3, CH2CH3, CF3, CHF2, Cl, CN or cyclopropyl and R3is H or CH3, provided that not both, R2and R3, are H;R4is H, CH3, CH2CH3, CF3, CHF2, OCH3, Cl, F, C3-5cycloalkyl or unsubstituted saturated 4 to 6 membered heterocyclyl, wherein C3-5cycloalkyl is optionally substituted with one or more F; orR3and R4are joined to form -CH2-CH2-CH2- or -CH2-O-CH2-;-X1- is -CH(R5b)- or -C(R5bl)(R5c)CH2-*, wherein the bond marked with an asterisk is attached to the nitrogen in formula (I);-X2- is -CH(R5d)- or -CH(R5dl)CH2-*, wherein the bond marked with an asterisk is attached to the nitrogen in formula (I);R5, R5a, R5bl, R5cand R5dlare independently selected from the group consisting of H, F and R5e;R5band R5dare independently selected from the group consisting of H and R5e;Each R5eis independently selected from the group consisting of cyclopropyl and Ci-4 alkyl, wherein R5eis optionally substituted with one or more substituents independently selected from the group consisting of OH and F;X3is -S(=0)2-*, -C(=0)-*, -C(=0)0-*, -C(=O)N(R6a)-*, -S(=O)2-N(R6a)-*, - S(=O)(R6a)=N-* or -S(=O)-N(R6a)-*, wherein the bond marked with an asterisk is attached to R6;R6ais H or CH3;R6is, in case X3is -S(=O)2-*, -C(=O)O-*, -C(=O)N(R6a)-*, -S(=O)2-N(R6a)-*, or - S(=O)-N(R6a)-*, selected to be Ci-4 alkyl, CHF2, CF3, T1, NHCH3or N(CH3)2, wherein Ci-4 alkyl is optionally substituted with OCH3or N(CH3)2; orR6is, in case X3is -C(=O)-*, selected to be C1-4 alkyl, CHF2, CF3, OC1-4 alkyl, T1, OT1, NHCH3or N(CH3)2, wherein C1-4 alkyl is optionally substituted with OCH3or N(CH3)2; orR6is, in case X3is -S(=O)(R6a)=N-*, selected to be C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more F; orR6and R5dare joined to form a bivalent group selected to be CH2or CH2-CH2;T1is cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, oxetanyl or tetrahydrofiiranyl, wherein T1is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of F, CH3, OCH3and OH.

[0028] In case a variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once, then the respective variants can be the same or different.

[0029] Surprisingly, the disclosed example compounds according to the present invention have favourable physico-chemical properties and / or selectivity, which combine to help to achieve beneficial therapeutic efficacy whilst limiting unintended liabilities.

[0030] As detailed in the biological assays section of the examples below, compounds according to the disclosure were tested in LPS-primed THP1 cells to assess their pharmacological capability to inhibit NLRP3 activation with Nigericin and the release of IL- ip into the supernatant. NLRP3 inhibitors decrease LPS / Nigericin-induced IL-1 releasewhich is indicated as a reduction in the HTRF (homogenous time resolved fluorescence) ratio. The results surprisingly and unexpectedly showed that multiple compounds according to the invention exhibited favourable IC50 values as disclosed in Table 9.I. Definitions

[0031] Within the meaning of the present invention the terms are used as follows:

[0032] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art, unless otherwise defined. Any suitable materials and / or methodologies known to those of ordinary skill in the art can be utilized in carrying out the methods described herein.

[0033] As used in the description of the invention and the appended claims, the singular forms “a”, “an” and “the” are used interchangeably and intended to include the plural forms as well and fall within each meaning, unless the context clearly indicates otherwise. Also, as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0034] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.

[0035] The term “optionally substituted” means unsubstituted or substituted. Generally - but not limited to-, “one or more substituents” means one, two or three, preferably one or two substituents and more preferably one substituent. Generally these substituents can be the same or different. The term “one or more substituents” also means by way of example one, two, three, four or five, preferably by way of example one, two, three or four.

[0036] “Alkyl” means a straight-chain or branched hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified.

[0037] “Alkenyl” means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent as further specified.

[0038] “Alkynyl” means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent as further specified.

[0039] “Ci-4 alkyl” means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e g. -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a C1-4 alkyl carbon may be replaced by a substituent as further specified. The term “C1-3 alkyl” is defined accordingly.

[0040] Ci-6 alkyl” means an alkyl chain having 1 - 6 carbon atoms, e g. if present at the end of a molecule: C1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or e.g. -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, - CH(C2H5)-, -C(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a C1-6 alkyl carbon may be replaced by a substituent as further specified.

[0041] C2-6alkenyl” means an alkenyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, - CH=CH-CH=CH2, or e.g. -CH=CH-, when two moieties of a molecule are linked by the alkenyl group. Each hydrogen of a C2-6alkenyl carbon may be replaced by a substituent as further specified.

[0042] “C2-6alkynyl” means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -CACH, -CH2-OCH, -CH2-CH2-OCH, -CH2-C =C-CH3. or e g. -C =C- when two moieties of a molecule are linked by the alkynyl group. Each hydrogen of a C2-6alkynyl carbon may be replaced by a substituent as further specified.

[0043] C3-7cycloalkyl” or “ C3-7cycloalkyl ring” means a cyclic alkyl chain having 3 - 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Preferably, cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified herein. The term “C3-5cycloalkyl” or “C3-5cycloalkyl ring” is defined accordingly.

[0044] C5cycloalkylene” refers to a bivalent cycloalkyl with five carbon atoms, i.e. a bivalent cyclopentyl ring.

[0045] C5cycloalkenylene” refers to a bivalent cycloalkenylene, i.e. a bivalent cyclopentene or cyclopentadiene.

[0046] “C4-12bicycloalkyl” or “C4-12bicycloalkyl ring” means a bicyclic fused, bridged or spiro alkyl chain having 4 to 12 carbon atoms, e.g. hexahydroindane, octahydropentalen, bicycle[2.2.1]heptane or spiro(3.2)hexane. Each hydrogen of a bicycloalkyl carbon may be replaced by a substituent as further specified herein.

[0047] “Halogen” means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.

[0048] “4 to 7 membered heterocyclyl” or “4 to 7 membered heterocycle” means a ring with 4, 5, 6 or 7 ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 4 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for a 4 to 7 membered heterocycle are azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. The term “5 to 6 membered heterocyclyl” or “5 to 6 membered heterocycle” is defined accordingly and and includes 5 to 6 membered aromatic heterocyclyl or heterocycle. The term “5 membered heterocyclyl” or “5 membered heterocycle” is defined accordingly and includes 5 membered aromatic heterocyclyl or heterocycle. The term “4 to 6 membered heterocyclyl” or “4 to 6 membered heterocycle” is defined accordingly.

[0049] The term “nitrogen ring atom containing 5-membered heterocyclene” refers to a bivalent 5-membered heterocycle, wherein at least one of the five ring atoms is a nitrogen atom and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom.

[0050] Saturated 4 to 7 membered heterocyclyl” or “saturated 4 to 7 membered heterocycle” means fully saturated “4 to 7 membered heterocyclyl” or “4 to 7 membered heterocycle”. “Saturated 4 to 6 membered heterocyclyl” or “saturated 4 to 6 membered heterocycle” means fully saturated “4 to 6 membered heterocyclyl” or “4 to 6 membered heterocycle”.

[0051] “4 to 7 membered at least partly saturated heterocyclyl” or “4 to 7 membered at least partly saturated heterocycle” means an at least partly saturated “4 to 7 membered heterocyclyl” or “4 to 7 membered heterocycle”.

[0052] “5 to 6 membered aromatic heterocyclyl” or “5 to 6 membered aromatic heterocycle” means a heterocycle derived from cyclopentadienyl or benzene, where at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-). Examples for such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine.

[0053] “5 membered aromatic heterocyclyl” or “5 membered aromatic heterocycle” means a heterocycle derived from cyclopentadienyl, where at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-). Examples for such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole.

[0054] "7 to 12 membered heterobicyclyl" or "7 to 12 membered heterobicycle" means a heterocyclic system of two rings with 7 to 12 ring atoms, where at least one ring atom is shared by both rings and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for a 7 to 12 membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline,dihydroisoquinoline, benzazepine, purine or pteridine. The term 7 to 12 membered heterobicycle also includes spiro structures of two rings like 6-oxa-2-azaspiro[3,4]octane, 2- oxa-6-azaspiro[3.3]heptan-6-yl or 2,6-diazaspiro[3.3]heptan-6-yl or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octan-2-yl or 3,8-diazabicyclo[3.2.1] octane.

[0055] Saturated 7 to 12 membered heterobicyclyl” or “saturated 7 to 12 membered heterobicycle” means fully saturated “7 to 12 membered heterobicyclyl” or “7 to 12 membered heterobicycle”.

[0056] “7 to 12 membered at least partly saturated heterobicyclyl” or “7 to 12 membered at least partly saturated heterobicycle” means an at least partly saturated “7 to 12 membered heterobicyclyl” or “7 to 12 membered heterobicycle”.

[0057] “9 to 11 membered aromatic heterobicyclyl” or “9 to 11 membered aromatic heterobicycle” means a heterocyclic system of two rings, wherein at least one ring is aromatic and wherein the heterocyclic ring system has 9 to 11 ring atoms, where two ring atoms are shared by both rings and that may contain up to the maximum number of double bonds (fully or partially aromatic) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for an 9 to 11 membered aromatic heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The terms “9 to 10 membered aromatic heterobicyclyl” or “9 to 10 membered aromatic heterobicycle” are defined accordingly.II. Exemplary Compounds of the Disclosure

[0058] Exemplary compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given above or below, with all combinations of preferred substituent definitions being a subject of the present invention. With respect to all preferred compounds of the formula (I) the present invention also includes alltautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts.

[0059] In exemplary embodiments of the present invention, the substituents mentioned below independently have the following meaning. Hence, one or more of these substituents can have the meanings given below.

[0060] In one aspect of the disclosure, R1is CF3, CHF2, F, Cl, OCH3, OCHF2, CH3or CN, preferably R1is CN, CH3, CF3, OCH3, F or Cl, even more preferably CF3.

[0061] In another aspect, R2is CH3and R3is H.

[0062] In another aspect, R4is H, CH3or CH2CH3, preferably CH3.

[0063] In another aspect, R1, R2and R3are selected to give formula (la)

[0064] In another aspect, R4is selected to give formula (lb) or (Ibl)(Ibl).

[0065] In another aspect, R5and R5aare H.

[0066] In another aspect, X1is -CH(R5b)-.

[0067] In another aspect, R5bis H or CH3, preferably H.

[0068] In another aspect, X2is -CH(R5d)-.

[0069] In another aspect, R5dis H or joined with R6, preferably H;

[0070] In another aspect, R5, R5a, X1and X2are selected to give formula (Ic)(Ic).

[0071] In another aspect, R5b, R5d, X3and R6are selected to give a formula selected from the formulas (Id1) to (Id8), preferably (Id3) or (Id6)

[0072] In another aspect, R6is CH3, CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, N-methylpyrrolidinyl, oxetanyl, azetidinyl, N,N-dimethylaminomethyl, methoxymethyl or methoxyethyl, preferably CH2CH3, CH(CH3)2or cyclopropyl.

[0073] Compounds of the present invention in which some or all of the above-mentioned groups have the preferred or more preferred meanings are also an object of the present invention.

[0074] Exemplary specific compounds of the present invention are selected from the group consisting of rac-2-[2-(l ,1 -dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl)- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;3-methyl-2-[2-(2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H- [1,2,5]thiadiazolo[2,3- a]pyrazin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol;2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-a ]pyrimidin- 2-yl]-l,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one;2-[2-(4-isopropylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5- yl] -3 -methyl-5 -(trifluoromethyl)phenol ;3 -methyl-2- [7-methyl-2-(2 -methyl- 1 , 1 -dioxo-3 a,4,6,7-tetrahydro-3H-[1.2.5]thiadiazolo[2,3-a]pyrazin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol; l-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-[1,2,4]triazolo[l,5-a]pyrimidin-2- yl]piperazin- 1 -yl] ethanone;3-methyl-2-[2-[rel-(3aR)-l,l-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3- a]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol;3-methyl-2-[2-[rel-(3aS)-l,l-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3- a ]pyrazin-5-yl]-[1,2,4]triazolo[1,5-a ]pyrimidin-5-yl]-5-( trifluoromethyl)phenol;3-methyl-2-[2-[rel-(3aR) -2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H-[1.2.5]thiadiazolo[2,3-a]pyrazin-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol;3-methyl-2-[2-[rel-(3cz5)-2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H-[1.2.5]thiadiazolo[2,3-a]pyrazin-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol; re / -(8aS)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]-l,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one; re / -(8a / ?)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]-l,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one;3-methyl-2-[7-methyl-2-[rel-(3a7?)-2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H-[1.2.5]thiadiazolo[2,3-«]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol;3-methyl-2-[7-methyl-2-[rel-(3aS)-2-methyl- 1 ,1 -dioxo-3a,4,6,7-tetrahydro-3H-[1.2.5]thiadiazolo[2,3-a ]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol;l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[l,5- a]pyrimi di n-2-y 1 ]pi perazi n- 1 -yl] ethanone; l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]propan-l-one; cyclopropyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1.2.4]triazolo[1,5-«]pyrimidin-2-yl]piperazin-l-yl]methanone; l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[l,5- a]pyrimidin-2-yl]piperazin-l-yl]-2-methoxy-ethanone;1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[l,5- a]pyrimidin-2-yl]piperazin- 1 -yl] -3 -methoxy-propan- 1 -one;2-(dimethylamino)-l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1.2.4]triazolo[1,5-«]pyrimidin-2-yl]piperazin-l-yl]ethanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(35)-tetrahydrofuran-3-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(25)-tetrahydrofuran-2-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin- 1 -yl] - [(2S)- 1 -methylpyrrolidin-2-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(2J?)-l-methylpyrrolidin-2-yl]methanone; rac-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin- 1 -yl] -( 1 -methylpyrrolidin-3 -yl)methanone;[(2J?)-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin- 2-yl]-2-methyl-piperazin-l-yl]-[(3R) -tetrahydrofuran-3-yl]methanone;[(25)-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimi di n-2-y I ] -2-methy l-pi perazi n- 1 -yl] - [(3R) -tetrahydrofuran-3 -yl] methanone; l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-2-methyl-propan-l-one;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[rel-(3R) -l-methylpyrrolidin-3-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[rel-(3S)-l-methylpyrrolidin-3-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-(oxetan-3-yl)methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(2R )-tetrahydrofuran-2-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimi di n-2-y 1 ]pi perazi n- 1 -yl] - [(3R) -tetrahydrofuran-3 -yl] methanone; methyl 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidi n-2-yl]pi perazi ne- 1 -carboxylate;4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl]-N- methyl-piperazine-1 -carboxamide;4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin- 2-yl]-N,N -dimethyl-piperazine- 1 -carboxamide;2-[2-(4-ethylsulfonylpiperazin-l-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3-methyl-5- (trifluoromethy l)phenol ;2-[2-(4-isopropylsulfonylpiperazin-l-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3- methyl-5-(trifluoromethyl)phenol;2-[2-(4-cyclobutylsulfbnylpiperazin-l-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3- methyl-5-(trifluoromethyl)phenol;2-[2-[4-(azetidin-l-ylsulfonyl)piperazin-l-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3- methyl-5-(trifluoromethyl)phenol;2-[2-(4-cyclobutylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5- yl] -3 -methyl-5 -(trifluoromethyl)phenol ;2-[2-[4-(azetidin-l-ylsulfonyl)piperazin-l-yl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[l,5- a]pyrimidin-2-yl]piperazin-l-yl]propan-l-one; methyl 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-l-carboxylate;ethyl 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-l -carboxylate; cyclopropyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone; cyclobutyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[ l,5-«]pyrimidin-2-yl]piperazin-l-yl]methanone;2-[2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3- methyl-5-(trifluoromethyl)phenol;3 -methyl-2- [2-(4-methylsulfonylpiperazin- 1 -yl)- [ 1 ,2,4]triazolo [1,5 -a] pyri m idi n-5 -yl] - 5-(trifluoromethyl)phenol;4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]-N,N -dimethyl-piperazine- 1 -sulfonamide;1-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2- yl]piperazin- 1 -yl]propan- 1 -one; cyclopropyl-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]methanone;2-[2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl-[l,2,4]triazolo[1,5-a]pyrimidin-5-yl]- 3 , 5-dimethyl-phenol;1-[4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]propan-l-one; cyclopropyl-[4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1.2.4]triazolo[1,5-«]pyrimidin-2-yl]piperazin-l-yl]methanone;2-[2-(4-ethyl sulfonyl piperazin- 1 -yl)-7-methyl-[1, 2, 4]triazolo[l ,5-a]pyrimidin-5-yl]-5- methoxy-3 -methyl-phenol;2-[2-(4-cyclobutylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5- yl]-5-methoxy-3-methyl-phenol; methyl 4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[1.2.4]triazolo[1,5-«]pyrimidin-2-yl]piperazine-l-carboxylate;1 - [4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]propan-l-one;cyclopropyl-[4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;5-(difluoromethyl)-2-[2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-3-methyl-phenol;2-[2-(4-cyclobutylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5- yl]-5-(difluoromethyl)-3-methyl-phenol;3-methyl-2-[7-methyl-2-[4-(oxetan-3-ylsulfonyl)piperazin-l-yl]-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; and rac-3 -methyl-2- [7-methyl-2-(4-tetrahydrofuran-3 -ylsulfonylpiperazin- 1 -yl)-[1.2.4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol.Further exemplary specific compounds of the present invention are selected from the group consisting of methyl 4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazine-l -carboxylate;(l-fluorocyclopropyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;(l-fluorocyclobutyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;(l-fluorocyclopropyl)-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7- methyl-[ 1 ,2,4]triazolo[ 1 , 5-a]pyrimidin-2-yl]piperazin- 1 -yl]methanone;(l-fluorocyclobutyl)-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;(3,3-difluorocyclobutyl)-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7- methyl-[ 1 ,2,4]triazolo[ 1 , 5-a]pyrimidin-2-yl]piperazin- 1 -yl] methanone; rac-(2,2-difluorocyclopropyl)-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]- 7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;2-[2-(4-cyclobutylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5- yl]-5-fluoro-3-methyl-phenol;3-methyl-2-[7-methyl-2-[4-[rel-(3S) -tetrahydrofuran-3-yl]sulfonylpiperazin-l-yl]- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol;3-methyl-2-[7-methyl-2-[4-[rel-(3A)-tetrahydrofuran-3-yl]sulfonylpiperazin-l-yl]- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[rel-(lS)-2,2-difluorocyclopropyl]methanone; and[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[rel-(lA)-2,2-difluorocyclopropyl]methanone.

[0075] Where tautomerism, like e.g., keto-enol tautomerism, of compounds of formula (I) may occur, the individual forms, like e.g., the keto and enol form, are comprised separately and together as mixtures in any ratio. Same applies to stereoisomers, like e.g., enantiomers, cis / trans isomers, conformers and the like.

[0076] Especially, when enantiomeric or diastereomeric forms are given in a compound according to formula (I), each pure form separately and any mixture of at least two of the pure forms in any ratio is comprised by formula (I) and is a subject of the present invention.

[0077] Isotopic labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S. Thus, compounds of the present invention are especially also encompassed, which have one or more hydrogens in the form of2H / deuterium D. Solvates and hydrates of compounds of formula (I) are also within the scope of the present invention.

[0078] If desired, isomers can be separated by methods well known in the art, e g., by liquid chromatography. Same applies for enantiomers by using e.g., chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e., coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials, reagents and / or catalysts.

[0079] In case the compounds according to formula (I) contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the formula (I) which comprise acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula (I) which contain one or more basic groups, i.e., groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedi sulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Pharmaceutical Compositions

[0080] As shown below in the Examples, compounds of the present invention are suitable for modulating NLRP3.

[0081] Accordingly, an aspect of the present invention is a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof of thepresent invention for use as a medicament as mentioned above. The same applies to a pharmaceutical composition of the present invention.

[0082] A further aspect of the present invention is a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof or a pharmaceutical composition of the present invention for use in a method of treating and / or preventing one or more disorders or diseases mentioned herein.

[0083] A further aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof or a pharmaceutical composition of the present invention for the manufacture of a medicament for the treatment or prophylaxis of one or more disorders or diseases associated with NLRP3.

[0084] Yet another aspect of the present invention is a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof of the present invention together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions. In one aspect, the one or more bioactive compounds are modulators of NLRP3 other than compounds of the present invention.

[0085] "Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

[0086] A pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like a mixture of compounds of formula (I) in the composition or other modulators of NLRP3.

[0087] The active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions).

[0088] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.

[0089] Starting materials for the synthesis of preferred embodiments of the invention may be purchased from commercially available sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, ABCR.

[0090] In general, several methods are applicable to prepare compounds of the present invention. In some cases, various strategies can be combined. Sequential or convergent routes may be used. Exemplary synthetic routes are described belowIV. Methods of Treatment

[0091] The present invention provides a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition of the present invention, to be used in the treatment or prevention of one or more diseases or disorders associated with NLRP3.

[0092] The therapeutic method described may be applied to mammals such as dogs, cats, cows, horses, rabbits, monkeys and humans. Preferably, the mammalian patient is a human patient.

[0093] Yet another aspect of the present invention is a method for treating, controlling, delaying and / or preventing in a mammalian patient in need of the treatment of one or more diseases, disorders or conditions associated with NLRP3, wherein the method comprises administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof or a pharmaceutical composition of the present invention.

[0094] Yet another aspect of the present invention is a method for treating, controlling, delaying and / or preventing in a mammalian patient in need of the treatment of one or more diseases, disorders or conditions mentioned herein, wherein the method comprises administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof or a pharmaceutical composition of the present invention.

[0095] Diseases or disorders amenable to treatment using the compounds and compositions of the invention include but are not limited to: (i) diseases associated with NLRP3 -mediated inflammation, including but not limited to cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem autoinflammatory syndrome (NOMID); (ii) chronic inflammatory diseases (e.g., gout, rheumatoid arthritis, inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis), (iii) metabolic diseases (e.g., atherosclerosis, diabetes, metabolic syndrome, obesity, liver steatosis, nonalcoholic steatohepatitis (NASH), and liver fibrosis); (iv) neurological diseases (e.g., Alzheimer’s disease (AD) and Parkinson’s disease (PD), multiple sclerosis (MS), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), Prion disease, Traumatic Brain Injury (TBI) and stroke); (v) diseases associated with inherited, autosomal dominant mutations in NLRP3 that promote NLRP3 inflammasome; (vi) asthma and allergic airway inflammation; (vii) hypertension; (viii) myocardial infarction; (ix) hyperinflammation following influenza and / or severe acute respiratory syndrome-coronavirus 2 (SARS CoV-2); (x) Graft-versus-host disease; (xi) silicosis; (xii) myelodysplastic syndrome; (xiii) contact hypersensitivity and joint inflammation triggered by chikungunya virus.

[0096] Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of formula (I) are administered orally.

[0097] The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.EXAMPLES

[0098] Example 1: Chemical Synthesis

[0099] Experimental procedures: The following Abbreviations and Acronyms are used:ACN acetonitrileBippyPhos 5-(di- / cv7-butylphosphino)- 1',3',5'-triphenyl- 1 'H-[ 1 ,4']bipyrazoleBoc Zez'Z-butyloxy carbonylBOC2O di-Zc / 'Z-butyl decarbonateBPin pinacol boronic esterBrine saturated solution of NaCl in waterCyJohnPhos 2-(dicyclohexylphosphino)biphenylDAST diethylaminosulfur trifluorideDCM dichloromethaneDIPEA 7V-ethyl-A-isopropyl-propari-2-amineDMF A,A-dimethylformamideDMSO dimethylsulfoxideDMSO-fik deuterated dimethylsulfoxideESI+positive ionisation modeESI’ negative ionisation modeEt3N triethylamineEtOAc ethyl acetateFBS fetal bovine serum h hour(s)HATU l-[bis(dimethylamino)methylene]-l / / -l,2,3-triazolo[4,5-Z>]pyridinium3-oxid hexafluorophosphateHC1 hydrochloric acidHPLC high-performance liquid chromatographyHERE homogenous time resolved fluorescenceIL- 10 interleukin- 1 betaK2CO3 potassium carbonateK3PO4 tripotassium phosphateLiOH lithium hydroxideLPS lipopolysaccharides m multipletMeOH methanol mg milligram(s)MgSO4magnesium sulphateMHz megahertz min minute(s) mL millilitre(s)MsCl methanesulfonyl chlorideN2nitrogen atmosphereNaHCO3sodium bicarbonateNaOH sodium hydroxideNa2SO4sodium sulphateNH2-NH2H2O hydrazine hydrateNH4CI ammonium chlorideNLRP3 nucleotide-binding domain (NBD), leucine-rich repeat (LRR)- containing (NLR) protein 3NMP A-methyl-2-pyrrolidoneNMR Nuclear Magnetic ResonancePd2(dba)3tris(dibenzylideneacetone)dipalladium(0)Pd(dppf)Cl2[1,1 ' -bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(OAc)2palladium(II)acetatePOC13phosphoryl trichloride r.t. room temperatureRT retention timeT3P propanephosphonic acid anhydrideTCFH N- [chloro(dimethylamino)methylidene]-N- methylmethanaminium hexafluorophosphateTFA 2,2,2-trifluoroacetic acidTsCl 4-methylbenzenesulfonyl chlorideTsOH 4-methylbenzene-l -sulfonic acid

[0100] Analytical LCMS conditions are as follows:

[0101] System 1 (SI): ACIDIC IPC METHOD:

[0102] Analytical (MET / uPLC / 1704) UHPLC-MS were performed in reverse phase system using a Waters UPLC™ BEH™ C18 column (2.1 mm x 50 mm, 1.7 pm; temperature: 40 °C), with an injection volume of 1 pL at a flow rate of 0.9 mL / min and a gradient of 5 - 100% B over 1.10 min, then 100% B for 0.25 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in ACN. A second gradient of 100 - 5% B was then applied over 0.05 min and held for 0.10 min. UV spectra were recorded at 215, 254 and 280 nm. Mass spectra were obtained using a Waters QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0103] System 2 (S2): ACIDIC FINAL METHOD:

[0104] Analytical (MET / uPLC / ABlOl) UHPLC-MS were performed in reverse phase using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 pm; temperature: 40 °C), with an injection volume of 1 pL at a flow rate of 0.6 mL / min and a gradient of 5 - 100% B over 5.30 min, then 100% B for 0.50 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in ACN. A second gradient of 100 - 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215, 254 and 280 nm. ELS data was collected on a Waters ELS detector when reported. Mass spectra were obtained using a Waters QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0105] System 3 (S3): ACIDIC LATE-ELUTING IPC METHOD:

[0106] Analytical (MET / uPLC / 1906) (Ml 2) UHPLC-MS were performed in reverse phase using a Waters UPLC™ CORTECS™ C8 column (2.1 mm x 50 mm, 1.6 pm; temperature: 40 °C), with an injection volume of 1 pL at a flow rate of 0.9 mL / min and a gradient of 5 - 100% B over 1.10 min, then 100% B for 0.30 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile. A second gradient of 100 - 5% B was then applied over 0.02 min and held for 0.28 min. UV spectra were recorded at 215 nm; spectrum range: 200 - 400 nm. ELS data was collected using a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD2 or a QDa; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0107] System 4 (S4): ACIDIC IPC METHOD:

[0108] Data were acquired on an Agilent 1260-6120 coupling with simultaneous DAD and MS detection using a Poroshell 120 EC-C18 column (2.1 mm * 50 mm, 1.9 pm column; temperature: 50 °C). An isocratic of 99% A and 1% B was held for 0.1 min (A= H2O + 0.1% formic acid, B = ACN + 0.05% formic acid) then a gradient of 1-100% B over 1.3 min, then 100% B for 0.5 min. A second gradient of 100-1% B was then applied over 0.1 min at a flow rate of 1 mL / min. Mass spectra data were recorded in full scan with simultaneous positive or negative ESI ionization. Data were processed using the OpenLab software from Agilent.

[0109] System 5 (S5): NEUTRAL FINAL METHOD:

[0110] Data were acquired on an Agilent 1260-6490 coupling, with simultaneous DAD and MS detection using a Poroshell 120 EC-C18 column (2.1 mm x 50 mm, 1.9 pm column; temperature: 50 °C). An isocratic of 99% A and 1% B was held for 0.25 min (A= lOmM ammonium acetate in water, B = ACN) then a gradient of 1-100% B over 225 min, then 100% B for 0.4 min. A second gradient of 100-1% B was then applied over 0.1 min at a flow rate of 0.8mL / min. Mass spectra data were recorded in full scan mode in either positive or negative ESI ionization (Agilent JetSteam). Data were integrated and reported using the MassHunter software from Agilent.

[0111] System 6 (S6): ACIDIC FINAL METHOD:

[0112] Data were acquired on a XBridge™ C18 column (2.1 mm x 50 mm, 1.7 pm; temperature: 50 °C). Mobile phase A: ACN / water (95:5) with 0.05% TFA; mobile phase B: ACN / water (5:95) with 0.05% TFA. Gradient: (0.0-3.0 min), 100% B, (3.0-3.5 min), flow: 1.0 mL / min. Detection: UV (220 nm) and MS (ESI + / -).

[0113] Purification methods are as follows:

[0114] Purifications by chromatography on silica gel were performed on Biotage Isolera systems using the appropriate Sfar Duo cartridge or on Teledyne ISCO CombiFlash systems using the appropriate RediSep cartridge.

[0115] Purification using preparative HPLC methods are as follows:

[0116] Method 1 (Ml) ACIDIC STANDARD METHOD: Purification (METCR / PrepOOl) (P2) LC were performed in reverse phase using a Waters Sunfire™ Cl 8 column (30 mm x 100 mm, 5 pm; temperature: room temperature), with an injection volume of 1500 pL at a flow rateof 40 mL / min at 30% B for 1.90 min then a gradient of 30 - 95% B over 9.60 min and held for 1.97 min, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile. A second gradient of 95 - 30% B was then applied over 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm.

[0117] Method 2 (M2) ACIDIC EARLY ELUTE METHOD: Purification (METCR / Prep004) (Pl) LC were performed in reverse phase using a Waters Sunfire™ C18 column (30 mm x 100 mm, 5 pm; temperature: room temperature), with an injection volume of 1500 pL at a flow rate of 40 mL / min at 10% B for 1.90 min then a gradient of 10 - 95% B over 14.10 min and held for 2.0 min, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile. A second gradient of 95 - 10% B was then applied over 0.20 min and held for a further 1.25 min. UV spectra were recorded at 215 nm.

[0118] Method 3 (M3) BASIC STANDARD METHOD: Purification (METCR / Prep003) (P4) LC were performed in reverse phase using a Waters XB ridge™ Cl 8 column (30 mm x 100 mm, 5 pm; temperature: room temperature), with an injection volume of 1500 pL at a flow rate of 40 mL / min at 30% B for 2.00 min then a gradient of 30 - 95% B over 9.50 min and held for 1.97 min, where A = 0.2% ammonium hydroxide in water and B = acetonitrile. A second gradient of 95 - 30% B was then applied over 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm.

[0119] Method 4 (M4) BASIC EARLY ELUTE METHOD: Purification(METCR / Prep002) (P3) LC were performed in reverse phase using a Waters XBridge™ C18 column (30 mm x 100 mm, 5 pm; temperature: room temperature), with an injection volume of 1500 pL at a flow rate of 40 mL / min at 10% B for 2.00 min then a gradient of 10 - 95% B over 14.00 min and held for 2.00 min, where A = 0.2% ammonium hydroxide in water and B = acetonitrile. A second gradient of 95 - 10% B was then applied over 0.20 min and held for 1.25 min. UV spectra were recorded at 215 nm.

[0120] Method 5 (M5) ACIDIC METHOD: Column: XBridge™ C18 (19 mm x 200 mm, 5 pm; temperature: room temperature), flow rate of 20 mL / min. Gradient:

[0121] Fraction collection was triggered by MS (ESU). Fractions containing the desired product were combined and dried via centrifugal evaporation.

[0122] NMR Conditions

[0123] Unless otherwise stated,1H NMR spectra were recorded at 500 MHz, 400 MHz or 300 MHz on either a Bruker Avance III HD 500 MHz, a Bruker Avance III HD 400 MHz or Bruker 300 MHz Fourier spectrometer respectively. Data was processed using MestReNova software. Chemical shifts, δ, are quoted in parts per million (ppm) and are referenced to the residual solvent peak. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), pent (pentet), hep (heptet), m (multiplet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.

[0124] General synthesis:

[0125] All the compounds have been synthesised with a purity > 95% unless otherwise specified.

[0126] Scheme for route 1Intermediate 1

[0127] Intermediate 1 : 3-(difluoromethyl)-5-methyl-phenolIntermediate 1

[0128] To a solution of 3-hydroxy-5-methylbenzaldehyde (2.0 g, 14.7 mmol) in DCM (30 mL) at 0 °C was added dropwise DAST (6.2 mL, 47.0 mmol), and the reaction was stirred at r.t. for 16 h. The reaction was diluted with DCM and slowly quenched with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM. The combined organics were washed with a saturated aqueous solution of NaHCO3then dried using a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0- 100% EtOAc in heptane) to afford the title compound (94% purity, 1.76 g, 10.5 mmol, 71% yield) as a yellow oil. 'HNMR (500 MHz, CDCl3) δ 6.90 (s, 1H), 6.80 (s, 1H), 6.79 - 6.75 (m, 1H), 6.56 (t, J= 56.6 Hz, 1H), 2.36 (s, 3H).

[0129] Scheme for route 2Intermediate 2

[0130] Intermediate 2: 5-(difluoromethyl)-2-iodo-3-methyl-phenol

[0131] To a stirred solution of 3-(difluoromethyl)-5-methyl-phenol (1.76 g, 11.1 mmol, Intermediate 1) in water (30 mL) under nitrogen at 0 °C was added hydrogen peroxide (50% in water, 1.3 mL, 22.3 mmol) followed by molecular iodine (2.82 g, 11.1 mmol), and the reaction was stirred while warming to r.t. for 22 h. The reaction was retreated with hydrogen peroxide (0.474 mL, 8.35 mmol) and molecular iodine (847 mg, 3.34 mmol) and stirred for a further 6 h. The reaction was extracted with EtOAc. The combined organic layers were washedwith brine, dried over MgSCL and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-30% EtOAc in heptane) to yield the title compound (51% purity, 2.25 g, 4.04 mmol, 36% yield) as a pale yellow oil. M / Z.' 283 [M-H]', ESI", RT = 0.88- 0.92 (SI).

[0132] Scheme for route 3

[0133] Step 3. a: 3-methyl-5-(trifluoromethyl)phenol

[0134] To a degassed mixture of l-bromo-3-methyl-5-(trifluoromethyl)benzene (100.0 g, 418.4 mmol) and LiOH (31.3 g, 1255.1 mmol) in 1,4-dioxane (650 mL) and water (122 mL) was added a degassed mixture of Pd2(dba)3(3.8 g, 4.2 mmol) and BippyPhos (4.1 g, 8.0 mmol) in 1,4-dioxane (50 mL). The reaction was stirred at 90 °C under a N2 atmosphere for 18 h. The reaction mixture was cooled to r.t. and filtered through glass fibre filter paper. The filtrate was concentrated in vacuo, dissolved in EtOAc and washed with an aqueous 1 M HC1 solution. After phase separation, the organic layer was concentrated in vacuo. The crude product was then stirred in an aqueous 5 M NaOH solution for 15 min. Next, heptane was added, and the biphasic mixture was stirred for 5 min. After phase separation, the basic aqueous layer was cooled to 0 °C and acidified with an aqueous 5 M HC1 solution until pH=4 was achieved. The aqueous layer was then extracted with heptane. The combined organic phases were washed with brine, dried over MgSO4and concentrated in vacuo to afford the title compound (55.0 g, 306.2 mmol, 73% yield) as an orange liquid.1H NMR (400 MHz, DMSO- / 6) 5 9.96 (s, 1H), 6.93 (qd, J= 1.6, 0.9 Hz, 1H), 6.88 - 6.80 (m, 2H), 2.29 (s, 3H); M / Z'. 221 [M+FA-H]', EST, RT = 0.88 (SI).

[0135] Step 3. b: 2-iodo-3-methyl-5-(trifluoromethyl)phenol

[0136] 3-methyl-5-(trifluoromethyl)phenol (55.0 g, 306.2 mmol) was dissolved in toluene (500 mL) and cooled to 0 °C under a N2 atmosphere. Sodium hydride (60% dispersion in mineral oil, 24.5 g, 612.3 mmol) was added portion-wise over 45 min. Next, a solution of iodine (77.7 g, 306.2 mmol) in toluene (500 mL) was added dropwise over 8 h at 0 °C. After stirring at r.t., the reaction was quenched to pH=7 with an aqueous 6 M HC1 solution at 0 °C. The mixture was partially concentrated in vacuo, before being extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-100% EtOAc in heptane, followed by 0-20% MeOH in EtOAc) to afford the title compound (90% purity, 74.3 g, 221.3 mmol, 72% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) 8 10.95 (s, 1H), 7.15 - 7.10 (m, 1H), 6.96 - 6.90 (m, 1H), 2.44 (s, 3H); M / Z: 301 [M-H]-, ESI-, RT = 1.00 (S2).

[0137] Intermediate 3 (step 3. c): 3-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 5-(trifluoromethyl)phenolIntermediate 3

[0138] To a degassed solution of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (20.00 g, 49.7 mmol), triethylamine (21 mL, 149.0 mmol), pinacol borane (22 mL, 149.0 mmol) and 2- (dicyclohexylphosphino)biphenyl (3.48 g, 9.9 mmol) in 1,4-dioxane (20 mL) was added Pd(OAc)2 (1.12 g, 5.0 mmol), and the reaction was heated to 80 °C under a N2 atmosphere for 22 h. The reaction mixture was cooled to r.t. and filtered through glass fibre filter paper. The filter cake washed with EtOAc and the filtrate was partially concentrated in vacuo. The organic layer was washed with a saturated aqueous solution of NH4CI and water, dried over MgSCL and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-12% EtOAc in heptane) to afford the title compound (8.18 g, 26.5 mmol, 53% yield) as a red oil.1H NMR (500 MHz, DMSO-fifc) 89.79 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 2.30 (s, 3H), 1.31 (s, 12H).19F NMR (376 MHz, DMSO-d6) δ -61.57.

[0139] Intermediate compounds in Table 2 were synthesized according to the general route 3 as exemplified by Intermediate 3 using the corresponding starting materials / intermediates.

[0140] Scheme for route 4Step a Step b Intermediate 8

[0141] Step 4. a: Zc / 7-butyl 4-methylsulfonylpiperazine-l -carboxylate

[0142] To a solution of ZcrZ-butyl piperazine- 1 -carboxylate (1.517 g, 7.98 mmol) in DCM (13 mL) at 0 °C was added triethylamine (1.65 mL, 7.98 mmol) and methanesulfonyl chloride (0.95 mL, 12.2 mmol), and the reaction was allowed to warm to r.t. and stirred for 2 h. Water was added to the reaction mixture and extracted with DCM. The combined organic layers were passed through a phase separator and concentrated in vacuo to afford the title compound (2.26 g, 8.22 mmol, 100% yield) as an off-white powder.1H NMR (300 MHz, DMSNMR (300 MHz, DMSO-d6) : δ (ppm) 3.41 (t, J= 5.1 Hz, 4H), 3.06 (t, J= 5.1 Hz, 4H), 2.87 (s, 3H), 1.40 (s, 9H); M / Z: 165 [M-Boc+H]+, ESI+, RT = 0.94 (S4).

[0143] Intermediate 8 (step 4.b): 1-methylsulfonylpiperazine hydrochlorideIntermediate 8

[0144] To a solution of tert-butyl 4-methylsulfonylpiperazine-l -carboxylate (2.26 g, 8.22 mmol) in 1,4-dioxane (20 mL) was added 4 M hydrogen chloride in 1,4-dioxane (20.5 mL, 82.0 mmol), and the reaction was stirred at r.t. for 2 h. The suspension was filtered, washed with diethyl ether and dried under vacuum to afford the title compound (1.43g, 7.15 mmol, 87% yield) as a white powder.1H NMR (300 MHz, DMSO-d6) δ 9.25(s ,2H) , 3.42 - 3.33 (m, 4H), 3.24 - 3.12 (m, 4H), 2.98 (s, 3H).

[0145] Scheme for route 5

[0146] Intermediate 9: tert-butyl 4-(5-amino-4H - 1, 2, 4-triazol-3-yl)piperazine- l -carboxyl ateIntermediate 9

[0147] To a solution of tert-butyl piperazine- 1 -carboxylate (20.0 g, 107 mmol) in acetonitrile (120 mL) was added dimethyl cyanocarbonodithioimidate (15.7 g, 107 mmol), and the reaction was stirred at 82 °C for 2 h. The reaction was cooled to r.t. and hydrazine hydrate (7.9 mL, 162 mmol) was added, then the reaction was stirred at 82 °C for 4 h. The reaction mixture was cooled to r.t., and the precipitate was collected via filtration. The filter cake was washed with acetonitrile to afford the title compound (21.6 g, 80.5 mmol, 75% yield) as a white solid. NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 5.76 (s, 2H), 3.38 - 3.33 (m, 4H), 3.15 - 3.08 (m, 4H), 1.40 (s, 9H); / Z: 269 [M+H]+, ESI+, RT = 1.47 (S2).

[0148] Intermediate compounds in Table 3 were synthesised according to the general route5 as exemplified by Intermediate 9 using the corresponding starting materials / intermediates.

[0149] Scheme for route 6Intermediate 12

[0151] To a solution of 5-bromo-4H -1,2,4-triazol-3-amine (9.00 g, 52.5 mmol) in ethanol (60 mL) was added ethyl (2E)-3-ethoxyprop-2-enoate (8.32 g, 57.7 mmol) and 5.4 M sodium methoxide (20 mL, 0.11 mol), and the reaction stirred at 90 °C for 16 h in a pressure tube. The reaction mixture was cooled to r.t. and poured onto ice. Aqueous 5 M HC1 solution was added until pH=3 was achieved, and the resulting slurry was stirred for 1.5 h at 0 °C. The precipitate was collected via filtration and washed with ethanol to afford the title compound (80% purity, 9.00 g, 33.5 mmol, 64% yield) as a light brown solid.1H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.59 (d, J = 7.9 Hz, 1H), 6.21 (d, J = 7.9 Hz, 1H); M / Z. 215 and 217 [M+H]+, , RT = 0.37 (S1).

[0152] Intermediate compounds in Table 4 were synthesised according to the general route6 as exemplified by Intermediate 12 using the corresponding starting material s / intermedi ate s .

[0153] Scheme for route 7Intermediate 15

[0154] Intermediate 15 : 2-bromo-7-methyl-4H -[1,2,4]triazolo[ l,5-a]pyrimidin-5-oneIntermediate 15

[0155] To a stirred solution of 5-bromo-4H -l,2,4-triazol-3-amine (0.50 g, 2.91 mmol) in acetonitrile (15.6 mL) was added ethyl 3-ethoxy-2-butenoate (0.692 g, 4.37 mmol) andpotassium carbonate (0.806 g, 5.83 mmol), and the reaction was stirred at 100 °C for 16 h in a pressure tube. Another portion of ethyl 3-ethoxy-2-butenoate (0.231 g, 1.46 mmol) was added, and the reaction was stirred at 100 °C for 16 h. The reaction mixture was cooled to r.t. and the precipitate was collected via filtration and washed with acetonitrile and methanol. The filtrate was concentrated in vacuo and triturated with methanol multiple times to afford the title compound (90% purity, 0.39 g, 1.53 mmol, 52% yield) as a yellow solid.(400 MHz, DMSO-d6) δ 5.62 - 5.57 (m, 1H), 2.29 - 2.24 (m, 3H); M / Z'. 229 and 231 [M+H]+, ESI+, RT = 0.45 (SI).

[0156] Intermediate compounds in Table 5 were synthesized according to the general route 7 as exemplified by Intermediate 15 using the corresponding starting materials / intermediates.

[0157] Scheme for route 8Intermediate 12 Intermediate 18

[0158] Intermediate 18: 2-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyrimidineIntermediate 18

[0159] To a stirred solution of 2-bromo--4H -[1,2,4]triazolo[1,5-a]pyrimidin-5-one (8.00 g, 29.8 mmol, Intermediate 12) in acetonitrile (24 mL) was added phosphoryl trichloride (16 mL, 0.167 mol), and the reaction was stirred at 95 °C for 3 h in a pressure tube. The reaction mixture was cooled to r.t. and poured onto ice. The precipitate was collected via filtration and washed with water to afford the title compound (6.20 g, 25.2 mmol, 85% yield) as a light brown powder. 'HNMR (400 MHz, DMSO-d6) δ 9.43 (d, J= 7.1 Hz, 1H), 7.58 (d, J= 7.1 Hz, 1H); M / Z-. 233 and 235 [M+H]+, ESI+, RT = 0.56 (SI).

[0160] Intermediate compounds in Table 6 were synthesized according to the general route 8 as exemplified by Intermediate 18 using the corresponding starting materials / intermediates.

[0161] Scheme for route 9

[0162] Intermediate 21 : tert-butyl 4-[5-(trifluoromethylsulfonyloxy)-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazine-l -carboxylate

[0163] To tert-butyl 4-(5-oxo-4rt-[1,2,4]triazolo[1,5-«]pyrimidin-2-yl)piperazine-l- carboxylate (7.00 g, 21.9 mmol, Intermediate 16) in DCM (140 mL) at 0 °C were added trifluoromethanesulfonyl chloride (4.19 mL, 39.3 mmol) and triethylamine (3.64 mL, 26.2 mmol), and the reaction was stirred at 0 °C for 2 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were passed through a phase separator to afford the title compound (85% purity, 6.89 g, 12.9 mmol, 59% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 7.0 Hz, 1H), 7.31 (d, J= 7.0 Hz, 1H), 3.57 - 3.52 (m, 4H), 3.48 - 3.42 (m, 4H), 1.42 (s, 911); M / Z: 397 [M+H]+, ESL, RT = 1.01 (SI).

[0164] Intermediate compounds in Table 7 were synthesized according to the general route9 as exemplified by Intermediate 21 using the corresponding starting material s / intermedi ate s .

[0165] Scheme for route 10

[0166] Intermediate 24: 2-(2-bromo-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol

[0167] To a degassed solution of 2-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyrimidine (980 mg, 3.78 mmol, Intermediate 18), 3-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 5-(trifluoromethyl)phenol (1.80 g, 5.67 mmol Intermediate 3) and tripotassium phosphate (1.68 g, 7.90 mmol) in 1,4-dioxane (9 mL) and water (1.5 mL) was added Pd(dppf)Cl2.DCM (464 mg, 0.567 mmol), and the reaction was stirred at 50 °C for 1 h. The reaction mixture was cooled to r.t. and filtered through Celite®, the filter cake was washed with EtOAc and water. The layers were separated and the organic layer was concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-50% EtOAc in heptane), and the product was triturated with methanol to afford the title compound (600 mg, 1.61 mmol, 43% yield) as an off-white solid. 'HNMR (400 MHz, DMSO-d6) δ 9.42 (d, J= 7.0 Hz, 1H), 7.47 (d, J= 7.0 Hz, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 2.18 (s, 3H); M / Z 373 and 375 [M+H]+, ESI+, RT = 3.04 (S2).

[0168] Intermediate compounds in Table 8 were synthesised according to the general route 10 as exemplified by Intermediate 24 using the corresponding starting material s / intermedi ate s .

[0169] Scheme for route 11Intermediate 29

[0170] Step 11. a: rac-tert-butyl l,l-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3- a]pyrazine-5-carboxylate

[0171] To a solution of rac-3,3a,4,5,6,7-hexahydro-27 / -[1,2,5]thiadiazolo[2,3-«]pyrazine 1,1 -dioxide hydrochloride (500 mg, 2.34 mmol) in DCM (22.5 mL) was added triethylamine (0.98 mL, 7.02 mmol) and BOC2O (562 mg, 2.57 mmol), and the reaction was stirred at r.t. for 16 h. Additional BOC2O (255 mg, 1.17 mmol) and triethylamine (0.49 mL, 3.51 mmol) were added, and the reaction was stirred at r.t. for 6 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3and extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-50% EtOAc in heptane) to afford the title compound (80% purity, 640 mg, 1.85 mmol, 79% yield) as a tan solid.1H NMR (500 MHz, DMSO-d6) δ 7.28 (s, 1H), 4.04 (q, J= 7.1 Hz, 1H), 3.97 - 3.86 (m, 1H), 3.42 (dd, J= 10.1, 6.3 Hz, 1H), 3.28 (dt, J = 11.7, 2.5 Hz, 1H), 3.21 - 3.10 (m, 1H), 3.00 (t, J = 9.5 Hz, 1H), 2.60 (td, J= 11 6, 3.5 Hz, 1H), 1.69 - 1.57 (m, 2H), 1.42 (s, 9H).

[0172] Step 1 Lb: rac-tert-butyl 2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H- [1,2,5]thiadiazolo[2,3-r / ]pyrazine-5-carboxylate

[0173] To a solution of rac-tert-butyl l,l-dioxo-2,3,3a,4,6,7-hexahydro- [1,2,5]thiadiazolo[2,3-a]pyrazine-5-carboxylate (630 mg, 2.27 mmol) in DMF (12.8 mL) at 0 °C, was added sodium hydride (182 mg, 4.54 mmol) and was stirred at 0 °C for 15 min. lodomethane (156 pL, 2.50 mmol) was added and the reaction was stirred for 1 h while warming to r.t. The reaction was cooled to 0°C and quenched with water, and the aqueous layer was extracted with DCM. The combined organic layers were passed through a phase separator and concentrated in vacuo to afford the title compound (90% purity, 610 mg, 1.88 mmol, 83% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 4.15 - 4.00 (m, 1H), 3.93 (d, J = 13.3 Hz, 1H), 3.48 (dd, J = 9.0, 5.9 Hz, 1H), 3.32 - 3.29 (m, 1H), 3.26 - 3.16 (m, 1H), 3.01 - 2.92 (m, 2H), 2.87 - 2.74 (m, 1H), 2.69 (td, J= 3.5 Hz, 1H), 2.63 (s, 3H), 1.42 (s, 9H).

[0174] Intermediate 29 (Step l i e): rac-2-methyl-3, 3a, 4,5,6, 7-hexahydro- [1,2,5]thiadiazolo[2,3-a]pyrazine 1,1-dioxide hydrochlorideIntermediate 29

[0175] To a solution of rac- tert-butyl 2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H- [1,2,5]thiadiazolo[2,3-a]pyrazine-5-carboxylate (90% purity, 610 mg, 1.88 mmol) in DCM (7 mL) was added 4 M HC1 in 1,4-dioxane (9.0 mL, 36.0 mmol), and the reaction was stirred at r.t. for 16 h. The reaction mixture was concentrated in vacuo to afford the title compound (465 mg, 1.94 mmol, 100% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.87 - 9.19 (m, 2H), 3.78 - 3.56 (m, 2H), 3.56 - 3.44 (m, 3H), 3.18 - 3.05 (m, 2H), 3.05 - 2.88 (m, 2H), 2.65 (s, 3H).

[0176] Scheme for route 12

[0177] Example 1 : rac-2-[2-(l,l-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3- a]pyrazin-5-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol

[0178] To a mixture of 2-(2-bromo-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5- (trifluoromethyl)phenol (100 mg, 0.255 mmol, Intermediate 24) and rac-3,3a,4,5,6,7- hexahydro-2H -[1,2,5]thiadiazolo[2,3-a]pyrazine 1,1-dioxide hydrochloride (326 mg, 1.53 mmol) was added N-ethyl-N-isopropyl-propan-2-amine (0.178 mL, 1.02 mmol) and stirred at 130 °C for 2 h at which point DMSO (0.40 mL) was added, and the reaction continued to stir at 130 °C for 30 min. The reaction was cooled to r.t. and purified by preparative HPLC (Ml)to afford the title compound (42.6 mg, 0.090 mmol, 35% yield) as an off-white solid.1H NMR. (500 MHz, CDCl3) δ 10.49 (s, 1H), 8.63 (d, J= 7.0 Hz, 1H), 7.19 (d, J = 1.9 Hz, 1H), 7.14 (d, J= 7.0 Hz, 1H), 7.11 (d, J= 1.8 Hz, 1H), 4.58 (ddd, J= 12.8, 3.4, 1.2 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.39 - 4.26 (m, 1H), 3.69 - 3.63 (m, 1H), 3.62 - 3.54 (m, 2H), 3.38 - 3.28 (m, 2H), 3.16 (dd, J = 12.9, 10.3 Hz, 1H), 3.05 (td, J= 11.8, 3.5 Hz, 1H), 2.56470 [M+H]+, ESI+, RT = 2.82 (S2).

[0179] Example compounds in Table 9 were synthesised according to the general route 12 as exemplified by Example 1 using the corresponding starting materials / intermediates.

[0180] Scheme for route 13

[0181] Example 7 and Example 8

[0182] Rac -2-[2-(l,l-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl)- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3-methyl-5-(trifhioromethyl)phenol (Example 1) was separated by preparative chiral HPLC to yield single enantiomers shown in Table 10.

[0183] Further example compounds in Table 10 were obtained from chiral preparative HPLC according to the general route 13 as exemplified for Examples 7 and 8 using the corresponding starting materials / methods.

[0184] Scheme for route 14

[0185] Intermediate 30: tert-butyl (2R )-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[ 1 ,2,4]triazolo[ 1 ,5-A|pyrimidin-2-yl]-2-methyl-piperazine-l - carboxylate

[0186] To a mixture of 2-(2-bromo-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5- (trifluoromethyl)phenol (300 mg, 0.724 mmol, Intermediate 24) and tert-butyl (2R)-2- methylpiperazine-1 -carboxylate (870 mg, 4.34 mmol) in DMSO (1.0 mL) was added A-ethyl- A-isopropyl-propan-2-amine (0.670 mL, 3.84 mmol), and the reaction was stirred at 130 °C for 7 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, fdtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-100% EtOAc in heptane) to afford the title compound (357 mg, 0.718 mmol, 99% yield) as a yellow solid. NMR (400 MHz, CDCl3) δ10.60 (s, 1H), 8.60 (d, J= 6.9 Hz, 1H), 7.17 (d, J= 1.8 Hz, 1H), 7.10 - 7.06 (m, 2H), 4.40 (m, 1H), 4.30 - 4.22 (m, 1H), 4.15 - 4.07 (m, 1H), 4.01 - 3.94 (m, 1H), 3.33 - 3.26 (m, 1H), 3.25 - 3.18 (m, 1H), 3.15 - 3.07 (m, 1H), 2.54 (s, 3H), 1.49 (s, 9H), 1.23 (d, J= 6.8 Hz, 3H); MZ: 493 [M+H]+, ESI+, RT = 1.02 (SI).

[0187] Intermediate compounds in Table 11 were synthesized according to the general route 14 as exemplified by Intermediate 30 using the corresponding starting material s / intermedi ate s .

[0188] Scheme for route 15

[0189] Intermediate 32: 3-methyl-2-(2-piperazin-l-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- 5-(trifluoromethyl)phenol hydrochloride

[0190] To tert-butyl 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]- [1, 2, 4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-l -carboxylate (4.7 g, 8.84 mmol, Intermediate 27) inDCM (50 mL) was added 4 MHCl in 1,4-dioxane (20.3 mL, 81.1 mmol), and the reaction mixture was stirred at r.t. for 16 h. The reaction mixture was concentrated in vacuo to afford the title compound (74% purity, 4.90 g, 8.74 mmol, 99% yield) as an off-white solid.1H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.26 (s, 2H), 9.16 (d, J= 6.8 Hz, 1H), 7.19 - 7.14 (m, 3H), 3.84 - 3.79 (m, 4H), 3.26 - 3.18 (m, 4H), 2.16 (s, 3H); M / . 379, [M+H]+, ESI+, RT = 0.58 (SI).

[0191] Intermediate compounds in Table 12 were synthesised according to the general route 15 as exemplified by Intermediate 32 using the corresponding starting material s / intermedi ate s .

[0192] Scheme for route 16

[0193] Example 15: l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]ethanone

[0194] To a mixture of acetic acid (0.02 mL, 0.29 mmol) and HATU (119 mg, 0.313 mmol) in DCM (2 mL) was added triethylamine (0.034 mL, 0.241 mmol), and the mixture was stirred at r.t. for 10 min. 3-methyl-2-(2-piperazin-l-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5- (trifluoromethyl)phenol hydrochloride (100.0 mg, 0.24 mmol, Intermediate 32) was added, and the reaction was stirred at r.t. for 2 h. Water was added to the reaction and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified with preparative HPLC (Ml) to afford the title compound (46.2 mg, 0.10 mmol, 45% yield) as an off-white solid.1HNMR (500 MHz, DMSO- d6) δ 10.31 (s, 1H), 9.12 (d, J= 6.8 Hz, 1H), 7.17 - 7.08 (m, 3H), 3.61 - 3.50 (m, 8H), 2.16 (s, 3H), 2.06 (s, 3H); M / Z: 421, [M+H]+, ESI+, RT = 2.69 (S2).

[0195] Example compounds in Table 13 were synthesised according to the general route 16 as exemplified by Example 15 using the corresponding starting materials / intermediates.

[0196] Scheme for route 17

[0197] Example 29 and Example 30

[0198] Rac-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-(l-methylpyrrolidin-3-yl)methanone (Example 25) was separated by preparative chiral HPLC to yield single enantiomers shown in Table 14.

[0199] Scheme for route 18

[0200] Example 31: [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]-(oxetan-3-yl)methanone

[0201] To a solution of 3-metliyl-2-(2-piperazin-l-yl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl)- 5-(trifluoromethyl)phenol hydrochloride (100 mg, 0.24 mmol, Intermediate 32) in acetonitrile (2 mL) was added oxetane-3 -carboxylic acid (30 mg, 0.294 mmol) and 1 -methyl- 1 / / -imidazole (0.08 mL, 1.0 mmol) followed by / V-[chloro(dimethylamino)methylidene]-JV- methylmethanaminium hexafluorophosphate (100 mg, 0.356 mmol), and the resulting mixture was stirred at r.t. for 3.5 h. A 5 w / w% aqueous solution of lithium chloride was added to the reaction and extracted with EtOAc. The combined organic layers were dried over MgSOr, fdtered, and concentrated in vacuo. The crude product was purified with preparative HPLC (Ml) to afford the title compound (6.3 mg, 0.013 mmol, 5% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.12 (d, J= 6.7 Hz, 1H), 7.15 (s, 1H), 7.12 (d, J = 6.8 Hz, 1H), 7.08 (s, 1H), 4.75 - 4.66 (m, 3H), 4.23 - 4.13 (m, 1H), 3.65 - 3.51 (m, 7H), 3.38 - 3.34 (m, 2H), 2.16 (s, 3H ); L / Z: 463 [M+H]+, ESI+, RT = 2.67 (S2).

[0202] Scheme for route 19

[0203] Example 32: [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]-[(2A)-tetrahydrofuran-2-yl]methanone

[0204] To a mixture of 3-methyl-2-(2-piperazin-l-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5- (trifluoromethyl)phenol hydrochloride (100 mg, 0.241 mmol, Intermediate 32), (27?)- tetrahydrofuran-2-carboxylic acid (35.0 mg, 0.301 mmol) and pyridine (0.059 mL, 0.729 mmol) in EtOAc (2.0 mL) at 0 °C, was added propanephosphonic acid anhydride (0.22 mL, 0.37 mmol), and the reaction was stirred for 18 h. Water was added to the reaction and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified with preparative HPLC (Ml) to afford the title compound (10.8 mg, 0.023 mmol, 9% yield) as a pale yellow solid. 'll NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.12 (d, J= 6.8 Hz, 1H), 7.14 (s, 1H), 7.12 (d, J= 6.8 Hz, 1H), 7.08 (s, 1H), 4.72 (dd, J= 1.1, 5.6 Hz, 1H), 3.82 - 3.73 (m, 2H), 3.69 - 3.51 (m, 8H), 2.16 (s, 3H), 2.12 - 1.97 (m, 2H), 1.90 - 1.79 (m, 2H); A / / Z: 477 [M+H]+, ESI+, RT = 2.85 (S2).

[0205] Example compounds in Table 15 were synthesised according to the general route 19 as exemplified by Example 32 using the corresponding starting materials / intermediates.

[0206] Scheme for route 20

[0207] Example 34: methyl 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-l-carboxylate

[0208] To a solution of 3-methyl-2-(2-piperazin-l-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- 5-(trifluoromethyl)phenol hydrochloride (100 mg, 0.241 mmol, Intermediate 32) in DCM (2 mL) at 0 °C, was added triethylamine (0.067 mL, 0.482 mmol) and methyl chloroformate (22.8 mg, 0.241 mmol), and the reaction was allowed to warm to r.t. and stirred for 30 min. Water was added to the reaction mixture and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified with preparative HPLC (Ml) to afford the title compound (60.6 mg, 0.139 mmol, 58% yield) as an off-white solid.1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.12 (d, J= 6.8 Hz, 1H), 7.17 - 7.05 (m, 3H), 3.64 (s, 3H), 3.59 - 3.48 (m, 8H), 2.16 (s, 3H); M / Z: 436 [M+H]+, ESI+, RT = 2.62 (S2).

[0209] Example compounds in Table 16 were synthesised according to the general route 20 as exemplified by Example 34 using the corresponding starting materials / intermediates

[0210] Scheme for route 21

[0211] Example 37: 2-[2-(4-ethylsulfonylpiperazin-l-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5- yl] -3 -methyl-5 -(trifluoromethyl)phenol

[0212] To a solution of 3-methyl-2-(2-piperazin-l-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- 5-(trifluoromethyl)phenol hydrochloride (100 mg, 0.241 mmol, Intermediate 32) in DCM (2 mL) at 0 °C was added triethylamine (67.2 pL, 0.482 mmol) and ethanesulfonyl chloride (27 pL, 0.289 mmol), and the reaction was allowed to warm to r.t. and stirred for 1 h. The reaction was cooled to 0 °C and quenched with water (5 mL), then a saturated aqueous solution of NaHCO3was added. The mixture was passed through a hydrophobic frit and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSCL. filtered, and concentrated in vacuo. The crude product was purified with preparative HPLC (Ml) to afford the title compound (38.8 mg, 0.0825 mmol, 34% yield) as an off-white solid.1H NMR (500 MHz, DMSO-cC) 5 10.31 (s, 1H), 9.13 (d, J= 6.8 Hz, 1H), 7.17 - 7.06 (m, 3H), 3.71 - 3.60 (m, 4H), 3.32 - 3.29 (m, 4H), 3.09 (q, J= 7.3 Hz, 2H), 2.16 (s, 3H), 1.23 (t, J= 7.4 Hz, 3H); M / Z-. 471 [M+H]+, ESI+, RT = 3.09 (S2).

[0213] Example compounds in Table 17 were synthesised according to the general route 21 as exemplified by Example 37 using the corresponding starting materials / intermediates.

[0214] Scheme for route 22Intermediate 36 Intermediate 37

[0215] Intermediate 37: l-[4-(5-chloro-7-methyl-[1,2,4]triazolo[1,5-«]pyrimidin-2- yl)piperazin- 1 -yl]propan- 1 -oneIntermediate 37

[0216] To a solution of 5-chloro-7-methyl-2-piperazin-l-yl-[1,2,4]triazolo[1,5-a]pyrimidine trifluoromethanesulfonic acid (350 mg, 0.606 mmol, Intermediate 36) in DCM (7.0 mL) was added propanoic acid (53.8 mg, 0.727 mmol) and triethylamine (0.169 mL, 1.21 mmol), and the mixture was stirred at r.t. for 5 minutes. HATU (299 mg, 0.787 mmol) was added to the reaction mixture and stirred at r.t. for 2 h Water was added to the reaction mixture and extracted with DCM. The combined organic layers were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0- 100% EtOAc in heptane followed by 0-100% MeOH in DCM) to afford the title compound (55% purity, 320 mg, 0.570 mmol, 94% yield) as an off-white solid.1H NMR (500 MHz, DMSO-d6) δ 7.23 - 7.19 (m, 1H), 3.59 - 3.49 (m, 8H), 2.65 - 2.62 (m, 3H), 2.37 (q, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H); M / Z'. 309 and 311 [M+H]+, ESI+, RT = 0.64 (SI).

[0217] Intermediate compounds in Table 18 were synthesized according to the general route 22 as exemplified by Intermediate 37 using the corresponding starting material s / intermedi ate s .

[0218] Scheme for route 23Intermediate 36 Intermediate 43

[0219] Intermediate 43 : 5-chloro-2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl- [1,2,4]triazolo[1,5-a]pyrimidineIntermediate 43

[0220] To a solution of 5-chloro-7-methyl-2-piperazin-l-yl-[1,2,4]triazolo[1,5-a]pyrimidine trifluoromethanesulfonic acid (400 mg, 0.715 mmol, Intermediate 36) in acetonitrile (10.0 mL) at 0 °C, was added triethylamine (0.399 mL, 2.86 mmol) and ethanesulfonyl chloride (0.081 mL, 0.858 mmol), and the reaction was warmed to r.t. and stirred for 45 min. Water was addedto the reaction mixture and extracted with EtOAc. The combined organic layers were passed through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-100% [3: 1 ethyl acetate: ethanol] in heptane) to afford the title compound (83% purity, 297 mg, 0.714 mmol, 100% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J= 0.9 Hz, 1H), 3.70 - 3.57 (m, 4H), 3.34 - 3.25 (m, 4H), 3.09 (q, J= 7.4 Hz, 2H), 2.65 (d, J= 0.9 Hz, 3H), 1.23 (t, J= 7.4 Hz, 3H); M / Z: 345 [M+H]+, ESI+, RT = 0.69 (SI).

[0221] Intermediate compounds in Table 19 were synthesized according to the general route 23 as exemplified by Intermediate 43 using the corresponding starting material s / intermedi ate s .

[0222] Scheme for route 24

[0223] Example 43: l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]propan-l-one

[0224] To a degassed solution of l-[4-(5-chloro-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2- yl)piperazin-l-yl]propan-l-one (320 mg, 0.757 mmol, Intermediate 37) (980 mg, 3.78 mmol), 3-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (251 mg, 0.832 mmol, Intermediate 3) and tripotassium phosphate (321 mg, 1.51 mmol) in 1,4-dioxane (4.0 mL) and water (1.0 mL) was added Pd(dppf)Cl2DCM (124 mg, 0.151 mmol), and the reaction was stirred at 100 °C for 2 h. The reaction mixture was cooled to r.t. and filtered through Celite®, the filter cake was washed with EtOAc and water. After phase separation, the aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, then dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-100% EtOAc in heptane) followed by preparative HPLC (Ml) to afford the title compound (103 mg, 0.230 mmol, 30% yield) as an off-white solid. 'HNMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H), 7.07 - 7.04 (m, 1H), 3.62 - 3.52 (m, 8H), 2.70 (s, 3H), 2.38 (q, J= 7.4 Hz, 2H), 2.14 (s, 3H), 1.02 (t, J = 7.4 Hz, 3H); A / / Z: 449 [M+H]+, ESI+, RT = 3.17 (S2).

[0225] Example compounds in Table 20 were synthesized according to the general route 24 as exemplified by Example 43 using the corresponding starting materials / intermediates.

[0226] Scheme for route 25

[0228] Example 73 and Example 747?czc-3-methyl-2-[7-methyl-2-(4-tetrahydrofuran-3-ylsulfonylpiperazin-l-yl)-[1 ,2,4]triazolo[l ,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol (Example 64) was separated by preparative chiral HPLC to yield single enantiomers shown in Table 21.

[0231] Example 75 and Example 76Rac- (2,2-difluorocyclopropyl)-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7- methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone (Example 71) was separated by preparative chiral HPLC to yield single enantiomers shown in Table 22.

[0232] Example 2: Biological Assays

[0233] The purpose of this example was to evaluate the activity of compounds synthesized in “Example 1: Chemical Synthesis”.

[0234] THP1 IL- 1 β Release Assay (HTRF): Example compounds were tested in LPS-primed THP1 cells to assess their pharmacological capability to inhibit NLRP3 activation with Nigericin and the release of IL-1β into the supernatant.

[0235] Day 1: THP1 cells were plated in 384-well Poly L-Lysine coated plates at a density of 18.000 cells per well in differentiation medium containing RPMI 1640 Medium (no Glutamine & Phenol red), 10% FBS, 2 mM L-Glutamine, 50 pM 2-Mercaptoethanol and 200 ng / ml PMA and incubated for 24 h at 37 °C and 5% CO2.

[0236] Day 2: After 24 h, medium was exchanged to growth medium containing RPMI 1640 Medium (no Glutamine & Phenol red), 10% FBS, 2 mM L-Glutamine, 50 pM 2- Mercaptoethanol and incubated for 24 h at 37 °C and 5% CO2.

[0237] Day 3: Example compounds were serially diluted in DMSO, spotted into intermediate plates and prediluted with serum-free growth medium (plate 1) or serum-free growth medium containing 50pM Nigericin (plate 2).

[0238] In addition to the example compound testing area, the plates also contained multiples of High control (0.2% DMSO, Ipg / ml LPS, 50pM Nigericin final) and Low control (reference inhibitor MCC950 (sodium salt) at lOx IC50, Ipg / ml LPS, 50pM Nigericin final) for assay normalization purposes.

[0239] THP1 cells were washed with serum- free growth medium and lOpl example compounds from the intermediate plate 1 was added into 40pl serum-free medium in the assay plate. After 30 minutes incubation at 37 °C, 5% CO2, LPS in serum-free growth medium was added to a final concentration of 1 μg / ml for priming followed by incubation for 2.5 h at 37°C and 5% CO2.

[0240] After priming, cells were washed with serum-free growth medium containing 50pM Nigericin and 10 pl example compounds from the intermediate plate 2 as well as 40 pl serum- free medium with Nigericin were added to the cells for activation and incubated for 2 h at 37 °C and 5% CO2. Finally, the supernatant was removed and stored at -20°C.

[0241] Day 4: IL-ip in the supernatant was quantified by HTRF (homogenous time resolved fluorescence) analysis using a human IL-ip Kit from Cisbio. Briefly, 8pl of supernatant as well as 2pl of pre-mixed anti-ILip-Crypta antibody and anti-ILβ -XL antibody were added to a 384 well plate (Greiner BioOne), incubated for 24 h at r.t. and measured with the PHERAstar FSX Reader (BMG LabTech) at excitation 337 nm (donor) and emission 620 / 665 nm (acceptor).

[0242] The HTRF ratio between donor and acceptor signals was calculated and normalized to High and Low controls to calculate IC50 values (nM). NLRP3 inhibitors decrease LPS / Nigericin-induced IL-ip release which is indicated as a reduction in the HTRF ratio.

[0243] THP1 IL-ip release of the tested example compounds is provided in Table 23.EQUIVALENTS

[0244] The present technology is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variationsare intended to fall within the scope of the present technology. It is to be understood that this present technology is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0245] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.INCORPORATION BY REFERENCE

[0246] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, patent application, or item of information was specifically and individually indicated to be incorporated by reference. To the extent publications, patents, patent applications, and items of information incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R1is CN, CH3, CF3, CHF2, OCH3, OCHF2, OCF3or halogen;R2is H, CH3, CH2CH3, CF3, CHF2, Cl, CN or cyclopropyl and R3is H or CH3, provided that not both, R2and R3, are H;R4is H, CH3, CH2CH3, CF3, CHF2, OCH3, Cl, F, C3-5cycloalkyl or unsubstituted saturated 4 to 6 membered heterocyclyl, wherein C3-5cycloalkyl is optionally substituted with one or more F, orR3and R4are joined to form -CH2-CH2-CH2- or -CH2-O-CH2-;-X1- is -CH(R5b)- or -C(R5bl)(R5c)CH2-*, wherein the bond marked with an asterisk is attached to the nitrogen in formula (I);-X2- is -CH(R5d)- or -CH(R5dl)CH2-*, wherein the bond marked with an asterisk is attached to the nitrogen in formula (I);R5, R5a, R5bl, R5Cand R5dlare independently selected from the group consisting of H, F and R5e;R5band R5dare independently selected from the group consisting of H and R5e;Each R5eis independently selected from the group consisting of cyclopropyl and C1-4 alkyl, wherein R5eis optionally substituted with one or more substituents independently selected from the group consisting of OH and F;X3is -S(=O)2-*, -C(=O)-*, -C(=O)O-*, -C(=O)N(R6a)-*, -S(=O)2-N(R6a)-*, -S(=O)(R6a)=N-* or -S(=O)-N(R6a)-*, wherein the bond marked with an asterisk is attached to R6;R6ais H or CH3;R6is, in case X3is -S(=O)2-*, -C(=O)O-*, -C(=O)N(R6a)-*, -S(=O)2-N(R6a)-*, or - S(=O)-N(R6a)-*, selected to be C1-4 alkyl, CHF2, CF3, T1, NHCH3or N(CH3)2, wherein Ci-4 alkyl is optionally substituted with OCH3or N(CH3)2; orR6is, in case X3is -C(=O)-*, selected to be C1-4 alkyl, CHF2, CF3, OC1-4alkyl, T1, OT1, NHCH3or N(CH3)2, wherein C1-4 alkyl is optionally substituted with OCH3or N(CH3)2; orR6is, in case X3is -S(=O)(R6a)=N-*, selected to be C1-4 alkyl, wherein C1-4alkyl is optionally substituted with one or more F; orR6and R5dare joined to form a bivalent group selected to be CH2or CH2-CH2; andT1is cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, oxetanyl or tetrahydrofuranyl, wherein T1is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of F, CH3, OCH3and OH.

2. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of claim 1, wherein R1is CF3, CHF2, F, Cl, OCH3, OCHF2, CH3or CN, preferably R1is CN, CH3, CF3, OCH3, F or Cl, even more preferably CF3.

3. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of claim 1 or 2, wherein R2is CH3and R3is H.

4. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 3, wherein R4is H, CH3or CH2CH3, preferably CH3.

5. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 4, wherein R1, R2and R3are selected to give formula (la)(la).

6. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of claim 5, wherein R4is selected to give formula (lb) or (Ibl)7. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 6, wherein R5and R5aare H.

8. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 7, wherein X1is -CH(R5b)-.

9. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 8, wherein R5bis H or CH3, preferably H.

10. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 9, wherein X2is -CH(R5d)-.

11. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 10, wherein R5dis H or joined with R6, preferably H.

12. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 11, wherein R5, R5a, X1and X2are selected to give formula (Ic)13. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 12, wherein R5b, R5d, X3and R6are selected to give a formula selected from the formulas (Id1) to (Id8), preferably (Id3) or (Id6)14. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 13, wherein R6is CH3, CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, N-methylpyrrolidinyl, oxetanyl, azetidinyl, N,N- dimethylaminomethyl, methoxymethyl or methoxyethyl, preferably CH2CH3, CH(CH3)2or cyclopropyl.

15. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 14, wherein the compound is selected from the group consisting of: rac-2-[2-(l,l-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazin-5- yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;3 -methyl-2- [2-(2-methyl- 1 , 1 -dioxo-3 a, 4, 6, 7 -tetrahydro-3H- [1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol;2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]-l,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one;2-[2-(4-isopropylsulfonylpiperazin-l-yl)-7-methyl-[ 1,2, 4]tri azolo[ 1,5- «]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;3-methyl-2-[7-methyl-2-(2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H-[1.2.5]thiadiazolo[2,3-«]pyrazin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol; l-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-[1,2,4]triazolo[l,5-a]pyrimidin-2- yl]piperazin- 1 -y 1] ethanone;3-methyl-2-[2-[rel-(3aR)-1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1.2.5]thiadiazolo[2,3-a]pyrazin-5-yl]-[ 1 ,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol;3-methyl-2-[2-[rel-(3a5)-l,l-dioxo-2,3,3a,4,6,7-hexahydro-[1.2.5]thiadiazolo[2,3-a]pyrazin-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-( trifluoromethyl)phenol;3-methyl-2-[2-[rel-(3aR)-2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H -[1.2.5]thiadiazolo[2,3-a]pyrazin-5-yl]-[ 1 ,2,4]triazolo[l ,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol;3-methyl-2-[2-[rel-(3a5)-2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H-[1 ,2,5]thiadiazolo[2,3-a]pyrazin-5-yl]-[ 1 ,2,4]triazolo[l ,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol; re / -(8aS)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]-l,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6- one; re / -(8aR )-2-[5-[2-hydroxy-6-methyl-4-(trifluoroniethyl)phenyl]-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]-l,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6- one;3-methyl-2-[7-methyl-2-[rel-(3aR)-2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro- 3H -[1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol;3-methyl-2-[7-methyl-2-[rel-(3a5)-2-methyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H-[1.2.5]thiadiazolo[2,3-a]pyrazin-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5- (trifluoromethyl)phenol; l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a] pyri m i di n-2-y 1 ] pi perazi n- 1 -yl] ethanone; l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a pyri mi di n-2-y 1 ] pi perazi n- 1 -yl]propan- 1 -one;cyclopropyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1.2.4]triazolo[1,5-a ]pyrimidin-2-yl]piperazin-l-yl]methanone; l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-2-methoxy-ethanone;1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin- 1 -yl] -3 -methoxy-propan- 1 -one;2-(dimethylamino)-l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]ethanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(35)-tetrahydrofuran-3-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- «]pyrimidin-2-yl]piperazin-l-yl]-[(25)-tetrahydrofuran-2-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]-[(2S)-l-methylpyrrolidin-2-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(2J?)-l-methylpyrrolidin-2-yl]methanone; rac-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin- 1 -yl] -( 1 -methylpyrrolidin-3 -yl)methanone;[(2J?)-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- «]pyrimidin-2-yl] -2-methyl-piperazin- 1 -yl] - [(3R )-tetrahy dr ofuran-3 -yl] methanone;[(25)-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]-2-methyl-piperazin-l-yl]-[(3R) -tetrahydrofuran-3-yl]methanone; l-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[ 1 ,2,4]triazolo [1,5 a]pyrimidin-2-yl]piperazin- 1 -yl] -2-methyl-propan- 1 -one;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-«]pyrimidin-2-yl]piperazin-l-yl]-[rel-(3R) -l-methylpyrrolidin-3-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[rel-(35)-l-methylpyrrolidin-3-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- «]pyrimidin-2-yl]piperazin-l-yl]-(oxetan-3-yl)methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- «]pyrimidin-2-yl]piperazin-l-yl]-[(2J?)-tetrahydrofuran-2-yl]methanone;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]piperazin-l-yl]-[(3R) -tetrahydrofuran-3-yl]methanone;methyl 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1, 2, 4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-l -carboxylate;4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl]-N - methyl-piperazine- 1 -carboxamide;4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- «]pyrimidin-2-yl]-N,N- dimethyl-piperazine- 1 -carboxamide;2-[2-(4-ethylsulfonylpiperazin-l-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3- methyl- 5 -(trifluoromethy l)phenol ;2-[2-(4-isopropylsulfonylpiperazin-l-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;2-[2-(4-cyclobutylsulfonylpiperazin-l-yl)-[1,2,4]triazolo[1,5-«]pyrimidin-5- yl] -3 -methyl-5 -(trifluoromethyl)phenol ;2-[2-[4-(azetidin-l-ylsulfonyl)piperazin-l-yl]-[1,2,4]triazolo[1,5-a]pyrimidin- 5-yl]-3-methyl-5-(trifluoromethyl)phenol;2-[2-(4-cyclobutylsulfonylpiperazin- 1 -yl)-7-methyl-[ 1 ,2,4]triazolo[ 1,5- a]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;2-[2-[4-(azetidin-l-ylsulfonyl)piperazin-l-yl]-7-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[ 1 ,2,4]triazolo [1,5 -a ]pyrimidin-2-yl]piperazin- 1 -yl]propan- 1 -one; methyl 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-l -carboxylate; ethyl 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-a ]pyrimidin-2-yl]piperazine-l -carboxylate; cyclopropyl- [4- [5- [2 -hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-a ]pyrimidin-2-yl]piperazin-l-yl]methanone; cyclobutyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;2-[2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin- 5-yl]-3-methyl-5-(trifluoromethyl)phenol;3-methyl-2-[2-(4-methylsulfonylpiperazin-l-yl)-[1,2,4]triazolo[1,5-«]pyrimidin-5-yl]-5-(trifluoromethyl)phenol;4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]-N,N- -dimethyl-piperazine- l -sulfonamide;1-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[l,5- «]pyrimidin-2-yl]piperazin-l-yl]propan- l-one; cyclopropyl- [4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;2-[2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5 -y 1] - 3 , 5-dimethyl-phenol ;1-[4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- «]pyrimidin-2-yl]piperazin- 1 -yl]propan- 1 -one; cyclopropyl-[4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;2-[2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl-[1,2,4]triazolo[1,5-a ]pyrimidin- 5-yl]-5-methoxy-3-methyl-phenol;2-[2-(4-cyclobutylsulfonylpiperazin- 1 -yl)-7-methyl-[ 1 ,2,4]triazolo[ 1,5- «]pyrimidin-5-yl]-5-methoxy-3-methyl-phenol; methyl 4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-l -carboxylate;1-[4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[ 1 ,2,4]triazolo [1,5 -a]pyrimidin-2-yl]piperazin- 1 -yl]propan- 1 -one; cyclopropyl-[4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;5-(difluoromethyl)-2-[2-(4-ethylsulfonylpiperazin-l-yl)-7-methyl-[1.2.4]triazolo[l ,5-a]pyrimidin-5-yl]-3-methyl-phenol;2-[2-(4-cyclobutylsulfonylpiperazin- 1 -yl)-7-methyl-[ 1 ,2,4]triazolo[ 1,5- a]pyrimidin-5-yl]-5-(difluoromethyl)-3-methyl-phenol;3-methyl-2-[7-methyl-2-[4-(oxetan-3-ylsulfonyl)piperazin-l-yl]-[1.2.4]triazolo[1,5-a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; and rac-3-methyl-2-[7-methyl-2-(4-tetrahydrofuran-3-ylsulfonylpiperazin-l-yl)-[1.2.4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol.

16. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 14, wherein the compound is selected from the group consisting of methyl 4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-l-carboxylate;(l-fluorocyclopropyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;(l-fluorocyclobutyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;(l-fluorocyclopropyl)-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]- 7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;(l-fluorocyclobutyl)-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7- methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]methanone;(3,3-difluorocyclobutyl)-[4-[5-[2-hydroxy-6-methyl-4- (trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l- yl]methanone; rac-(2,2-difluorocyclopropyl)-[4-[5-[2-hydroxy-6-methyl-4- (trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l- yl]methanone;2-[2-(4-cyclobutylsulfonylpiperazin- 1 -yl)-7-methyl-[ 1 ,2,4]triazolo[ 1,5- a]pyrimidin-5-yl]-5-fluoro-3-methyl-phenol;3-methyl-2-[7-methyl-2-[4-[rel-(3S)-tetrahydrofuran-3-yl]sulfonylpiperazin-l- yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol;3-methyl-2-[7-methyl-2-[4-[rel-(3A)-tetrahydrofuran-3-yl]sulfonylpiperazin-l- yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol;[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]-[rel-(lS)-2,2- difluorocyclopropyl] methanone; and[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1.2.4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-l-yl]-[rel-(1R )-2,2- difluorocyclopropyl] methanone.

17. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 16 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

18. A compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 16 for use as a medicament.

19. A compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 16 or a pharmaceutical composition of claim 17 for use in a method of treating and / or preventing of one or more diseases, disorders or conditions associated withNLRP3.

20. A compound or a pharmaceutically acceptable salt or stereoisomer thereof of any one of claims 1 to 16 or a pharmaceutical composition of claim 17 for use in a method of treating and / or preventing one or more diseases, disorders or conditions associated with NLRP3 -mediated inflammation, comprising administering to the subject a compound or composition according to any one of claims 1 to 17.

21. The compound or composition for use of claim 20, wherein the one or more diseases, disorders or conditions are selected from the group consisting of cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem autoinflammatory syndrome (NOMID).

22. The compound or composition for use of claim 20, wherein the disease, disorder or condition is selected from the group consisting of (a) chronic inflammatory diseases, (b) metabolic diseases, (c) neurological diseases, (d) diseases associated with inherited, autosomal dominant mutations in NLRP3 that promote NLRP3 inflammasome; (e) asthma and allergic airway inflammation; (f) hypertension; (g) myocardial infarction; (h) hyperinflammation following influenza and / or severe acute respiratory syndromecoronavirus 2 (SARS CoV-2); (i) Graft-versus-host disease; (j) silicosis; (k) myelodysplastic syndrome; and (1) contact hypersensitivity and joint inflammation triggered by chikungunya virus.

23. The compound or composition for use of claim 22, wherein:(a) the chronic inflammatory disease is selected from the group consistingof gout, rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis;(b) the metabolic disease is selected from the group consisting of atherosclerosis, diabetes, metabolic syndrome, obesity, liver steatosis, nonalcoholic steatohepatitis (NASH), and liver fibrosis; or(c) the neurological disease is selected from the group consisting of Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), Prion disease, Traumatic Brain Injury (TBI) and stroke.

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