NLRP3 modulators

Abstract

The present application relates to compounds of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , X 1 , X 2 , X 3 and X 6 have the meanings as indicated in the claims and description. The present application also relates to pharmaceutical compositions comprising said compounds, their use as medicaments and in methods for the treatment and / or prevention of one or more diseases, disorders or conditions associated with NLRP3. (I)

Description

Background of the Invention NLRP3 is a member of the nucleotide-binding domain (NBD), leucine-rich repeat (LRR) (NLR) protein family that mediates innate inflammatory processes following infection or tissue damage. Upon activation, it forms an inflammasome complex with ASC and caspase-1, leading to the release of IL-1β and IL-18 and pyroptosis.

[0002] The pathological function of NLRP3-mediated inflammation has been described in genetic diseases (such as cryoinflammatory-associated periodic syndrome (CAPS)) as well as chronic inflammatory diseases (such as rheumatoid arthritis), metabolic diseases (such as diabetes) or neurological diseases (such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis).

[0003] NLRP3 is an intracellular sensor molecule that is activated in two steps: initiation and activation. The initiation step involves stimulation of pattern recognition receptors (PRRs), such as Toll-like receptors, and activation of the nuclear factor-κB (NFκB) pathway, which increases the expression of NLRP3, caspase-1, quercetin D, and pro-inflammatory cytokines. The NLRP3 activation step leads to the formation of active inflammasomes, which can be triggered by bacterial, viral, and fungal infections (PAMP; pathogen-associated molecular patterns; e.g., nigericin, DNA, RNA), aseptic inflammation mediated by endogenous molecules (DAMP; damage-associated molecular patterns; e.g., ATP, cholesterol crystals, α-synuclein, amyloid-β), and exposure to environmental stimuli (Swanson et al., Nature Review Immunology, 2019, Vol 19, 477–489).

[0004] PAMP and DAMP induce cellular stress, which is sensed by NLRP3. Many of them activate NLRP3 by leading to a decrease in cytoplasmic potassium ions, thereby inducing a conformational change in inactive NLRP3 protein, resulting in the formation of the NLRP3 complex, which recruits ASC (a CARD-containing adaptor protein, apoptosis-associated speckle-like protein). ASC binds to its precursor, caspase-1, which is activated within the multiprotein inflammasome complex (also known as the ASC speckle). Active caspase-1 cleaves the pro-inflammatory cytokines IL-1β and IL-18, as well as GSDMD (apoptosis-derived cytokinase D), which forms pores within the membrane, allowing the release of mature IL-1β and IL-18 and triggering pyroptosis. During pyroptosis, the release of intracellular contents (including the NLRP3 inflammasome, high-mobility group box 1 (HMGB1), leukotrienes, and prostaglandins) amplifies the inflammatory response and promotes 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] The pathological consequence of NLRP3 activation has been observed in patients carrying inherited autosomal dominant mutations in NLRP3, which promote the activation of the NLRP3 inflammasome. Patients with these gain-of-function mutations suffer from a rare systemic autoinflammatory syndrome called cold inflammatory-associated periodic syndrome (CAPS), characterized by an inflammation-associated phenotype with periodic fever, aseptic urticaria, and joint inflammation. CAPS comprises three overlapping disease entities: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal episodic multisystem autoinflammatory syndrome (NOMID).

[0006] Preclinical studies of NLRP3 gene deletion or small molecule inhibitors have linked NLRP3-mediated inflammation to many peripheral and central nervous system diseases. These include chronic inflammatory diseases, including gout, rheumatoid arthritis, and inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis; metabolic diseases, such as atherosclerosis, diabetes, metabolic syndrome, obesity and hepatic steatosis, non-alcoholic 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), prions, traumatic brain injury (TBI), and stroke; as well as asthma and allergic airway inflammation, hypertension, myocardial infarction, excessive inflammation following influenza and / or severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), graft-versus-host disease, silicosis, myelodysplastic syndromes, contact hypersensitivity reactions, 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, Vol. 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 to directly or indirectly inhibit NLRP3. They exhibit weak potency and / or off-target effects in the micromolar range (Coll et al., Trends in Pharmacological Science, 2022, Vol. 43, 653-668). MCC950 has been used as a tool compound in many preclinical studies, demonstrating good potency and selectivity exceeding that of NLRC4 and NLRP1. However, high doses in clinical studies have resulted in hepatotoxicity (Mangan et al., Nature Reviews Drug Discovery, 2018, Vol. 17, 588-606).

[0008] The pro-inflammatory cytokine IL-1β is a potent NLRP3-dependent effector and therefore a major target for limiting NLRP3-driven pathologies. Biologics such as anakinin, cannabidiol, and linacip, which inhibit the IL1 axis, have been approved for the treatment of CAPS and are being tested in clinical trials for rheumatoid arthritis and gout. However, biologics require injection, which causes inflammation at the injection site and has poor brain penetration (Mangan et al., Nature Reviews DrugDiscovery, 2018, Vol. 17, 588-606).

[0009] There is a need for orally available, preferably brain-penetrating, NLRP3 inhibitors with improved potency and selectivity. Invention Overview This application generally relates to compounds, compositions, and methods for modulating the activity of NLRP3. It also discloses compounds, compositions, and methods for treating diseases, symptoms, or conditions, including but not limited to: (i) diseases associated with NLRP3-mediated inflammation, including but not limited to cryoinflammatory syndrome-associated periodicity (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal paroxysmal multisystem autoinflammatory syndrome (NOMID); (ii) chronic inflammatory diseases (e.g., gout, rheumatoid arthritis, inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis); and (iii) metabolic diseases (e.g., atherosclerosis, diabetes, etc.). Metabolic syndrome, hepatic steatosis, nonalcoholic steatohepatitis (NASH), and liver fibrosis; (iv) neurological disorders (e.g., Alzheimer's disease (AD) and Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), prions, traumatic brain injury (TBI), and stroke); (v) diseases associated with inherited autosomal dominant mutations in NLRP3 that promote the NLRP3 inflammasome; (vi) asthma and allergic airway inflammation; (vii) hypertension; (viii) myocardial infarction; (ix) excessive inflammation following influenza and / or severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2); (x) graft-versus-host disease; (xi) silicosis; (xii) myelodysplastic syndromes; (xiii) contact hypersensitivity reactions and joint inflammation triggered by chikungunya virus. This also includes obesity as a metabolic disease.

[0011] In one aspect, this disclosure includes compounds of formula (I). (I), in R 1It is CN, CH3, CF3, CHF2, OCH3, OCHF2, OCF3, or a halogen; R 2 It is H, CH3, CH2CH3, CF3, CHF2, Cl, CN, or cyclopropyl, and R 3 It is H or CH3, provided that R 2 and R 3 Not all of them are H; R 4 It is H, CH3, CH2CH3, CF3, CHF2, OCH3, Cl, F, C 3-5 Cycloalkyl or unsubstituted saturated 4-6 membered heterocyclic groups, wherein C 3-5 The cycloalkyl group is optionally substituted with one or more F; or R 3 and R 4 Connect to form -CH2-CH2-CH2- or -CH2-O-CH2-; -X 1 -is-CH(R) 5b - or –C(R) 5b1 (R) 5c )CH2-*, where the asterisk-marked bond is connected to nitrogen in formula (I); -X 2 -is-CH(R) 5d - or –CH(R) 5d1 )CH2-*, where the asterisk-marked bond is connected to nitrogen in formula (I); R 5 R 5a R 5b1 R 5c and R 5d1 Independently selected from H, F, and R 5e ; R 5b and R 5d Independently selected from H and R 5e ; Each R 5e Independently selected from cyclopropyl and C 1-4 Alkyl, wherein R 5e Optionally substituted by one or more substituents independently selected from OH and F; X 3 It is -S(=O)2-*, -C(=O)-*, -C(=O)O-*, -C(=O)N(R) 6a )-*、-S(=O)2-N(R 6a )-*、-S(=O)(R 6a )=N-* or -S(=O)-N(R 6a)-*, where the key marked with an asterisk is related to R 6 connect; R 6a It is H or CH3; When X 3 It is -S(=O)2-*, -C(=O)O-*, -C(=O)N(R) 6a )-*、-S(=O)2-N(R 6a -* or -S(=O)-N(R) 6a When )-*, R 6 Selected as C 1-4 Alkyl, CHF2, CF3, T 1 NHCH3 or N(CH3)2, where C 1-4 The alkyl group is optionally replaced by OCH3 or N(CH3)2; or When X 3 When it is -C(=O)-*, R 6 Selected as C 1-4 Alkyl, CHF2, CF3, OC 1-4 Alkyl, T 1 OT 1 NHCH3 or N(CH3)2, where C 1-4 The alkyl group is optionally replaced by OCH3 or N(CH3)2; or When X 3 It is -S(=O)(R) 6a When )=N-*, R 6 Selected as C 1-4 Alkyl, wherein C 1-4 The alkyl group is optionally substituted with one or more F; or R 6 and R 5d Linked to form a divalent group, wherein the divalent group is selected as CH2 or CH2-CH2; and T 1 It is cyclopropyl, cyclobutyl, aziridine, pyrrolidinyl, oxacyclobutyl or tetrahydrofuranyl, wherein T 1 Optionally substituted with one or more substituents, which may be the same or different and are selected from F, CH3, OCH3 and OH.

[0012] In another aspect of the compound of formula (I), R 1 It is CF3, CHF2, F, Cl, OCH3, OCHF2, CH3, or CN. On the other hand, R... 1 It is CN, CH3, CF3, OCH3, F, or Cl, and furthermore, R 1 It's CF3.

[0013] In one embodiment of the compound of formula (I), R 2 It is CH3 and R 3 It is H. In another aspect regarding the compounds of formula (I), R... 4 It is H, CH3 or CH2CH3, preferably CH3.

[0014] In another embodiment of the compound of formula (I), R 1 R 2 and R 3 Selected to give equation (Ia) (Ia).

[0015] For compound (R) of formula (I) 1 R 2 and R 3 R is chosen to give one aspect of equation (Ia)). 4 The choice is made to give either equation (Ib) or (Ib1). .

[0016] In another aspect of the compound of formula (I), R 5 and R 5a It's H. On the other hand, X 1 It is -CH(R) 5b )-. In a further aspect, R 5b It is H or CH3, preferably H. In another aspect, X 2 It is -CH(R) 5d )-. In one respect, R 5d Is it H or R? 6 Connection, preferably H. In another aspect, R 5 R 5a X 1 and X 2 Selected to give formula (Ic) (Ic).

[0017] In one embodiment of the compound described herein, R 5b R 5d X 3 and R 6 The formula selected to give a formula chosen from (Id1) to (Id8), preferably (Id3) or (Id6): .

[0018] In one embodiment of the compound described herein, R 6 It is CH3, CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, N-methylpyrrolyl, oxecyclobutyl, azircyclobutyl, N,N-dimethylaminomethyl, methoxymethyl or methoxyethyl, preferably CH2CH3, CH(CH3)2 or cyclopropyl.

[0019] In another embodiment of the compound described herein, the compound is: rac -2-[2-(1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3- a ]pyrazine-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-3a,4,6,7-tetrahydro-3-] H -[1,2,5]thiadiazo[2,3- a ]pyrazine-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]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-] a ]Pyrazin-6-one; 2-[2-(4-isopropylsulfonylpiperazin-1-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-3a,4,6,7-tetrahydro-3-] H -[1,2,5]thiadiazo[2,3- a ]pyrazine-5-yl)-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 1-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]acetone; 3-Methyl-2-[2-[ rel -(3 aR )-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 -(3 aS )-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 -(3 aR )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[2,3- a ]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[ rel -(3 aS )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[2,3- a ]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; rel -(8 aS )-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-] a ]Pyrazin-6-one; rel -(8 aR )-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-] a ]Pyrazin-6-one; 3-Methyl-2-[7-Methyl-2-[ rel -(3 aR )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[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 -(3 aS )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[2,3- a ]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]acetone; 1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]prop-1-one; Cyclopropyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; 1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]-2-methoxy-ethyl ketone; 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-prop-1-one; 2-(dimethylamino)-1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]acetone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-]a ]pyrimidin-2-yl]piperazin-1-yl]-[(3 S [Tetrahydrofuran-3-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 S [Tetrahydrofuran-2-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 S 1-Methylpyrrolidone-2-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 R 1-Methylpyrrolidone-2-yl]methyl ketone; rac -[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]-(1-methylpyrrolidone-3-yl)methyl ketone; [(2 R )-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a ]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]-[(3 R [Tetrahydrofuran-3-yl]methyl ketone; [(2 S )-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a ]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]-[(3 R [Tetrahydrofuran-3-yl]methyl ketone; 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-prop-1-one; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[rel -(3 R 1-Methylpyrrolidone-3-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[ rel -(3 S 1-Methylpyrrolidone-3-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a [Pyrimidin-2-yl]piperazin-1-yl]-(oxetane-3-yl)methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 R [Tetrahydrofuran-2-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(3 R [Tetrahydrofuran-3-yl]methyl ketone; 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a Methyl pyrimidin-2-yl]piperazine-1-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-1-yl)-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(4-isopropylsulfonylpiperazin-1-yl)-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[4-(azacyclobutane-1-ylsulfonyl)piperazin-1-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-(azacyclobutane-1-ylsulfonyl)piperazin-1-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]prop-1-one; 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a Methyl pyrimidin-2-yl]piperazine-1-carboxylate; 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a Ethyl pyrimidin-2-yl]piperazine-1-carboxylate; Cyclopropyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; Cyclobutyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; 2-[2-(4-ethylsulfonylpiperazin-1-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]prop-1-one; Cyclopropyl-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; 2-[2-(4-ethylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3,5-dimethylphenol; 1-[4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]prop-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-1-yl]methyl ketone; 2-[2-(4-ethylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-5-methoxy-3-methylphenol; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-5-methoxy-3-methylphenol; 4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[1,2,4]triazolo[1,5- a Methyl pyrimidin-2-yl]piperazine-1-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]prop-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-1-yl]methyl ketone; 5-(difluoromethyl)-2-[2-(4-ethylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-3-methylphenol; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-5-(difluoromethyl)-3-methylphenol; 3-Methyl-2-[7-Methyl-2-[4-(oxecyclobutane-3-ylsulfonyl)piperazin-1-yl]-[1,2,4]triazolo[1,5- a [Pyrimidin-5-yl]-5-(trifluoromethyl)phenol; or 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.

[0020] In another embodiment of the compound described herein, the compound is: 4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-1-carboxylic acid methyl ester; (1-Fluorocyclopropyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-1-yl]methyl ketone; (1-Fluorocyclobutyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-1-yl]methyl ketone; (1-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]methyl ketone; (1-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]methyl ketone; (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]methyl ketone; 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-1-yl]methyl ketone; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-methylphenol; 3-Methyl-2-[7-methyl-2-[4-[rel-(3 S [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[7-Methyl-2-[4-[rel-(3 R [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-1-yl]-[rel-(1 S [2,2-difluorocyclopropyl] methyl ketone; or [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-1-yl]-[rel-(1 R [2,2-difluorocyclopropyl] methyl ketone.

[0021] This invention provides compounds of formula (I). This invention also provides pharmaceutical compositions comprising any of the compounds described herein. This invention further provides the use of compounds of formula (I) as medicines and in methods of treating and / or preventing one or more diseases, symptoms, or conditions associated with NLRP3.

[0022] In another aspect, methods for treating and / or preventing one or more NLRP3-related diseases and / or conditions using the compounds described herein are described, or methods for using the compounds or compositions described herein (for) treating and / or preventing one or more NLRP3-related diseases, conditions or illnesses are described.

[0023] The above overview and detailed description are exemplary and illustrative. They are intended to provide further details of the invention but should not be construed as limiting. Other objects, advantages, and novel features will become apparent to those skilled in the art from the following detailed description of the invention. Invention Details The purpose of this invention is to provide a new class of compounds as NLRP3 modulators that can effectively treat NLRP3-related diseases and conditions and exhibit improved pharmaceutically relevant properties, including oral bioavailability, brain permeability, activity, solubility, selectivity, ADMET properties, and / or reduced side effects.

[0025] The pathological functions of NLRP3-mediated inflammation have been described in the following contexts: genetic diseases such as CAPS, as well as chronic inflammatory diseases (e.g., rheumatoid arthritis), metabolic diseases (e.g., diabetes), or neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis). Furthermore, as mentioned above, NLRP3-mediated inflammation is associated with both peripheral and central nervous system disorders. These diseases include chronic inflammatory diseases, including gout, rheumatoid arthritis, and inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis; metabolic diseases, such as atherosclerosis, diabetes, metabolic syndrome, obesity and hepatic steatosis, non-alcoholic 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), prions, traumatic brain injury (TBI), and stroke; as well as asthma and allergic airway inflammation, hypertension, myocardial infarction, excessive inflammation following influenza and / or severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), graft-versus-host disease, silicosis, myelodysplastic syndrome, contact hypersensitivity reactions, and joint inflammation triggered by chikungunya virus.

[0026] This invention provides compounds of the invention in free or pharmaceutically acceptable salt forms or in solvates, hydrates, tautomers, or stereoisomers. These compounds can be used to treat the diseases or conditions mentioned herein. The same applies to the pharmaceutical compositions of the invention. Therefore, one aspect of the invention is a pharmaceutically acceptable salt of the compounds of the invention. Another aspect of the invention is a stereoisomer of the compounds of the invention.

[0027] Therefore, the present invention provides compounds of formula (I): (I), in R 1 It is CN, CH3, CF3, CHF2, OCH3, OCHF2, OCF3, or a halogen; R2 It is H, CH3, CH2CH3, CF3, CHF2, Cl, CN, or cyclopropyl, and R 3 It is H or CH3, provided that R 2 and R 3 Not all of them are H; R 4 It is H, CH3, CH2CH3, CF3, CHF2, OCH3, Cl, F, C 3-5 Cycloalkyl or unsubstituted saturated 4-6 membered heterocyclic groups, wherein C 3-5 The cycloalkyl group is optionally substituted with one or more F; or R 3 and R 4 Connect to form -CH2-CH2-CH2- or -CH2-O-CH2-; -X 1 -is-CH(R) 5b - or –C(R) 5b1 (R) 5c )CH2-*, where the asterisk-marked bond is connected to nitrogen in formula (I); -X 2 -is-CH(R) 5d - or –CH(R) 5d1 )CH2-*, where the asterisk-marked bond is connected to nitrogen in formula (I); R 5 R 5a R 5b1 R 5c and R 5d1 Independently selected from H, F, and R 5e ; R 5b and R 5d Independently selected from H and R 5e ; Each R 5e Independently selected from cyclopropyl and C 1-4 Alkyl, wherein R 5e Optionally substituted by one or more substituents independently selected from OH and F; X 3 It is -S(=O)2-*, -C(=O)-*, -C(=O)O-*, -C(=O)N(R) 6a )-*、-S(=O)2-N(R 6a )-*、-S(=O)(R 6a )=N-* or -S(=O)-N(R 6a )-*, where the key marked with an asterisk is related to R 6 connect; R 6aIt is H or CH3; When X 3 It is -S(=O)2-*, -C(=O)O-*, -C(=O)N(R) 6a )-*、-S(=O)2-N(R 6a -* or -S(=O)-N(R) 6a When )-*, R 6 Selected as C 1-4 Alkyl, CHF2, CF3, T 1 NHCH3 or N(CH3)2, where C 1-4 The alkyl group is optionally replaced by OCH3 or N(CH3)2; or When X 3 When it is -C(=O)-*, R 6 Selected as C 1-4 Alkyl, CHF2, CF3, OC 1-4 Alkyl, T 1 OT 1 NHCH3 or N(CH3)2, where C 1-4 The alkyl group is optionally replaced by OCH3 or N(CH3)2; or When X 3 It is -S(=O)(R) 6a When )=N-*, R 6 Selected as C 1-4 Alkyl, wherein C 1-4 The alkyl group is optionally substituted with one or more F; or R 6 and R 5d Connected to form a divalent group, wherein the divalent group is selected as CH2 or CH2-CH2; T 1 It is cyclopropyl, cyclobutyl, aziridine, pyrrolidinyl, oxacyclobutyl or tetrahydrofuranyl, wherein T 1 Optionally substituted with one or more substituents, which may be the same or different and are selected from F, CH3, OCH3 and OH.

[0028] If a variable or substituent can be selected from a different set of variants, and the variable or substituent appears more than once, the corresponding variants can be the same or different.

[0029] Surprisingly, the compounds of the embodiments disclosed in this invention have advantageous physicochemical properties and / or selectivity, which, when combined, contribute to achieving beneficial therapeutic effects while limiting unintended drawbacks.

[0030] As detailed in the following bioassays, the compounds according to this disclosure were tested in LPS-pretreated THP1 cells to evaluate their pharmacological ability to inhibit nigrain-activated NLRP3 and IL-1β release into the supernatant. The NLRP3 inhibitors reduced LPS / nigrain-induced IL-1β release, manifested as a decrease in the HTRF (homogeneous time-resolved fluorescence) ratio. The results surprisingly and unexpectedly showed that various compounds according to the invention exhibited the advantageous IC50 values ​​disclosed in Table 9. 50 value.

[0031] I. Definition In this invention, the terminology is used as follows: Unless otherwise defined, the technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art. Any suitable materials and / or methods known to one of ordinary skill in the art may be used to implement the methods described herein.

[0032] The singular forms “a,” “an,” and “described” used in this specification and the appended claims are interchangeable and are intended to include the plural forms as well, and fall within their respective meanings unless the context clearly specifies otherwise. Furthermore, as used herein, “and / or” refers to and covers any and all possible combinations of one or more of the listed items, as well as the lack of combinations when interpreted as an alternative (“or”).

[0033] As used herein, “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If, even taking into account the context in which the term is used, its use is unclear to those skilled in the art, then “about” means a maximum of 10% plus or minus that particular term.

[0034] The term "optional substitution" refers to either unsubstituted or substituted substances. Generally (but not limited to this), "one or more substituents" refers to one, two, or three substituents, preferably one or two substituents, more preferably one substituent. Generally, these substituents can be the same or different. The term "one or more substituents" also refers to, for example, 1, 2, 3, 4, or 5, preferably, for example, 1, 2, 3, or 4.

[0035] "Alkyl" refers to a straight-chain or branched hydrocarbon chain. Each hydrogen atom in an alkyl carbon can be replaced by a further specified substituent.

[0036] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen atom of an alkenyl carbon may be replaced by a further specified substituent.

[0037] "Alynyl" refers to a straight-chain or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen atom of the alkynyl carbon may be replaced by a further specified substituent.

[0038] “C 1-4 "Alkyl" refers to an alkyl chain having 1-4 carbon atoms, for example, if it is present at the end of the molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or for example -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, in which case the two parts of the molecule are connected by an alkyl group. 1-4 Each hydrogen atom in an alkyl carbon can be replaced by a further specified substituent. The term "C" 1-3 "Alkyl" is defined accordingly.

[0039] “C 1-6 "Alkyl" refers to an alkyl chain having 1-6 carbon atoms, for example, if it is present at the end of the molecule: C 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or for example -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, where the two parts of the molecule are connected by an alkyl group. C 1-6 Each hydrogen atom in an alkyl carbon can be replaced by a further specified substituent.

[0040] “C 2-6 "Alkenyl" refers to an alkenyl chain with 2-6 carbon atoms, for example, if it exists at the end of a molecule: -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2, or for example -CH=CH-, in which case the two parts of the molecule are connected by an alkenyl group. C 2-6 Each hydrogen atom of the alkenyl carbon can be replaced by a further specified substituent.

[0041] “C 2-6 "Alkyne" refers to an alkynyl chain with 2-6 carbon atoms, for example, if it exists at the end of a molecule: -C≡CH, -CH2-C≡CH, -CH2-CH2-C≡CH, -CH2-C≡C-CH3, or for example -C≡C-, in which case the two parts of the molecule are connected by the alkynyl group. 2-6 Each hydrogen atom in the alkynyl carbon can be replaced by a further specified substituent.

[0042] “C 3-7 "Cycloalkyl" or "C" 3-7"Cycloalkyl ring" refers to a cyclic alkyl chain having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, or cycloheptyl. Preferably, cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Each hydrogen atom of the cycloalkyl carbon may be replaced by a substituent as further specified herein. The term "C" 3-5 "Cycloalkyl" or "C" 3-5 "Cycloalkyl ring" is defined accordingly.

[0043] "C5 cycloalkylene" refers to a divalent cycloalkylene ring with five carbon atoms, namely a divalent cyclopentyl ring.

[0044] "C5 cycloene group" refers to a divalent cycloene group, namely divalent cyclopentene or cyclopentadiene.

[0045] “C 4-12 "Bicycloalkyl" or "C" 4-12 "Bicycloalkyl ring" refers to a bicyclic fused, bridged, or spirocycloalkyl chain having 4 to 12 carbon atoms, such as hexahydroindane, octahydrocyclopentadiene, bicyclo[2.2.1]heptane, or spiro(3.2)hexane. Each hydrogen atom of the bicycloalkyl carbon may be replaced by a substituent as further specified herein.

[0046] "Halogen" refers to fluorine, chlorine, bromine, or iodine. Fluorine or chlorine are generally preferred halogens.

[0047] "4- to 7-membered heterocyclic group" or "4- to 7-membered heterocycle" refers to a ring having 4, 5, 6 or 7 ring atoms, which may contain up to a maximum number of double bonds (aromatic or non-aromatic rings, fully saturated, partially saturated or unsaturated), wherein at least one ring atom and up to 4 ring atoms are replaced by heteroatoms selected from sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is connected to the rest of the molecule by a carbon or nitrogen atom. Examples of 4- to 7-membered heterocycles include: azirmonobutane, oxacyclobutane, thiohexacyclobutane, furan, thiophene, pyrrole, pyrrolin, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazazole, isothiazoline, thiadiazole, thiadiazole, tetrahydrofuran, tetrahydrothiophene, pyrrole, imidazoline, pyrazoline, oxazoline, isoxazoline, thiazoline, isothiazoline, thiadiazole, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazoline, pyridine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetraazole, triazole, triazoline, tetrazoline, diazacycloheptane, azazoline, or homopiperazine. The terms "5- to 6-membered heterocyclic group" or "5- to 6-membered heterocycle" are defined accordingly, including 5- to 6-membered aromatic heterocyclic groups or heterocycles. The terms "5-membered heterocyclic group" or "5-membered heterocycle" are defined accordingly, including 5-membered aromatic heterocyclic groups or heterocycles. The terms "4- to 6-membered heterocyclic group" or "4- to 6-membered heterocycle" are defined accordingly.

[0048] The term "five-membered subheterocyclic group containing nitrogen ring atoms" refers to a divalent five-membered heterocycle in which at least one of the five ring atoms is a nitrogen atom, and in which the ring is connected to the rest of the molecule by a carbon or nitrogen atom.

[0049] "Saturated 4- to 7-membered heterocyclic group" or "saturated 4- to 7-membered heterocyclic ring" refers to a fully saturated "4- to 7-membered heterocyclic group" or "4- to 7-membered heterocyclic ring". "Saturated 4- to 6-membered heterocyclic group" or "saturated 4- to 6-membered heterocyclic ring" refers to a fully saturated "4- to 6-membered heterocyclic group" or "4- to 6-membered heterocyclic ring".

[0050] "At least partially saturated 4- to 7-membered heterocyclic group" or "at least partially saturated 4- to 7-membered heterocyclic ring" refers to a "4- to 7-membered heterocyclic group" or "4- to 7-membered heterocyclic ring" that is at least partially saturated.

[0051] "5- to 6-membered aromatic heterocyclic group" or "5- to 6-membered aromatic heterocycle" refers to a heterocycle derived from cyclopentadienyl or benzene, wherein at least one carbon atom is replaced by a heteroatom selected from sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-). Examples of such heterocycles include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiazolium, thiadiazole, triazole, tetraazole, pyridine, pyrimidine, pyridazine, pyrazine, and triazine.

[0052] "5-membered aromatic heterocyclic group" or "5-membered aromatic heterocycle" refers to a heterocycle derived from cyclopentadienyl, in which at least one carbon atom is replaced by a heteroatom selected from sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-). Examples of such heterocycles include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiazolium, thiadiazole, triazole, and tetraazole.

[0053] "7- to 12-membered heterobicyclic group" or "7- to 12-membered heterobicyclic" refers to a heterocyclic system of two rings having 7 to 12 ring atoms, wherein at least one ring atom is shared by the two rings and may contain up to a maximum number of double bonds (aromatic or non-aromatic rings, fully saturated, partially saturated or unsaturated), wherein at least one ring atom and up to six ring atoms are replaced by heteroatoms selected from sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is connected to the rest of the molecule by a carbon or nitrogen atom. Examples of 7- to 12-membered heterobicyclic compounds include: indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzoimidazolium, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzozazazoline, purine, or pteridine. The term “7 to 12-membered heterobicyclic” also includes spirocyclic structures with two rings, such as 6-oxa-2-azaspiro[3,4]octane, 2-oxa-6-azaspiro[3.3]heptane-6-yl or 2,6-diazaspiro[3.3]heptane-6-yl, or bridged heterocyclic structures, such as 8-azabicyclic[3.2.1]octane or 2,5-diazabicyclic[2.2.2]octane-2-yl or 3,8-diazabicyclic[3.2.1]octane.

[0054] "Saturated 7- to 12-membered heterobicyclic group" or "saturated 7- to 12-membered heterobicyclic group" refers to a fully saturated "7- to 12-membered heterobicyclic group" or "7- to 12-membered heterobicyclic group".

[0055] "At least partially saturated 7- to 12-membered heterobicyclic group" or "at least partially saturated 7- to 12-membered heterobicyclic group" refers to "at least partially saturated 7- to 12-membered heterobicyclic group" or "7- to 12-membered heterobicyclic group".

[0056] "9 to 11-membered aromatic heterobicyclic group" or "9 to 11-membered aromatic heterobicyclic" refers to a heterocyclic system with two rings, wherein at least one ring is aromatic, and wherein the heterocyclic system has 9 to 11 ring atoms, wherein the two ring atoms are shared by the two rings, and may contain up to a maximum number of double bonds (fully or partially aromatic), wherein at least one ring atom and up to 6 ring atoms are replaced by heteroatoms selected from sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), and wherein the ring is connected to the rest of the molecule by a carbon atom or a nitrogen atom. Examples of 9- to 11-membered aromatic heterobicyclic compounds include: indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzoimidazolium, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzozazolium, purine, or pteridine. The terms "9- to 10-membered aromatic heterobicyclic group" or "9- to 10-membered aromatic heterobicyclic" are defined accordingly.

[0057] II. Exemplary Compounds of this Disclosure Exemplary compounds of formula (I) refer to those compounds in which one or more residues have the meanings described above or below, and all preferred combinations of substituents are the subject of this invention. For all preferred compounds of formula (I), this invention also includes all tautomers and stereoisomers thereof and mixtures thereof in all proportions, as well as pharmaceutically acceptable salts thereof.

[0058] In exemplary embodiments of the present invention, the substituents mentioned below independently have the following meanings. Therefore, one or more of these substituents may have the meanings presented below.

[0059] In one aspect of this disclosure, R 1 It is CF3, CHF2, F, Cl, OCH3, OCHF2, CH3 or CN, preferably R. 1 It is CN, CH3, CF3, OCH3, F or Cl, or even more preferably CF3.

[0060] In another respect, R 2 It is CH3 and R 3 It's H.

[0061] In another respect, R 4 It is H, CH3 or CH2CH3, preferably CH3.

[0062] In another respect, R 1 R 2 and R 3 Selected to give equation (Ia) (Ia).

[0063] In another respect, R 4 The choice is made to give either equation (Ib) or (Ib1). (Ib) (Ib1).

[0064] In another respect, R 5 and R 5a It's H.

[0065] In another respect, X 1 It is -CH(R) 5b )-.

[0066] In another respect, R 5b It is H or CH3, preferably H.

[0067] In another respect, X 2 It is -CH(R) 5d )-.

[0068] In another respect, R 5d Is it H or R? 6 Connection, preferably H; In another respect, R 5 R 5a X 1 and X 2 Selected to give formula (Ic) (Ic).

[0069] In another respect, R 5b R 5d X 3 and R 6 The formula chosen to give a formula selected from (Id1) to (Id8), preferably (Id3) or (Id6). (Id1), .

[0070] In another respect, R 6 It is CH3, CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, N-methylpyrrolyl, oxecyclobutyl, azircyclobutyl, N,N-dimethylaminomethyl, methoxymethyl or methoxyethyl, preferably CH2CH3, CH(CH3)2 or cyclopropyl.

[0071] Compounds of the present invention in which some or all of the above-mentioned groups have a preferred or more preferred meaning are also the target of the present invention.

[0072] The exemplary specific compounds of the present invention are selected from: rac -2-[2-(1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3- a ]pyrazine-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-3a,4,6,7-tetrahydro-3-] H -[1,2,5]thiadiazo[2,3- a ]pyrazine-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]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-] a ]Pyrazin-6-one; 2-[2-(4-isopropylsulfonylpiperazin-1-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-3a,4,6,7-tetrahydro-3-] H -[1,2,5]thiadiazo[2,3- a ]pyrazine-5-yl)-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 1-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]acetone; 3-Methyl-2-[2-[ rel -(3 aR )-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 -(3 aS )-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 -(3 aR )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[2,3- a ]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[ rel -(3 aS )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[2,3- a ]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; rel -(8 aS )-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-] a ]Pyrazin-6-one; rel -(8 aR )-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-] a ]Pyrazin-6-one; 3-Methyl-2-[7-Methyl-2-[ rel -(3 aR )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[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 -(3 aS )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[2,3- a ]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]acetone; 1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]prop-1-one; Cyclopropyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; 1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]-2-methoxy-ethyl ketone; 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-prop-1-one; 2-(dimethylamino)-1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]acetone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(3 S [Tetrahydrofuran-3-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a]pyrimidin-2-yl]piperazin-1-yl]-[(2 S [Tetrahydrofuran-2-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 S 1-Methylpyrrolidone-2-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 R 1-Methylpyrrolidone-2-yl]methyl ketone; rac -[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]-(1-methylpyrrolidone-3-yl)methyl ketone; [(2 R )-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a ]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]-[(3 R [Tetrahydrofuran-3-yl]methyl ketone; [(2 S )-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a ]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]-[(3 R [Tetrahydrofuran-3-yl]methyl ketone; 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-prop-1-one; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[ rel -(3 R 1-Methylpyrrolidone-3-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a]pyrimidin-2-yl]piperazin-1-yl]-[ rel -(3 S 1-Methylpyrrolidone-3-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a [Pyrimidin-2-yl]piperazin-1-yl]-(oxetane-3-yl)methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 R [Tetrahydrofuran-2-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(3 R [Tetrahydrofuran-3-yl]methyl ketone; 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a Methyl pyrimidin-2-yl]piperazine-1-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-1-yl)-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(4-isopropylsulfonylpiperazin-1-yl)-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[4-(azacyclobutane-1-ylsulfonyl)piperazin-1-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-(azacyclobutane-1-ylsulfonyl)piperazin-1-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]prop-1-one; 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a Methyl pyrimidin-2-yl]piperazine-1-carboxylate; 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a Ethyl pyrimidin-2-yl]piperazine-1-carboxylate; Cyclopropyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; Cyclobutyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; 2-[2-(4-ethylsulfonylpiperazin-1-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]prop-1-one; Cyclopropyl-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; 2-[2-(4-ethylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3,5-dimethylphenol; 1-[4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]prop-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-1-yl]methyl ketone; 2-[2-(4-ethylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-5-methoxy-3-methylphenol; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-5-methoxy-3-methylphenol; 4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[1,2,4]triazolo[1,5- a Methyl pyrimidin-2-yl]piperazine-1-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]prop-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-1-yl]methyl ketone; 5-(difluoromethyl)-2-[2-(4-ethylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-3-methylphenol; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-5-(difluoromethyl)-3-methylphenol; 3-Methyl-2-[7-Methyl-2-[4-(oxecyclobutane-3-ylsulfonyl)piperazin-1-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.

[0073] Further exemplary specific compounds of the present invention are selected from: 4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-1-carboxylic acid methyl ester; (1-Fluorocyclopropyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-1-yl]methyl ketone; (1-Fluorocyclobutyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-1-yl]methyl ketone; (1-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]methyl ketone; (1-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]methyl ketone; (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]methyl ketone; 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-1-yl]methyl ketone; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-methylphenol; 3-Methyl-2-[7-Methyl-2-[4-[rel-(3 S [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[7-Methyl-2-[4-[rel-(3 R [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-1-yl]-[rel-(1 S [2,2-difluorocyclopropyl] methyl ketone; and [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-1-yl]-[rel-(1 R [2,2-difluorocyclopropyl] methyl ketone.

[0074] When tautomerism (e.g., keto-enol tautomerism) is possible in compounds of formula (I), each form (e.g., ketone and enol forms) is included individually or in mixtures in any proportion. This also applies to stereoisomers, such as enantiomers, cis / trans isomers, conformational isomers, etc.

[0075] In particular, when a compound according to formula (I) is given as an enantiomer or diastereomer, each pure form alone and any mixture of at least two pure forms in any proportion are included in formula (I) and are the subject of this invention.

[0076] Isotope-labeled compounds of formula (I) are also within the scope of this invention. Isotope labeling methods are known in the art. Preferred isotopes are isotopes of the elements H, C, N, O, and S. Therefore, compounds containing one or more of these is also particularly covered. 2 The compounds of this invention are hydrogen in the form of H / deuterium. Solvents and hydrates of compounds of formula (I) are also within the scope of this invention.

[0077] If necessary, isomers can be separated using methods well known in the art, such as liquid chromatography. The same applies to enantiomers, which can be separated using, for example, a chiral stationary phase. Alternatively, enantiomers can be separated by converting the enantiomer to a diastereomer, i.e., by coupling it with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomer and cleavage of the auxiliary residues. Alternatively, any enantiomer of the compound of formula (I) can be obtained by stereoselective synthesis using optically pure starting materials, reagents, and / or catalysts.

[0078] If a compound according to formula (I) contains one or more acidic or basic groups, the invention also includes its corresponding pharmaceutically or toxicologically acceptable salt, particularly its pharmaceutically usable salt. Thus, compounds of formula (I) containing acidic groups can, according to the invention, be used, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precisely, examples of such salts include sodium, potassium, calcium, magnesium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, or amino acids). Compounds of formula (I) containing one or more basic groups (i.e., groups that can be protonated) can be present and can be used according to the invention as addition salts of inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, neopentanoic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compound of formula (I) contains both acidic and basic groups in its molecule, the invention also includes, in addition to the salt forms mentioned, internal salts or betaine (zwitterions). The corresponding salts according to formula (I) can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. The present invention also includes all salts of compounds of formula (I), which are not directly applicable to pharmaceuticals due to low physiological compatibility, but may be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0079] III. Pharmaceutical Compositions As shown in the following examples, the compounds of the present invention are suitable for regulating NLRP3.

[0080] Therefore, one aspect of the present invention is the use of the compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, as the aforementioned medicament. This also applies to the pharmaceutical compositions of the present invention.

[0081] Another aspect of the invention is a method of using the compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer, or pharmaceutical composition thereof for treating and / or preventing one or more of the conditions or diseases described herein.

[0082] Another aspect of the invention is the use of the compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer or pharmaceutical composition thereof for the manufacture of a medicament for the treatment or prevention of one or more conditions or diseases associated with NLRP3.

[0083] Another aspect of the invention is a pharmaceutical composition comprising at least one compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, optionally combined with one or more other bioactive compounds or pharmaceutical compositions. In one aspect, said one or more bioactive compounds are NLRP3 modulators other than the compounds of the invention.

[0084] "Pharmaceutical composition" means one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product directly or indirectly produced by: combination, complexation or aggregation of any two or more ingredients, dissociation of one or more ingredients, or other types of reaction or interaction of one or more ingredients. Therefore, the pharmaceutical compositions of the present invention include any composition prepared by mixing the compounds of the present invention with a pharmaceutically acceptable carrier.

[0085] The pharmaceutical compositions of the present invention may include one or more additional compounds as active ingredients, such as a mixture of compounds of formula (I) in the composition or other NLRP3 modifiers.

[0086] The active ingredient may be contained in one or more different pharmaceutical compositions (a combination of pharmaceutical compositions).

[0087] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali or acid (including inorganic alkali or acid and organic alkali or acid).

[0088] The starting materials for the synthesis of the preferred embodiments of the present invention can be purchased from commercially available sources, such as Array, SigmaAldrich, Acros, Fisher, Fluka, and ABCR.

[0089] Generally, there are various methods available for preparing the compounds of this invention. In some cases, multiple strategies can be combined. Sequential or convergent routes can be used. Exemplary synthetic routes are described below.

[0090] IV. Treatment Methods This invention provides compounds of the invention or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, or pharmaceutical compositions, for the treatment or prevention of one or more diseases or conditions associated with NLRP3.

[0091] The described treatment method can be applied to mammals such as dogs, cats, cattle, horses, rabbits, monkeys, and humans. Preferably, the mammalian patient is a human patient.

[0092] Another aspect of the invention is a method for treating, controlling, delaying, and / or preventing one or more NLRP3-related diseases, symptoms, or conditions in a mammalian patient requiring treatment, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof.

[0093] Another aspect of the invention is a method for treating, controlling, delaying, and / or preventing one or more diseases, symptoms, or conditions described herein in a mammalian patient requiring treatment, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof.

[0094] Diseases or conditions that can be treated with the compounds and compositions of the present invention include, but are not limited to: (i) diseases associated with NLRP3-mediated inflammation, including but not limited to cryoinflammatory syndrome-associated periodicity (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal paroxysmal 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, etc.). (iv) Obesity, hepatic steatosis, nonalcoholic steatohepatitis (NASH), and liver fibrosis; (v) Neurological disorders (e.g., Alzheimer's disease (AD) and Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), prions, traumatic brain injury (TBI), and stroke); (v) Diseases associated with NLRP3 genetic autosomal dominant mutations that promote the NLRP3 inflammasome; (vi) Asthma and allergic airway inflammation; (vii) Hypertension; (viii) Myocardial infarction; (ix) Excessive inflammation following influenza and / or severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2); (x) Graft-versus-host disease; (xi) Silicosis; (xii) Myelodysplastic syndromes; (xiii) Contact hypersensitivity reactions and joint inflammation triggered by chikungunya virus.

[0095] Any suitable route of administration may be used to deliver an effective dose of the compounds of the present invention to mammals, especially humans. For example, oral, rectal, topical, parenteral, ocular, pulmonary, and nasal administration routes are possible. Dosage forms include tablets, lozenges, dispersants, suspensions, solutions, capsules, creams, ointments, and aerosols. Oral administration of the compound of formula (I) is preferred.

[0096] The effective dosage of the active ingredient used can vary depending on the specific compound used, the method of administration, the condition being treated, and the severity of the condition. Those skilled in the art can readily determine this dosage. Example

[0097] Example 1: Chemical Synthesis Experimental Procedure: Use the following abbreviations and acronyms: ACN Acetonitrile BippyPhos 5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′ H -[1,4′]bipyrazole Boc tert-butyloxycarbonyl Boc2O ditert-butyl dicarbonate BPin pinacol boronic acid ester Saturated aqueous solution of NaCl CyJohnPhos 2-(dicyclohexylphosphino)biphenyl DAST diethylaminosulfur trifluoride DCM dichloromethane DIPEA N -Ethyl- N -Isopropyl-propyl-2-amine DMF N , N -Dimethylformamide DMSO (dimethyl sulfoxide) DMSO- d 6 Deuterated dimethyl sulfoxide ESI + Positive ionization mode ESI - negative ionization mode Et3N Triethylamine EtOAc (ethyl acetate) FBS Fetal Bovine Serum h hours HATU 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b Pyridinium 3-oxide hexafluorophosphate HCl hydrochloric acid HPLC (High Performance Liquid Chromatography) HTRF homogeneous time-resolved fluorescence IL-1β Interleukin-1β K2CO3 (potassium carbonate) K3PO4 (tripotassium phosphate) LiOH (Lithium hydroxide) LPS (lipopolysaccharide) m multiplet MeOH (methanol) mg MgSO4 Magnesium sulfate MHz min minutes mL MsCl methanesulfonyl chloride N2 Nitrogen atmosphere NaHCO3 Sodium bicarbonate NaOH (sodium hydroxide) Na2SO4 Sodium sulfate NH2-NH2·H2O hydrazine hydrate NH4Cl ammonium chloride NLRP3 contains a nucleotide-binding domain (NBD) and a leucine-rich repeat sequence (LRR) (NLR) protein 3. NMP N 2-Methyl-2-pyrrolidone NMR (Nuclear Magnetic Resonance) Pd2(dba)3 Tris(dibenzylacetone)dipalladium(0) Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd(OAc)2 Palladium(II) acetate POCl3 Phosphorus oxychloride rt room temperature RT Retention Time T3P propanephosphonic anhydride TCFH N -[chloro(dimethylamino)methylene]- N methylmethylammonium hexafluorophosphate TFA 2,2,2-trifluoroacetic acid TsCl 4-methylbenzenesulfonyl chloride TsOH 4-Methylbenzene-1-sulfonic acid The conditions for analytical LCMS are as follows: System 1 (S1): Acidic IPC method: Waters UPLC TM BEH TM A C18 column (2.1 mm × 50 mm, 1.7 µm; temperature: 40 °C) was used for analytical HPLC-MS in a reversed-phase system (MET / uPLC / 1704) at an injection volume of 1 µL and a flow rate of 0.9 mL / min. The gradient was 5–100% B for 1.10 min, followed by 100% B for 0.25 min, where A = 0.1% formic acid / water and B = 0.1% formic acid / ACN. A second gradient of 100–5% B was then applied for 0.05 min and held for 0.10 min. UV spectra were recorded at 215 nm, 254 nm, and 280 nm. Mass spectra were obtained using a Waters QDA detector; ionization mode: electrospray positive or negative ion. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0098] System 2 (S2): Acidic final method: Analytical UHPLC-MS was performed in reverse phase using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 µm; temperature: 40 °C) at an injection volume of 1 µL and a flow rate of 0.6 mL / min. The gradient was 5–100% B for 5.30 min, followed by 100% B for 0.50 min, where A = 0.1% formic acid / water and B = 0.1% formic acid / ACN. A second gradient of 100–5% B was then applied for 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm, 254 nm, and 280 nm. ELS data were collected on a Waters ELS detector for reporting. Mass spectra were obtained using a Waters QDA detector; ionization mode: electrospray positive or negative ion. The data was integrated and reported using Waters MassLynx and OpenLynx software.

[0099] System 3 (S3): Acidic late elution IPC method: Using Waters UPLC TM CORTECS TM C8 column (2.1 mm × 50 mm, 1.6 µm; temperature: 40 °C) was used in reverse-phase UHPLC-MS (MET / uPLC / 1906) (M12) with an injection volume of 1 µL, a flow rate of 0.9 mL / min, and a gradient of 5–100% B for 1.10 min, followed by 100% B for 0.30 min, where A = 0.1% formic acid / water and B = 0.1% formic acid / acetonitrile. A second gradient of 100–5% B was then applied for 0.02 min and held for 0.28 min. UV spectra were recorded at 215 nm; spectral range: 200–400 nm. ELS data were collected using a Waters ELS detector for reporting. Mass spectra were obtained using a Waters SQD2 or QDa; ionization mode: electrospray positive or negative ion. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0100] System 4 (S4): Acidic IPC Method: Data were acquired using a Poroshell 120 EC-C18 column (2.1 mm × 50 mm, 1.9 µm column; temperature: 50 °C) on an Agilent 1260-6120 coupled with simultaneous DAD and MS detection. Isocratic elution of 99% A and 1% B was maintained for 0.1 min (A = H₂O + 0.1% formic acid, B = ACN + 0.05% formic acid), followed by a gradient of 1–100% B for 1.3 min, then 100% B for 0.5 min. A second gradient of 100–1% B was then applied for 0.1 min at a flow rate of 1 mL / min. Mass spectrometry data were recorded in full scan mode with simultaneous positive or negative ESI ionization. Data were processed using OpenLab software from Agilent.

[0101] System 5 (S5): Neutral Final Method: Data were acquired using a Poroshell 120 EC-C18 column (2.1 mm × 50 mm, 1.9 µm column; temperature: 50 °C) on an Agilent 1260-6490 coupled with simultaneous DAD and MS detection. Isocratic elution of 99% A and 1% B was maintained for 0.25 min (A = 10 mM ammonium acetate / water, B = ACN), followed by a gradient of 1–100% B for 2.25 min, then 100% B for 0.4 min. A second gradient of 100–1% B was then applied for 0.1 min at a flow rate of 0.8 mL / min. Mass spectrometry data were recorded in full scan mode with positive or negative ESI ionization (Agilent JetSteam). Data were integrated and reported using MassHunter software from Agilent.

[0102] System 6 (S6): Acidic final method: At XBridge TM Data were obtained on a C18 column (2.1 mm × 50 mm, 1.7 µm; temperature: 50 °C). Mobile phase A: ACN / water (95:5) containing 0.05% TFA; Mobile phase B: ACN / water (5:95) containing 0.05% TFA. Gradient: (0.0–3.0 min), 100% B, (3.0–3.5 min), flow rate: 1.0 mL / min. Detection: UV (220 nm) and MS (ESI + / -).

[0103] The purification method is as follows: Purification was performed by silica gel chromatography using a suitable Sfär Duo column on the Biotage Isolera system or a suitable RediSep column on the Teledyne ISCOCombiFlash system.

[0104] The purification using preparative HPLC methods is as follows: Method 1 (M1) Acidic Standard Method: 30% B for 1.90 min, followed by a 9.60 min gradient of 30–95% B and a 1.97 min hold, using Waters Sunfire. TM Purification was performed on a C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) in reverse phase (METCR / Prep001) (P2) LC, with an injection volume of 1500 mL and a flow rate of 40 mL / min, wherein A = 0.1% formic acid / water and B = 0.1% formic acid / acetonitrile. A second gradient of 95–30% B was then applied for 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm.

[0105] Method 2 (M2) Acidic Early Elution Method: 10% B for 1.90 min, followed by a gradient of 10–95% B for 14.10 min and a hold for 2.0 min, using Waters Sunfire. TM Purification was performed on a C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) in reverse phase (METCR / Prep004) by (P1) LC, with an injection volume of 1500 μL and a flow rate of 40 mL / min, wherein A = 0.1% formic acid / water and B = 0.1% formic acid / acetonitrile. A second gradient of 95–10% B was then applied for 0.20 min and held for another 1.25 min. UV spectra were recorded at 215 nm.

[0106] Method 3 (M3) Alkaline Standard Method: 30% B for 2.00 min, followed by a 9.50 min gradient of 30–95% B and a 1.97 min hold, using Waters XBridge. TMPurification was performed on a C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) in reverse phase (METCR / Prep003) (P4) LC, with an injection volume of 1500 μL and a flow rate of 40 mL / min, wherein A = 0.2% ammonium hydroxide / water and B = acetonitrile. A second gradient of 95–30% B was then applied for 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm.

[0107] Method 4 (M4) Alkaline Early Elution Method: 10% B for 2.00 min, followed by a gradient of 10–95% B for 14.00 min and a hold for 2.00 min, using Waters XBridge. TM Purification was performed on a C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) in reverse phase (METCR / Prep002) (P3) LC, with an injection volume of 1500 μL and a flow rate of 40 mL / min, wherein A = 0.2% ammonium hydroxide / water and B = acetonitrile. A second gradient of 95–10% B was then applied for 0.20 min and held for 1.25 min. UV spectra were recorded at 215 nm.

[0108] Method 5 (M5) Acidic Method: Column: XBridge TM C18 (19 mm × 200 mm, 5 μm; temperature: room temperature), flow rate 20 mL / min. Gradient: Through MS (ESI) + Trigger fraction collection. Combine fractions containing the desired product and dry them by centrifugation and evaporation.

[0109] NMR conditions Unless otherwise specified, records were made at 500 MHz, 400 MHz, or 300 MHz on a Bruker Avance III HD 500 MHz, Bruker Avance III HD 400 MHz, or Bruker 300 MHz Fourier spectrometer, respectively. 11H NMR spectra. Data were processed using MestReNova software. Chemical shifts δ are given in parts per million (ppm) with reference to residual solvent peaks. The following abbreviations are used to denote multiplicity and general distribution: s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), ddd (double doublet), dt (double triplet), dq (double quartet), pent (pentet), hep (septet), m (multiplet), td (triple doublet), qd (quartet), app. (apparent), and br. (peak width). Coupling constants. J The value is given with an accuracy of 0.1 Hz.

[0110] General synthesis: All compounds have been synthesized to a purity >95%, unless otherwise specified.

[0111] Route 1 plan Intermediate 1: 3-(difluoromethyl)-5-methylphenol DAST (6.2 mL, 47.0 mmol) was added dropwise to a solution of 3-hydroxy-5-methylbenzaldehyde (2.0 g, 14.7 mmol) in DCM (30 mL) at 0 °C, and the reaction was stirred at room temperature 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 NaHCO3, dried using a phase separator, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0–100% EtOAc / heptane) to provide the title compound (94% purity, 1.76 g, 10.5 mmol, 71% yield) as a yellow oil. 1 H NMR (500 MHz, CDCl3) δ6.90 (s, 1H), 6.80 (s, 1H), 6.79 – 6.75 (m, 1H), 6.56 (t, J = 56.6 Hz, 1H), 2.36 (s, 3H).

[0112] Route 2 plan Intermediate 2: 5-(difluoromethyl)-2-iodo-3-methylphenol Hydrogen peroxide (50%, 1.3 mL, 22.3 mmol in water) was added to a stirred solution of 3-(difluoromethyl)-5-methylphenol (1.76 g, 11.1 mmol, intermediate 1) in water (30 mL) under nitrogen atmosphere at 0 °C, followed by the addition of molecular iodine (2.82 g, 1.1 mmol). The reaction was stirred and heated to room temperature for 22 h. The reaction was then further treated with hydrogen peroxide (0.474 mL, 8.35 mmol) and molecular iodine (847 mg, 3.34 mmol) and stirred for another 6 h. The reaction was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0–30% EtOAc / heptane) to give the title compound (51% purity, 2.25 g, 4.04 mmol, 36% yield) as a pale yellow oil. M / Z :283 [MH] - ESI - , RT = 0.88-0.92 (S1).

[0113] Route 3 plan Step 3.a: 3-Methyl-5-(trifluoromethyl)phenol A degassed mixture of 1-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 to 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 mixture was stirred at 90 °C under N2 atmosphere for 18 h. The reaction mixture was cooled to room temperature and filtered through glass fiber filter paper. The filtrate was concentrated under vacuum, dissolved in EtOAc, and washed with 1 M HCl aqueous solution. After phase separation, the organic layer was concentrated under vacuum. The crude product was then stirred in 5 M NaOH aqueous solution for 15 min. Next, heptane was added, and the two-phase mixture was stirred for 5 min. After phase separation, the alkaline aqueous layer was cooled to 0 °C and acidified with 5 M HCl aqueous solution until pH=4 was reached. The aqueous layer was then extracted with heptane. The combined organic phases were washed with brine, dried over MgSO4, and concentrated under vacuum to provide the title compound (55.0 g, 306.2 mmol, 73% yield) as an orange liquid. 1 H NMR (400 MHz, DMSO-d 6) δ 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] - ESI - , RT = 0.88 (S1).

[0114] Step 3.b: 2-Iodo-3-methyl-5-(trifluoromethyl)phenol 3-Methyl-5-(trifluoromethyl)phenol (55.0 g, 306.2 mmol) was dissolved in toluene (500 mL) under a nitrogen atmosphere and cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 24.5 g, 612.3 mmol) was added in portions 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 room temperature, the reaction was quenched to pH 7 with 6 M HCl aqueous solution at 0 °C. The mixture was partially concentrated under vacuum and then extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-100% EtOAc / heptane, followed by 0-20% MeOH / EtOAc) to provide the title compound (90% purity, 74.3 g, 221.3 mmol, 72% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.95(s, 1H), 7.15 – 7.10 (m, 1H), 6.96 – 6.90 (m, 1H), 2.44 (s, 3H); M / Z 301 [MH] - ESI - , RT = 1.00 (S2).

[0115] Intermediate 3 (Step 3.c): 3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5-(trifluoromethyl)phenol Pd(OAc)₂ (1.12 g, 5.0 mmol) was added to a degassed solution of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (20.00 g, 49.7 mmol), triethylamine (21 mL, 149.0 mmol), pinacolborane (22 mL, 149.0 mmol), and 2-(dicyclohexylphosphino)biphenyl (3.48 g, 9.9 mmol) in 1,4-dioxane (20 mL). The reaction mixture was heated to 80 °C for 22 h under N₂ atmosphere. The reaction mixture was cooled to room temperature and filtered through glass fiber filter paper. The filter cake was washed with EtOAc, and the filtrate was partially concentrated under vacuum. The organic layer was washed with a saturated aqueous solution of NH₄Cl and water, dried over MgSO₄, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-12% EtOAc / heptane) to provide the title compound (8.18 g, 26.5 mmol, 53% yield) as a red oil. 1 H NMR (500 MHz, DMSO- d 6) δ 9.79 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 2.30 (s, 3H), 1.31 (s, 12H). 19 F NMR (376 MHz, DMSO- d 6) δ-61.57.

[0116] The intermediate compounds in Table 2 are synthesized using the corresponding starting materials / intermediates according to general route 3, as illustrated by example via intermediate 3.

[0117] Route 4 Step 4.a: 4-Methylsulfonylpiperazine-1-carboxylic acid tert-butyl ester A solution of piperazine-1-carboxylate tert-butyl ester (1.517 g, 7.98 mmol) in DCM (13 mL) was added to triethylamine (1.65 mL, 7.98 mmol) and methanesulfonyl chloride (0.95 mL, 12.2 mmol), and the reaction was allowed to rise to room temperature 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 under vacuum to provide the title compound (2.26 g, 8.22 mmol, 100% yield) as a grayish-white powder. 1 H NMR (300MHz, DMSO- d6 ) δ 1 H NMR (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).

[0118] Intermediate 8 (Step 4.b): 1-Methylsulfonylpiperazine hydrochloride A solution of tert-butyl 4-methylsulfonylpiperazine-1-carboxylate (2.26 g, 8.22 mmol) in 1,4-dioxane (20 mL) was added to 4 M hydrogen chloride in 1,4-dioxane (20.5 mL, 82.0 mmol), and the reaction was stirred at room temperature for 2 h. The suspension was filtered, washed with diethyl ether, and dried under vacuum to provide the title compound (1.43 g, 7.15 mmol, 87% yield) as a white powder. 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.28 (s, 2H), 3.42 –3.33 (m, 4H), 3.24 – 3.12 (m, 4H), 2.98 (s, 3H).

[0119] Route 5 plan Intermediate 9: 4-(5-amino-4 ... H tert-butyl 1,2,4-triazol-3-yl)piperazine-1-carboxylate A solution of piperazine-1-carboxylate tert-butyl ester (20.0 g, 107 mmol) in acetonitrile (120 mL) was added to dimethyl cyanoiminodithiocarbonate (15.7 g, 107 mmol), and the reaction was stirred at 82 °C for 2 h. The reaction mixture was cooled to room temperature and hydrazine hydrate (7.9 mL, 162 mmol) was added, and the reaction was stirred at 82 °C for 4 h. The reaction mixture was cooled to room temperature, and the precipitate was collected by filtration. The filter cake was washed with acetonitrile to provide the title compound (21.6 g, 80.5 mmol, 75% yield) as a white solid.1 H NMR (400 MHz, DMSO- d 6 ) 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); M / Z 269 ​​[M+H] + ESI + ,RT = 1.47 (S2).

[0120] The intermediate compounds in Table 3 are synthesized using the corresponding starting materials / intermediates according to the general route 5 illustrated by example via intermediate 9.

[0121] Route 6 plan Intermediate 12: 2-Bromo-4 H -[1,2,4]triazolo[1,5- a ]Pyrimidin-5-one To 5-bromo-4 H A solution of 1,2,4-triazol-3-amine (9.00 g, 52.5 mmol) in ethanol (60 mL) was added to 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 was stirred in a pressure tube at 90 °C for 16 h. The reaction mixture was cooled to room temperature and poured onto ice. 5 M HCl aqueous solution was added until pH=3 was reached, and the resulting slurry was stirred at 0 °C for 1.5 h. The precipitate was collected by filtration and washed with ethanol to provide the title compound (80% purity, 9.00 g, 33.5 mmol, 64% yield) as a light brown solid. 1 H NMR (400 MHz, DMSO- d 6 ) 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] + ESI + , RT = 0.37 (S1).

[0122] The intermediate compounds in Table 4 are synthesized using the corresponding starting materials / intermediates according to the general route 6 illustrated by example via intermediate 12.

[0123] Route 7 plan Intermediate 15: 2-bromo-7-methyl-4 H -[1,2,4]triazolo[1,5- a ]Pyrimidin-5-one To 5-bromo-4 H A stirred solution of 1,2,4-triazol-3-amine (0.50 g, 2.91 mmol) in acetonitrile (15.6 mL) was reacted with ethyl 3-ethoxy-2-butenoate (0.692 g, 4.37 mmol) and potassium carbonate (0.806 g, 5.83 mmol), and the reaction was stirred in a pressure tube at 100 °C for 16 h. 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 room temperature, and the precipitate was collected by filtration and washed with acetonitrile and methanol. The filtrate was concentrated under vacuum and milled several times with methanol to provide the title compound (90% purity, 0.39 g, 1.53 mmol, 52% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 5.62 – 5.57 (m, 1H), 2.29 – 2.24 (m, 3H); M / Z : 229 and 231 [M+H] + ESI + , RT = 0.45 (S1).

[0124] The intermediate compounds in Table 5 are synthesized using the corresponding starting materials / intermediates according to the general route 7 illustrated by example via intermediate 15.

[0125] Route 8 plan Intermediate 18: 2-bromo-5-chloro-[1,2,4]triazolo[1,5- a Pyrimidine To 2-bromo-4 H -[1,2,4]triazolo[1,5- a A stirred solution of pyrimidin-5-one (8.00 g, 29.8 mmol, intermediate 12) in acetonitrile (24 mL) was mixed with phosphorus oxychloride (16 mL, 0.167 mol), and the reaction was stirred in a pressure tube at 95 °C for 3 h. The reaction mixture was cooled to room temperature and poured onto ice. The precipitate was collected by filtration and washed with water to provide the title compound (6.20 g, 25.2 mmol, 85% yield) as a light brown powder. 1 H NMR (400 MHz, DMSO- d 6 ) 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 (S1).

[0126] The intermediate compounds in Table 6 are synthesized using the corresponding starting materials / intermediates according to the general route 8 illustrated by example via intermediate 18.

[0127] Route 9 plan Intermediate 21: 4-[5-(trifluoromethylsulfonyloxy)-[1,2,4]triazolo[1,5- a tert-butyl pyrimidin-2-yl]piperazine-1-carboxylate 4-(5-oxo-4-) in DCM (140 mL) at 0 °C H -[1,2,4]triazolo[1,5- a tert-butyl pyrimidin-2-yl)piperazine-1-carboxylate (7.00 g, 21.9 mmol, intermediate 16) was added to 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 provide the title compound (85% purity, 6.89 g, 12.9 mmol, 59% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.37 (d, J = 7.0Hz, 1H), 7.31 (d, J = 7.0 Hz, 1H), 3.57 – 3.52 (m, 4H), 3.48 – 3.42 (m, 4H), 1.42 (s, 9H); M / Z 397 [M+H] + ESI + , RT = 1.01 (S1).

[0128] The intermediate compounds in Table 7 are synthesized using the corresponding starting materials / intermediates according to the general route 9 illustrated by example via intermediate 21.

[0129] Route 10 plan Intermediate 24: 2-(2-bromo-[1,2,4]triazolo[1,5- a pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol To 2-bromo-5-chloro-[1,2,4]triazolo[1,5- a A degassed solution of pyrimidine (980 mg, 3.78 mmol, intermediate 18), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-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 to 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 room temperature and subjected to Celite... ® The mixture was filtered, and the filter cake was washed with EtOAc and water. The layers were separated, and the organic layer was concentrated under vacuum. The crude product was purified by silica gel chromatography (0-50% EtOAc / heptane), and the product was ground with methanol to provide the title compound (600 mg, 1.61 mmol, 43% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) 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).

[0130] The intermediate compounds in Table 8 are synthesized using the corresponding starting materials / intermediates according to the general route 10 illustrated by example via intermediate 24.

[0131] Route 11 plan Step 11.a: rac -1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazo[2,3- a ]Pyrazine-5-carboxylic acid tert-butyl ester Towards rac -3,3a,4,5,6,7-hexahydro-2 H -[1,2,5]thiadiazo[2,3- a A solution of pyrazine 1,1-dioxide hydrochloride (500 mg, 2.34 mmol) in DCM (22.5 mL) was reacted with triethylamine (0.98 mL, 7.02 mmol) and Boc₂O (562 mg, 2.57 mmol), and the reaction was stirred at room temperature for 16 h. Further Boc₂O (255 mg, 1.17 mmol) and triethylamine (0.49 mL, 3.51 mmol) were added, and the reaction was stirred at room temperature for 6 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO₃ and extracted with DCM. The combined organic layers were dried over MgSO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0–50% EtOAc / heptane) to provide the title compound (80% purity, 640 mg, 1.85 mmol, 79% yield) as a yellowish-brown solid. 1 H NMR (500 MHz, DMSO- d 6 ) 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).

[0132] Step 11.b: rac -2-Methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[2,3- a ]Pyrazine-5-carboxylic acid tert-butyl ester At 0 °C rac -1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazo[2,3- a A solution of pyrazine-5-carboxylate tert-butyl ester (630 mg, 2.27 mmol) in DMF (12.8 mL) was added to sodium hydride (182 mg, 4.54 mmol) and stirred at 0 °C for 15 min. Iodomethane (156 µL, 2.50 mmol) was added and the reaction was stirred for 1 h while the temperature was raised to room temperature. The reaction was cooled to 0 °C and quenched with water, and the aqueous layer was extracted with DCM. The combined organic layers were separated by a phase separator and concentrated under vacuum to provide the title compound (90% purity, 610 mg, 1.88 mmol, 83% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) 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).

[0133] Intermediate 29 (Step 11.c): rac -2-Methyl-3,3a,4,5,6,7-hexahydro-[1,2,5]thiadiazo[2,3- a Pyrazine 1,1-dioxide hydrochloride Towards rac -2-Methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[2,3- a A solution of tert-butyl pyrazine-5-carboxylate (90% purity, 610 mg, 1.88 mmol) in DCM (7 mL) was added to 4 M HCl in 1,4-dioxane (9.0 mL, 36.0 mmol), and the reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum to provide the title compound (465 mg, 1.94 mmol, 100% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) 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).

[0134] Route 12 plan Example 1: rac -2-[2-(1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3- a ]pyrazine-5-yl)-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol To 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-2 H -[1,2,5]thiadiazo[2,3- aA mixture of pyrazine 1,1-dioxide hydrochloride (326 mg, 1.53 mmol) was added. N -Ethyl- N -Isopropyl-propyl-2-amine (0.178 mL, 1.02 mmol) was added and stirred at 130 °C for 2 h. DMSO (0.40 mL) was then added, and the reaction was continued at 130 °C for 30 min. The reaction was cooled to room temperature and purified by preparative HPLC (M1) to provide the title compound (42.6 mg, 0.090 mmol, 35% yield) as a grayish-white solid. 1 H 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), 2.56 (s, 3H); M / Z : 470 [M+H] + ESI + , RT = 2.82 (S2).

[0135] The example compounds in Table 9 were synthesized using the corresponding starting materials / intermediates according to the general route 12 illustrated by example 1.

[0136] Route 13 Examples 7 and 8 rac -2-[2-(1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3- a ]pyrazine-5-yl)-[1,2,4]triazolo[1,5- a [Pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol (Example 1) was separated by preparative chiral HPLC to obtain the single enantiomers shown in Table 10.

[0137] The compounds in the further examples in Table 10 were obtained from chiral preparative HPLC using the corresponding starting materials / methods according to the general route 13 illustrated in Examples 7 and 8.

[0138] Route 14 Intermediate 30: (2 R )-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a tert-butyl pyrimidin-2-yl]-2-methyl-piperazine-1-carboxylate To 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 (2 R The mixture of tert-butyl 2-methylpiperazine-1-carboxylate (870 mg, 4.34 mmol) in DMSO (1.0 mL) was added N -Ethyl- N -Isopropyl-propyl-2-amine (0.670 mL, 3.84 mmol) was added, 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, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-100% EtOAc / heptane) to provide the title compound (357 mg, 0.718 mmol, 99% yield) as a yellow solid. 1 H 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); M / Z : 493 [M+H] + ESI + , RT = 1.02(S1).

[0139] The intermediate compounds in Table 11 are synthesized using the corresponding starting materials / intermediates according to the general route 14 illustrated by example via intermediate 30.

[0140] Route 15 Intermediate 32: 3-Methyl-2-(2-piperazin-1-yl-[1,2,4]triazolo[1,5- a 5-pyrimidinyl)-5-(trifluoromethyl)phenol hydrochloride 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] in DCM (50 mL) a tert-butyl pyrimidin-2-yl]piperazine-1-carboxylate (4.7 g, 8.84 mmol, intermediate 27) was added to 4 M HCl in 1,4-dioxane (20.3 mL, 81.1 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum to provide the title compound (74% purity, 4.90 g, 8.74 mmol, 99% yield) as a grayish-white solid. 1 H NMR (500 MHz, DMSO- d 6 ) 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 / Z 379, [M+H] + ESI + , RT = 0.58 (S1).

[0141] The intermediate compounds in Table 12 are synthesized using the corresponding starting materials / intermediates according to the general route 15 illustrated by example via intermediate 32.

[0142] Route 16 Example 15: 1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]acetone Triethylamine (0.034 mL, 0.241 mmol) was added to a mixture of acetic acid (0.02 mL, 0.29 mmol) and HATU (119 mg, 0.313 mmol) in DCM (2 mL), and the mixture was stirred for 10 min at room temperature. 3-Methyl-2-(2-piperazin-1-yl-[1,2,4]triazolo[1,5-) was added. a Pyrimidin-5-yl)-5-(trifluoromethyl)phenol hydrochloride (100.0 mg, 0.24 mmol, intermediate 32) was reacted with the mixture at room temperature for 2 h. Water was added to the reaction mixture and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (M1) to provide the title compound (46.2 mg, 0.10 mmol, 45% yield) as a grayish-white solid. 1 H NMR (500 MHz, DMSO- d 6 ) δ10.31 (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).

[0143] The example compounds in Table 13 were synthesized using the corresponding starting materials / intermediates according to the general route 16 illustrated by example 15.

[0144] Route 17 Examples 29 and 30 rac -[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]-(1-methylpyrrolidone-3-yl)methyl ketone (Example 25) was separated by preparative chiral HPLC to obtain the single enantiomers shown in Table 14.

[0145] Route 18 Example 31: [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]-(oxecyclobutane-3-yl)methyl ketone To 3-methyl-2-(2-piperazin-1-yl-[1,2,4]triazolo[1,5- a A solution of pyrimidin-5-yl)-5-(trifluoromethyl)phenol hydrochloride (100 mg, 0.24 mmol, intermediate 32) in acetonitrile (2 mL) was reacted with oxetane-3-carboxylic acid (30 mg, 0.294 mmol) and 1-methyl-1 H-Imidazole (0.08 mL, 1.0 mmol), then add N -[chloro(dimethylamino)methylene]- N 100 mg of methylammonium hexafluorophosphate (100 mg, 0.356 mmol) was added, and the resulting mixture was stirred at room temperature for 3.5 h. A 5 w / w% aqueous lithium chloride solution was added to the reaction mixture and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (M1) to provide the title compound (6.3 mg, 0.013 mmol, 5% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) 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); M / Z : 463 [M+H] + ESI + , RT = 2.67 (S2).

[0146] Route 19 Example 32: [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 R [Tetrahydrofuran-2-yl]methyl ketone At 0 °C, 3-methyl-2-(2-piperazin-1-yl-[1,2,4]triazolo[1,5- a Pyrimidin-5-yl)-5-(trifluoromethyl)phenol hydrochloride (100 mg, 0.241 mmol, intermediate 32), (2 RA mixture of tetrahydrofuran-2-carboxylic acid (35.0 mg, 0.301 mmol) and pyridine (0.059 mL, 0.729 mmol) in EtOAc (2.0 mL) was added to propanephosphonic anhydride (0.22 mL, 0.37 mmol), and the reaction was stirred for 18 h. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (M1) to provide the title compound (10.8 mg, 0.023 mmol, 9% yield) as a pale yellow solid. 1 H NMR (500 MHz, DMSO- d 6 ) 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 = 7.7, 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); M / Z : 477 [M+H] + ESI + ,RT = 2.85 (S2).

[0147] The example compounds in Table 15 were synthesized using the corresponding starting materials / intermediates according to the general route 19 illustrated by example 32.

[0148] Route 20 plan Example 34: 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a Methyl pyrimidin-2-yl]piperazine-1-carboxylate At 0 °C, 3-methyl-2-(2-piperazin-1-yl-[1,2,4]triazolo[1,5- aA solution of pyrimidin-5-yl)-5-(trifluoromethyl)phenol hydrochloride (100 mg, 0.241 mmol, intermediate 32) in DCM (2 mL) was reacted with triethylamine (0.067 mL, 0.482 mmol) and methyl chloroformate (22.8 mg, 0.241 mmol), and the reaction was allowed to rise to room temperature 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 under vacuum. The crude product was purified by preparative HPLC (M1) to provide the title compound (60.6 mg, 0.139 mmol, 58% yield) as a grayish-white solid. 1 H NMR (500 MHz, DMSO- d 6 ) 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).

[0149] The example compounds in Table 16 were synthesized using the corresponding starting materials / intermediates according to the general route 20 illustrated by example 34.

[0150] Route 21 plan Example 37: 2-[2-(4-ethylsulfonylpiperazin-1-yl)-[1,2,4]triazolo[1,5-] a ]pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol At 0 °C, 3-methyl-2-(2-piperazin-1-yl-[1,2,4]triazolo[1,5- aA solution of pyrimidin-5-yl)-5-(trifluoromethyl)phenol hydrochloride (100 mg, 0.241 mmol, intermediate 32) in DCM (2 mL) was reacted with triethylamine (67.2 µL, 0.482 mmol) and ethanesulfonyl chloride (27 µL, 0.289 mmol), and the reaction was allowed to rise to room temperature and stirred for 1 h. The reaction was cooled to 0 °C and quenched with water (5 mL), followed by the addition of a saturated aqueous solution of NaHCO3. The mixture was passed through a hydrophobic sieve and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (M1) to provide the title compound (38.8 mg, 0.0825 mmol, 34% yield) as a grayish-white solid. 1 H NMR (500 MHz, DMSO-) d 6 ) δ 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).

[0151] The example compounds in Table 17 were synthesized using the corresponding starting materials / intermediates according to the general route 21 illustrated by example 37.

[0152] Route 22 Intermediate 37: 1-[4-(5-chloro-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-2-yl]piperazin-1-yl]prop-1-one Propionic acid (53.8 mg, 0.727 mmol) and triethylamine (0.169 mL, 1.21 mmol) were added to a solution of 5-chloro-7-methyl-2-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine trifluoromethanesulfonic acid (350 mg, 0.606 mmol, intermediate 36) in DCM (7.0 mL), and the mixture was stirred at room temperature for 5 min. HATU (299 mg, 0.787 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture, and the mixture was extracted with DCM. The combined organic layers were passed through a phase separator and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-100% EtOAc / heptane, followed by 0-100% MeOH / DCM) to provide the title compound (55% purity, 320 mg, 0.570 mmol, 94% yield) as a grayish-white solid. 1 H NMR (500 MHz, DMSO- d 6 ) 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 (S1).

[0153] The intermediate compounds in Table 18 are synthesized using the corresponding starting materials / intermediates according to the general route 22 illustrated by example via intermediate 37.

[0154] Route 23 Intermediate 43: 5-chloro-2-(4-ethylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5- a Pyrimidine At 0 °C, 5-chloro-7-methyl-2-piperazin-1-yl-[1,2,4]triazolo[1,5- aA solution of pyrimidine trifluoromethanesulfonic acid (400 mg, 0.715 mmol, intermediate 36) in acetonitrile (10.0 mL) was reacted with triethylamine (0.399 mL, 2.86 mmol) and ethanesulfonyl chloride (0.081 mL, 0.858 mmol), and the reaction was heated to room temperature and stirred for 45 min. Water was added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layers were separated by a phase separator and concentrated under vacuum. The crude product was purified by silica gel chromatography (0–100% [3:1 ethyl acetate:ethanol] / heptane) to provide the title compound (83% purity, 297 mg, 0.714 mmol, 100% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.23 (d, J = 0.9Hz, 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 (S1).

[0155] The intermediate compounds in Table 19 are synthesized using the corresponding starting materials / intermediates according to the general route 23 illustrated by example via intermediate 43.

[0156] Route 24 Example 43: 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]prop-1-one Pd(dppf)Cl2·DCM (124 mg, 0.151 mmol) was added to a degassed solution of 1-[4-(5-chloro-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)piperazin-1-yl]prop-1-one (320 mg, 0.757 mmol, intermediate 37) (980 mg, 3.78 mmol), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-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), and the reaction was stirred at 100 °C for 2 h. Cool the reaction mixture to room temperature and pass it through Celite. ® The mixture was filtered, and 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, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-100% EtOAc / heptane) followed by preparative HPLC (M1) to provide the title compound (103 mg, 0.230 mmol, 30% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) 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); M / Z : 449 [M+H] + ESI + , RT =3.17 (S2).

[0157] The example compounds in Table 20 were synthesized using the corresponding starting materials / intermediates according to the general route 24 illustrated by example 43.

[0158] Route 25 Examples 73 and 74 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 (Example 64) was separated by preparative chiral HPLC to obtain the single enantiomers shown in Table 21.

[0159] Route 26 Examples 75 and 76 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-1-yl]methyl ketone (Example 71) was separated by preparative chiral HPLC to obtain the single enantiomers shown in Table 22.

[0160] Example 2: Biological assay The purpose of this embodiment is to evaluate the activity of the compounds synthesized in "Example 1: Chemical Synthesis".

[0161] THP1 IL-1β Release Assay (HTRF): The compound of example was tested in LPS-pretreated THP1 cells to evaluate its pharmacological ability to inhibit nigrain-activated NLRP3 and the release of IL-1β into the supernatant.

[0162] Day 1: THP1 cells were seeded at a density of 18,000 cells per well in 384-well poly-L-lysine-coated plates containing RPMI 1640 medium (glutamine and phenol red-free), 10% FBS, 2 mM L-glutamine, 50 µM 2-mercaptoethanol and 200 ng / ml PMA, and incubated at 37°C and 5% CO2 for 24 hours.

[0163] Day 2: After 24 hours, the culture medium was replaced with growth medium containing RPMI 1640 medium (without glutamine and phenol red), 10% FBS, 2 mM L-glutamine, and 50 µM 2-mercaptoethanol, and incubated at 37°C and 5% CO2 for 24 hours.

[0164] Day 3: The compounds of the examples were serially diluted in DMSO, spotted onto intermediate plates, and pre-diluted with serum-free growth medium (plate 1) or serum-free growth medium containing 50 µM Nigerian mycin (plate 2).

[0165] In addition to the test area for the compounds in the examples, the plate also contains multiple high controls (0.2% DMSO, 1 µg / ml LPS, 50 µM Nigerian mycin final concentration) and low controls (10x IC50). 50 The reference inhibitor MCC950 (sodium salt), 1 µg / ml LPS, 50 µM Nigerian styracin final concentration, was used for the purpose of standardization of determination.

[0166] THP1 cells were washed with serum-free growth medium, and 10 µl of the compound from intermediate plate 1 was added to 40 µl of serum-free medium in the assay plate. After incubation at 37°C and 5% CO2 for 30 min, LPS from the serum-free growth medium was added to a final concentration of 1 µg / ml for pretreatment, followed by incubation at 37°C and 5% CO2 for 2.5 h.

[0167] After pretreatment, cells were washed with serum-free growth medium containing 50 µM nigrain, and 10 µl of the example compound from intermediate plate 2 and 40 µl of serum-free medium containing nigrain were added to the cells for activation. The cells were incubated at 37°C and 5% CO2 for 2 hours. Finally, the supernatant was collected and stored at -20°C.

[0168] Day 4: IL-1β in the supernatant was quantified by HTRF (homogeneous time-resolved fluorescence) analysis using the Cisbio Human IL-1β Kit. In short, 8 µl of supernatant and 2 µl of premixed anti-IL1β-Crypta antibody and anti-IL1β-XL antibody were added to a 384-well plate (Greiner BioOne), incubated at room temperature for 24 hours, and measured using a Pherastar FSX reader (BMG LabTech) at excitation wavelength of 337 nm (donor) and emission wavelengths of 620 / 665 nm (acceptor).

[0169] The HTRF ratio between donor and recipient signals was calculated and normalized with high and low controls to calculate IC50. 50 Value (nM). NLRP3 inhibitors reduce LPS / nigrain-induced IL-1β release, which manifests as a decrease in the HTRF ratio.

[0170] Table 23 shows the THP1 IL-1β release of the tested example compounds.

[0171] Equivalent scheme This technology is not limited to the specific embodiments described in this application, which are intended only as illustrative of various aspects of the technology. Many modifications and variations can be made to this technology without departing from its spirit and scope, as will be apparent to those skilled in the art. In addition to those listed herein, functionally equivalent methods and instruments within the scope of this technology will also be apparent to those skilled in the art based on the foregoing description. Such modifications and variations are intended to fall within the scope of this technology. It should be understood that this technology is not limited to specific methods, reagents, compounds, compositions, or biological systems, which can, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be restrictive.

[0172] Furthermore, when features or aspects of this disclosure are described in accordance with the Markush group, those skilled in the art will recognize that this disclosure is therefore also described in accordance with any single member or subgroup of members of the Markush group.

[0173] By incorporating references All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent, patent application, or information item is expressly and individually indicated to be incorporated by reference. In the event of any conflict between a publication, patent, patent application, or information item incorporated by reference and the disclosure contained in this specification, the specification shall prevail, and / or the specification shall take precedence over any such conflicting material.

Claims

1. Compounds of formula (I) (I)， Or its pharmaceutically acceptable salt or stereoisomer, wherein: R 1 It is CN, CH3, CF3, CHF2, OCH3, OCHF2, OCF3, or a halogen; R 2 It is H, CH3, CH2CH3, CF3, CHF2, Cl, CN, or cyclopropyl, and R 3 It is H or CH3, provided that R 2 and R 3 Not all of them are H; R 4 It is H, CH3, CH2CH3, CF3, CHF2, OCH3, Cl, F, C 3-5 Cycloalkyl or unsubstituted saturated 4-6 membered heterocyclic groups, wherein C 3-5 The cycloalkyl group is optionally substituted with one or more F; or R 3 and R 4 Connect to form -CH2-CH2-CH2- or -CH2-O-CH2-; -X 1 -is-CH(R) 5b - or –C(R) 5b1 (R) 5c )CH2-*, where the asterisk-marked bond is connected to nitrogen in formula (I); -X 2 -is-CH(R) 5d - or –CH(R) 5d1 )CH2-*, where the asterisk-marked bond is connected to nitrogen in formula (I); R 5 R 5a R 5b1 R 5c and R 5d1 Independently selected from H, F, and R 5e ; R 5b and R 5d Independently selected from H and R 5e ; Each R 5e Independently selected from cyclopropyl and C 1-4 Alkyl, wherein R 5e Optionally substituted by one or more substituents independently selected from OH and F; X 3 It is -S(=O)2-*, -C(=O)-*, -C(=O)O-*, -C(=O)N(R) 6a )-*、-S(=O)2-N(R 6a )-*、-S(=O)(R 6a )=N-* or -S(=O)-N(R 6a )-*, where the key marked with an asterisk is related to R 6 connect; R 6a It is H or CH3; When X 3 It is -S(=O)2-*, -C(=O)O-*, -C(=O)N(R) 6a )-*、-S(=O)2-N(R 6a -* or -S(=O)-N(R) 6a When )-*, R 6 Selected as C 1-4 Alkyl, CHF2, CF3, T 1 NHCH3 or N(CH3)2, where C 1-4 The alkyl group is optionally replaced by OCH3 or N(CH3)2; or When X 3 When it is -C(=O)-*, R 6 Selected as C 1-4 Alkyl, CHF2, CF3, OC 1-4 Alkyl, T 1 OT 1 NHCH3 or N(CH3)2, where C 1-4 The alkyl group is optionally replaced by OCH3 or N(CH3)2; or When X 3 It is -S(=O)(R) 6a When )=N-*, R 6 Selected as C 1-4 Alkyl, wherein C 1-4 The alkyl group is optionally substituted with one or more F; or R 6 and R 5d Linked to form a divalent group, wherein the divalent group is selected as CH2 or CH2-CH2; and T 1 It is cyclopropyl, cyclobutyl, aziridine, pyrrolidinyl, oxacyclobutyl or tetrahydrofuranyl, wherein T 1 Optionally substituted with one or more substituents, which may be the same or different and are selected from F, CH3, OCH3 and OH.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 It is CF3, CHF2, F, Cl, OCH3, OCHF2, CH3 or CN, preferably R. 1 It is CN, CH3, CF3, OCH3, F or Cl, or even more preferably CF3.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 It is CH3 and R 3 It is H.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 It is H, CH3 or CH2CH3, preferably CH3.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 R 2 and R 3 The one chosen to be given equation (Ia) (It)。 6. The compound of claim 5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 The choice is made to give either equation (Ib) or (Ib1). (One) (Ib1)。 7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 and R 5a It is H.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 1 It is -CH(R) 5b )-.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5b It is H or CH3, preferably H.

10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 2 It is -CH(R) 5d )-.

11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5d Is it H or R? 6 Connection, preferably H.

12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 R 5a X 1 and X 2 Selected to give formula (Ic) (Ic)。 13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5b R 5d X 3 and R 6 The formula chosen to give a formula selected from (Id1) to (Id8), preferably (Id3) or (Id6). 。 14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 It is CH3, CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, N-methylpyrrolyl, oxecyclobutyl, azircyclobutyl, N,N-dimethylaminomethyl, methoxymethyl or methoxyethyl, preferably CH2CH3, CH(CH3)2 or cyclopropyl.

15. The compound according to any one of claims 1-14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from: rac -2-[2-(1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3- a ]pyrazine-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-3a,4,6,7-tetrahydro-3-] H -[1,2,5]thiadiazo[2,3- a ]pyrazine-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]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-] a ]Pyrazin-6-one; 2-[2-(4-isopropylsulfonylpiperazin-1-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-3a,4,6,7-tetrahydro-3-] H -[1,2,5]thiadiazo[2,3- a ]pyrazine-5-yl)-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 1-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]acetone; 3-Methyl-2-[2-[ rel -(3 aR )-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 -(3 aS )-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 -(3 aR )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[2,3- a ]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[ rel -(3 aS )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[2,3- a ]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; rel -(8 aS )-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-] a ]Pyrazin-6-one; rel -(8 aR )-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-] a ]Pyrazin-6-one; 3-Methyl-2-[7-Methyl-2-[ rel -(3 aR )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[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 -(3 aS )-2-methyl-1,1-dioxo-3a,4,6,7-tetrahydro-3 H -[1,2,5]thiadiazo[2,3- a ]pyrazin-5-yl]-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]acetone; 1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]prop-1-one; Cyclopropyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; 1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]-2-methoxy-ethyl ketone; 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-prop-1-one; 2-(dimethylamino)-1-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]acetone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(3 S [Tetrahydrofuran-3-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 S [Tetrahydrofuran-2-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 S 1-Methylpyrrolidone-2-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 R 1-Methylpyrrolidone-2-yl]methyl ketone; rac -[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]-(1-methylpyrrolidone-3-yl)methyl ketone; [(2 R )-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a ]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]-[(3 R [Tetrahydrofuran-3-yl]methyl ketone; [(2 S )-4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a ]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]-[(3 R [Tetrahydrofuran-3-yl]methyl ketone; 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-prop-1-one; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[ rel -(3 R 1-Methylpyrrolidone-3-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[ rel -(3 S 1-Methylpyrrolidone-3-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a [Pyrimidin-2-yl]piperazin-1-yl]-(oxetane-3-yl)methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(2 R [Tetrahydrofuran-2-yl]methyl ketone; [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5-] a ]pyrimidin-2-yl]piperazin-1-yl]-[(3 R [Tetrahydrofuran-3-yl]methyl ketone; 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-[1,2,4]triazolo[1,5- a Methyl pyrimidin-2-yl]piperazine-1-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-1-yl)-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(4-isopropylsulfonylpiperazin-1-yl)-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[4-(azacyclobutane-1-ylsulfonyl)piperazin-1-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-(azacyclobutane-1-ylsulfonyl)piperazin-1-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]prop-1-one; 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a Methyl pyrimidin-2-yl]piperazine-1-carboxylate; 4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5- a Ethyl pyrimidin-2-yl]piperazine-1-carboxylate; Cyclopropyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; Cyclobutyl-[4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; 2-[2-(4-ethylsulfonylpiperazin-1-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]prop-1-one; Cyclopropyl-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]methyl ketone; 2-[2-(4-ethylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-3,5-dimethylphenol; 1-[4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5- a [Pyrimidin-2-yl]piperazin-1-yl]prop-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-1-yl]methyl ketone; 2-[2-(4-ethylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-5-methoxy-3-methylphenol; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-5-methoxy-3-methylphenol; 4-[5-[4-(difluoromethyl)-2-hydroxy-6-methyl-phenyl]-7-methyl-[1,2,4]triazolo[1,5- a Methyl pyrimidin-2-yl]piperazine-1-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]prop-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-1-yl]methyl ketone; 5-(difluoromethyl)-2-[2-(4-ethylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl]-3-methylphenol; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-] a [Pyrimidin-5-yl]-5-(difluoromethyl)-3-methylphenol; 3-Methyl-2-[7-methyl-2-[4-(oxecyclobutane-3-ylsulfonyl)piperazin-1-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.

16. The compound according to any one of claims 1-14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from: 4-[5-(2-hydroxy-4-methoxy-6-methyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazine-1-carboxylic acid methyl ester; (1-Fluorocyclopropyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-1-yl]methyl ketone; (1-Fluorocyclobutyl)-[4-[5-(2-hydroxy-4,6-dimethyl-phenyl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-1-yl]methyl ketone; (1-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]methyl ketone; (1-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]methyl ketone; (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]methyl ketone; 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-1-yl]methyl ketone; 2-[2-(4-cyclobutylsulfonylpiperazin-1-yl)-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-fluoro-3-methylphenol; 3-Methyl-2-[7-methyl-2-[4-[rel-(3 S [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[7-methyl-2-[4-[rel-(3 R [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-1-yl]-[rel-(1 S [2,2-difluorocyclopropyl] methyl ketone; and [4-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]piperazin-1-yl]-[rel-(1 R [2,2-difluorocyclopropyl] methyl ketone.

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

18. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt or stereoisomer thereof, used as a medicine.

19. The compound of any one of claims 1-16 or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 17, for use in methods of treating and / or preventing one or more diseases, symptoms or conditions associated with NLRP3.

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

21. The compound or composition used according to claim 20, wherein the one or more diseases, symptoms or conditions are selected from cold inflammatory-associated periodic syndrome (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal paroxysmal multisystem autoinflammatory syndrome (NOMID).

22. The compound or composition used according to claim 20, wherein the disease, symptom, or condition is selected from (a) chronic inflammatory diseases; (b) metabolic diseases; (c) neurological diseases; (d) diseases associated with NLRP3 genetic autosomal dominant mutations that promote NLRP3 inflammasomes; (e) asthma and allergic airway inflammation; (f) hypertension; (g) myocardial infarction; (h) excessive inflammation following influenza and / or severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2); (i) graft-versus-host disease; (j) silicosis; (k) myelodysplastic syndrome; and (l) contact hypersensitivity reactions and joint inflammation triggered by chikungunya virus.

23. The compound or composition used according to claim 22, wherein: (a) The chronic inflammatory diseases mentioned are selected from gout, rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis; (b) The metabolic disease is selected from atherosclerosis, diabetes, metabolic syndrome, obesity, hepatic steatosis, non-alcoholic steatohepatitis (NASH), and liver fibrosis; or (c) The neurological diseases mentioned are selected from Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), prions, traumatic brain injury (TBI), and stroke.

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