NLRP3 modulators

Abstract

The present application relates to compounds of Formula (I), or isotopically-labeled compounds thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , X 1 , X 2 have the meanings as indicated in the claims and specification. The present application also relates to pharmaceutical compositions comprising said compounds, their use as medicaments and in methods for the treatment and prevention of one or more diseases or conditions associated with NLRP3.

Description

Background of the Invention NLRP3 is a member of the NLR protein family, which contains a nucleotide-binding domain (NBD) and a leucine-rich repeat sequence (LRR) that mediates innate inflammatory processes following infection or tissue damage. Upon activation, it forms an inflammasome complex with ASC and cysteine-aspartic protease-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 cold pyrrolizine-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, cysteine-aspartate protease-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), endogenous molecule-mediated aseptic inflammation (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 proteins, resulting in the formation of the NLRP3 complex, which recruits ASC (an adaptor protein containing CARD, known as apoptosis-associated speckle-like protein). ASC binds to cysteine ​​aspartate proteasome-1, which is activated within the multiprotein inflammasome complex (also known as the ASC speckle). Active cysteine ​​aspartate proteasome-1 cleaves the pro-inflammatory cytokines IL-1β and IL-18, as well as GSDMD (apoptosis-associated protein D), forming pores within the membrane that allow the release of mature IL-1β and IL-18, potentially 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 leads to inflammatory pathology (Mangan et al., Nature Reviews Drug Discovery, 2018, Vol.17, 588-606; Swanson et al., Nature Review Immunology, 2019, Vol 19., 477–489).

[0005] The pathological consequence of NLRP3 activation has been observed in patients carrying inherited autosomal dominant NLRP3 mutations that promote the activation of the NLRP3 inflammasome. Patients with these gain-of-function mutations suffer from a rare systemic autoinflammatory syndrome called cold pyridine-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-onset 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. This includes 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, 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).

[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 relative to 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 cold pyridine-associated periodic syndrome (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem autoinflammatory syndrome (NOMID); (ii) chronic inflammatory diseases (e.g., gout, rheumatoid arthritis, inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis); and (iii) metabolic diseases (e.g., atherosclerosis, diabetes, metabolic disorders). (iv) Syndromes, hepatic steatosis, non-alcoholic 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.

[0011] This invention provides compounds of formula (I) or isotopically labeled compounds thereof. This invention also provides pharmaceutical compositions comprising said compounds. This invention further provides the use of compounds of formula (I) or isotopically labeled compounds thereof as pharmaceuticals, and methods for treating and preventing one or more diseases or conditions associated with NLRP3.

[0012] 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.

[0014] 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 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.

[0015] This invention provides compounds of the invention in free or pharmaceutically acceptable salt or solvate, hydrate, tautomer, or stereoisomer forms. These compounds can be used to treat the diseases or conditions mentioned herein. The same applies to the pharmaceutical compositions of the invention.

[0016] Therefore, the present invention provides compounds of formula (I): Or its isotope-labeled compounds, wherein: R 1 It can be CN, CH3, CF3, CHF2, OCH3, OCHF2, OCF3, or a halogen; R 2It is H, CH3, CH2CH3, CF3, CHF2, Cl, CN or cyclopropyl, and R 3 It can be H or CH3, provided that R 2 and R 3 Not all of them are H; R 4 For H, C 1-4 Alkyl, C 3-5 Cycloalkyl, unsubstituted saturated 4- to 6-membered heterocyclic group, OCH3, Cl or F, wherein C 1-4 Alkyl and C 3-5 The cycloalkyl group is optionally substituted with one or more F; or R 3 and R 4 The connection forms -CH2-CH2-CH2- or -CH2-O-CH2-; -X 1 -for-C(R) 5b (R) 5c - or -C(R) 5b (R) 5c CH2-*, where the asterisked bonds are attached to oxygen in formula (I); -X 2 -for-CH(R) 5d - or -CH(R) 5d CH2-*, where the asterisked bonds are attached to oxygen in formula (I); R 5 R 5a R 5b R 5c and R 5d Independently selected from H, F, 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; or R 5 and R 5b They connect, together with the carbon atoms they are attached to, to form a ring T. 1 ;or R 5b and R 5c Linked together, together with the carbon atoms to which they are linked, to form a cyclopropyl ring, wherein the cyclopropyl ring is optionally substituted with one or more F atoms; or R 5 and R 5a The linkage forms a divalent group -CH2-, -CH2CH2-, or -CH2OCH2-, where each hydrogen can be independently replaced by F; or R 5b and R 5d The linkage forms a divalent group -CH2-, -CH2CH2-, or -CH2OCH2-, where each hydrogen can be independently replaced by F; or R 5b and R 5a The linkage forms a divalent group -CH2-, where each hydrogen can be independently replaced by F; and T 1 It is cyclopropyl or N-methylpyrrolidine, wherein T 1 Optionally replaced by one or more Fs.

[0017] 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.

[0018] 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.

[0019] 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 10. 50 value.

[0020] 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.

[0021] 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”).

[0022] 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.

[0023] 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.

[0024] "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.

[0025] "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.

[0026] "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.

[0027] “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.

[0028] “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.

[0029] “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.

[0030] “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.

[0031] “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.

[0032] "C5 cycloalkylene" refers to a divalent cycloalkylene ring with five carbon atoms, namely a divalent cyclopentyl ring.

[0033] "C5 cycloene group" refers to a divalent cycloene group, namely divalent cyclopentene or cyclopentadiene.

[0034] “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, octahydropentalen, 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.

[0035] "Halogen" refers to fluorine, chlorine, bromine, or iodine. Fluorine or chlorine are generally preferred halogens.

[0036] "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.

[0037] 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.

[0038] "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".

[0039] "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.

[0040] "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.

[0041] "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.

[0042] "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.

[0043] "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".

[0044] "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".

[0045] "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.

[0046] II. Exemplary Compounds of this Disclosure Exemplary compounds of formula (I) or their isotopically labeled compounds 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) or their isotopically labeled compounds, this invention also includes all tautomers and stereoisomers thereof and mixtures thereof in all proportions, as well as pharmaceutically acceptable salts thereof.

[0047] 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.

[0048] In one aspect of this disclosure, the present invention provides compounds of formula (I'): in: R 1 It can be 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 can be H or CH3, provided that R 2 and R 3 Not all of them are H; R 4 For H, C 1-4 Alkyl, C 3-5 Cycloalkyl, unsubstituted saturated 4- to 6-membered heterocyclic group, OCH3, Cl or F, wherein C1-4 Alkyl and C 3-5 The cycloalkyl group is optionally substituted with one or more F; or R 3 and R 4 The connection forms -CH2-CH2-CH2- or -CH2-O-CH2-; -X 1 -for-C(R) 5b (R) 5c - or -C(R) 5b (R) 5c CH2-*, where the asterisked bonds are attached to oxygen in formula (I); -X 2 -for-CH(R) 5d - or -CH(R) 5d CH2-*, where the asterisked bonds are attached to oxygen in formula (I); R 5 R 5a R 5b R 5c and R 5d Independently selected from H, F, and R 5e ;and 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.

[0049] On the other hand, R 1 It can be CF3, CHF2, F, Cl, OCH3, OCHF2, CH3, or CN, more preferably R. 1 The form is CN, CH3, CF3, OCH3, F, or Cl, with CF3 being more preferred.

[0050] On the other hand, R 2 It could be CH3.

[0051] In one aspect of this disclosure, R is selected. 3 and R 4 To obtain the formulas selected from (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig): .

[0052] In another aspect of this disclosure, the compound has the formula (Ib), (Ic) or (If), more preferably (Ib).

[0053] On the other hand, choosing R 2 R 3 and R 4 To obtain the formulas selected from (Ia'), (Ib'), (Ic'), (Id'), (Ie'), (If'), and (Ig'): .

[0054] In a further aspect: (i)-X 1 -for-C(R) 5b (R) 5c (ii)-X 2 -for-CH(R) 5d )-;(iii)R 5 (iv) R 5a H; (v)R 5b For H or CH3; (vi)R 5c and R 5b For H; or (vii) any combination thereof.

[0055] In one respect, choose R 5 R 5a X 1 and X 2 To obtain the formulas selected from (Ih), (Ii), (Ij), (Ik), and (Il): .

[0056] The purpose of this invention is to provide compounds in which some or all of the aforementioned groups have a preferred or more preferred meaning.

[0057] The exemplary specific compounds of this invention are selected from: 3-Methyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol; 3-Hydroxy-5-methyl-4-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzylnitrile; 5-Methoxy-3-methyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol; 5-Chloro-3-methyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol; 3,5-Dimethyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol; 5-Fluoro-3-methyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol; 3-Methyl-2-(7-methyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-methyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[(2) R [-2-methylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[(2) S [-2-methylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 2-(7-Ethyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(7-Cyclopropyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(11-morpholino-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)-5-(trifluoromethyl)phenol; 5-(difluoromethyl)-3-methyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol; 3-Methyl-2-[2-[(3 S [-3-methylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[(3 R [-3-methylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 5-Methoxy-3-methyl-2-(11-morpholino-4-oxa-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)phenol; 3-Methyl-2-(11-morpholino-4-oxa-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)-5-(trifluoromethyl)phenol and 2-(6-deuter-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol.

[0058] Other exemplary specific compounds of the present invention are selected from: 3,5-Dimethyl-2-(11-morpholino-4-oxa-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)phenol; 2-(11-morpholino-4-oxa-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)-5-(trifluoromethyl)phenol; 5-Methyl-2-(11-morpholino-4-oxa-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)phenol; 2-(7-methoxy-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-(1,4-oxazacycloheptane-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 2-[2-(2,2-dimethylmorpholin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 2-[2-(2-cyclopropylmorpholin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 2-[2-(2-ethylmorpholin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 3,5-Dimethyl-2-[2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol 2-[2-[(3 S )-3-(hydroxymethyl)morpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 2-[2-[(3 R [-3-isopropylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 3,5-Dimethyl-2-[2-[(1 S 4 S )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 2-[2-[(3 R )-3-(hydroxymethyl)morpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 3,5-Dimethyl-2-[2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 3,5-Dimethyl-2-[2-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 3,5-Dimethyl-2-[2-[2-(trifluoromethyl)morpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 2-[2-[(3 S [-3-isopropylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 3,5-Dimethyl-2-[2-(2,2,6-trimethylmorpholin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 3,5-Dimethyl-2-[2-[(1 R 4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 2-[2-[(2 R 6 R [-2,6-dimethylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 3,5-Dimethyl-2-[2-(4-oxa-7-azaspiro[2.5]oct-7-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 2-(6-Deuter-7-methyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol; and 3-Methyl-2-[2-morpholino-7-(oxecyclobutane-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol.

[0059] Therefore, in one aspect, exemplary specific compounds of the present invention are compounds 1-16, 21, 22, and 42 of the examples. In another aspect, exemplary specific compounds of the present invention are compounds 17-20, 23, 24, 26-39, 41, 43, and 44 of the examples.

[0060] 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.

[0061] 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.

[0062] 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 Compounds of the present invention containing hydrogen in the form of H / deuterium. For example, compound 2-(6-deuter-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol. Solvates and hydrates of compounds of formula (I) are also within the scope of the present invention.

[0063] 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.

[0064] 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.

[0065] III. Pharmaceutical Composition As shown in the following examples, the compounds of the present invention are suitable for regulating NLRP3.

[0066] 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.

[0067] 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 or preventing one or more of the conditions or diseases described herein.

[0068] 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.

[0069] 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.

[0070] "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.

[0071] 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.

[0072] The active ingredient may be contained in one or more different pharmaceutical compositions (a combination of pharmaceutical compositions).

[0073] 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).

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] Another aspect of the invention is a method for treating, controlling, delaying, or preventing one or more NLRP3-related diseases 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.

[0079] Another aspect of the invention is a method for treating, controlling, delaying, or preventing one or more diseases 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.

[0080] 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 cold pyridine-associated periodic syndrome (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem autoinflammatory syndrome (NOMID); (ii) chronic inflammatory diseases (e.g., gout, rheumatoid arthritis, inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis); and (iii) metabolic diseases (e.g., atherosclerosis, diabetes, metabolic syndrome, etc.). (iv) Hepatic steatosis, nonalcoholic steatohepatitis (NASH), and liver fibrosis; (v) Neurological disorders such as 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 inherited 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.

[0081] 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.

[0082] 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

[0083] Example 1: Chemical Synthesis The purpose of this embodiment is to provide an exemplary chemical synthesis method for the compounds of the present invention.

[0084] Experimental Procedure: Use the following abbreviations and acronyms: The LCMS analysis conditions are as follows: System 1 (S1): Acidic IPC method: Waters UPLC TM BEH TM Analysis was performed on a C18 column (2.1 mm × 50 mm, 1.7 µm; temperature: 40 °C) in a reverse-phase system (MET / uPLC / 1704) using UHPLC-MS. The injection volume was 1 µL, the flow rate was 0.9 mL / min, and 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.

[0085] System 2 (S2): Acidic final method: Reversed-phase analysis was performed using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 µm; temperature: 40 °C) (MET / uPLC / AB101) UHPLC-MS. The injection volume was 1 µL, the flow rate was 0.6 mL / min, and 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 at the time of 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.

[0086] System 3 (S3): Alkaline IPC method: Reversed-phase analysis was performed using a Phenomenex Kinetex® Evo C18 column (2.1 mm × 50 mm, 1.7 µm; temperature 40°C) (MET / uPLC / 2301) (M15) UHPLC-MS. The injection volume was 1 µL, the flow rate was 1.0 mL / min, and the gradient was: 1 – 100% B for 1.10 min, followed by 100% B for 0.25 min, where A = water + 0.2% ammonium hydroxide and B = ACN. A second gradient of 100 – 1% B was then applied for 0.05 min and held for 0.40 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.

[0087] System 4 (S4): Neutral IPC Method Mass spectrometry data were acquired using a Poroshell 120 CS-C18 column (2.1 mm x 50 mm, 2.7 µm column; temperature: 50 °C) with simultaneous DAD and MS detection on an Agilent 1260-6120 coupled system. Isocratic 99.5% A and 0.5% B were held for 0.1 min (A = 10 mM ammonium acetate / H₂O, B = ACN), followed by a gradient of 0.5–100% B for 1.6 min, then 100% B for 0.3 min. A second gradient of 100–0.5% B was then applied for 0.1 min at a flow rate of 1 mL / min. Mass spectrometry data were recorded using a full scan, with simultaneous positive or negative ESI ionization. Data were processed using Agilent's OpenLab software.

[0088] System 5 (S5): Neutral Final Method: Mass spectrometry data were acquired using a Poroshell 120 EC-C18 column (2.1 mm x 50 mm, 1.9 µm column; temperature: 50 °C) with simultaneous DAD and MS detection on an Agilent 1260-6490 coupled system. Isocratic 99% A and 1% B were held for 0.25 min (A = 10 mM ammonium acetate / H₂O, 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 using a full scan and subjected to positive or negative ESI ionization (Agilent JetSteam). Data were integrated and reported using Agilent's MassHunter software.

[0089] System 6 (S6): Acidic late elution IPC method: Waters UPLC TM CORTECS TMReversed-phase analysis was performed on a C8 column (2.1 mm × 50 mm, 1.6 µm; temperature: 40 °C) (MET / uPLC / 1906) (M12) UHPLC-MS. The injection volume was 1 µL, the flow rate was 0.9 mL / min, and the gradient was: 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.

[0090] System 7 (S7): Acidic IPC Method: Mass spectrometry data were acquired using a Poroshell 120 EC-C18 column (2.1 mm x 50 mm, 1.9 µm column; temperature: 50°C) with simultaneous DAD and MS detection on an Agilent 1260-6120 coupled system. Isocratic 99% A and 1% B were incubated 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 using a full scan, with simultaneous positive or negative ESI ionization. Data were processed using Agilent's OpenLab software.

[0091] System 8 (S8): Acidic final method: At XBridge TM Data were acquired on a C18 column (2.1 mm × 50 mm, 1.7 µm; temperature: 50 °C). Mobile phase A: ACN / water (5:95), containing 0.05% TFA or 10 mM acetic acid; Mobile phase B: ACN / water (95:5), containing 0.05% TFA or 10 mM acetic acid. Gradient: 0–100% B (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 + / -).

[0092] The purification method is as follows: purification is performed by silica gel chromatography on a Biotage Isolera system using a suitable Sfär Duo column or on a Teledyne ISCO CombiFlash system using a suitable RediSep column.

[0093] NMR conditions: Unless otherwise stated, 1 ¹H NMR spectra were recorded 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 transform spectrometer. Data were processed using MestReNova software. Chemical shift δ is expressed in parts per million (ppm) with reference to the residual solvent peak. The following abbreviations are used to denote multiplicity and general attribution: s (single peak), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (septet), m (multiplet), pent (quintet), td (triplet of doublets), qd (quartet of doublets), app. (apparent), and br. (broad peak). The coupling constant J is referenced to the nearest 0.1 Hz.

[0094] General Synthesis: Unless otherwise stated, all compounds were synthesized with a purity greater than 95%.

[0095] Route 1 plan: Intermediate 1: 3-Methyl-5-(trifluoromethyl)phenol 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 (650 mL) and water (122 mL) was added to the 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 (50 mL). The reaction mixture was stirred at 90°C for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through glass fiber filter paper. The filtrate was concentrated under vacuum, dissolved in ethyl acetate, and washed with 1M HCl. After phase separation, the organic layer was concentrated under vacuum. The crude product was then stirred in 5M NaOH aqueous solution for 15 minutes. Next, heptane was added, and the two-phase mixture was stirred for 5 minutes. After phase separation, the alkaline aqueous layer was cooled to 0°C and acidified with 5M 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 with magnesium sulfate, and concentrated under vacuum to give 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). MS (ESI); M / Z :221 [MH] - ESI - , RT = 0.88 (S1).

[0096] Route 2: Intermediate 2: 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. The reaction was stirred at room temperature for 16 h. The reaction was diluted with dichloromethane and slowly quenched with a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane. The combined organic phases were dried using a phase separator and concentrated under vacuum. The crude product was purified by silica gel chromatography (0–100% ethyl acetate / heptane) to give the title compound (1.76 g, 10.5 mmol, 71% yield) as a yellow oil. 1 H NMR (500 MHz, CDCl3) δ 6.90 (s,1H), 6.80 (s, 1H), 6.79 – 6.75 (m, 1H),6.56 (t, J = 56.6 Hz, 1H), 2.36 (s, 3H); no mass ions were observed.

[0097] Route 3: Intermediate 3: 3-hydroxy-4-iodo-5-methylbenzaldehyde Hydrogen peroxide (50%, in water) (50%, 999 mg, 14.7 mmol) and molecular weight iodine (1.86 g, 7.34 mmol) were added to a stirred solution of 3-hydroxy-5-methylbenzaldehyde (1.00 g, 7.34 mmol) in water (20 mL) at room temperature under a nitrogen atmosphere. The reaction was stirred for 24 h. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0–30% ethyl acetate / heptane) to give the title compound (83% purity, 1.31 g, 4.15 mmol, 56% yield) as a white solid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 10.88 (s, 1H), 9.87 (s, 1H), 7.31 (dd, J =1.9, 0.8 Hz, 1H), 7.12 (d J =1.8 Hz, 1H), 2.46 (s, 3H); M / Z : 261 [MH] - ESI - , RT = 0.81 (S1).

[0098] The intermediate compounds in Table 1 were synthesized using the corresponding starting materials / intermediates according to the general route 3 illustrated by intermediate 3.

[0099] Route 4: Intermediate 5: 3-hydroxy-4-iodo-5-methylbenzylnitrile To a solution of 3-hydroxy-4-iodo-5-methylbenzaldehyde (83% purity, 1.31 g, 4.15 mmol, intermediate 3) in toluene (25 mL), (aminooxy)(diphenyl)phosphine oxide (1.11 g, 4.77 mmol) was added, and the mixture was stirred at room temperature for 3 hours, followed by stirring overnight at 85 °C. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography (0–30% ethyl acetate / heptane) to give the title compound (92% purity, 743 mg, 2.64 mmol, 64% yield) as a light pink solid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.22 (s, 1H), 7.22 (dd, J = 2.0, 0.8 Hz, 1H), 6.96 (d, J = 1.9 Hz, 1H), 2.40 (s, 3H); M / Z 258 [MH] - ESI - , RT = 0.85 (S1).

[0100] Route 5: Step 5.a: 2-Iodo-3-methyl-5-(trifluoromethyl)phenol 3-Methyl-5-(trifluoromethyl)phenol (55.0 g, 306.2 mmol, intermediate 1) was dissolved in toluene (500 mL) and cooled to 0°C under a nitrogen atmosphere. Sodium hydride (60% mineral oil dispersion, 24.5 g, 612.3 mmol) was added dropwise over 45 minutes. Next, a solution of iodine (77.7 g, 306.2 mmol) in toluene (500 mL) was added dropwise over 8 hours at 0°C. After stirring at room temperature, the reaction was quenched to pH 7 with 6M hydrochloric acid aqueous solution at 0°C. The mixture was partially concentrated under vacuum and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / heptane, then 0-20% MeOH / ethyl acetate) to give 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); MS (ESI); M / Z 301 [MH] - ESI - , RT = 1.00 (S2).

[0101] Intermediate 6 (Step 5.b): 3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)phenol Palladium(II) acetate (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 dicyclohexyl-(2-phenylphenyl)phosphine (3.48 g, 9.9 mmol) in 1,4-dioxane (20 mL). The reaction mixture was heated to 80°C for 22 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through glass fiber filter paper. The filter cake was washed with ethyl acetate, and the filtrate was partially concentrated under vacuum. The organic layer was washed with a saturated aqueous solution of ammonium chloride and water, dried over magnesium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-12% ethyl acetate / heptane) to give 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.

[0102] The intermediate compounds in Table 2 were synthesized using the corresponding starting materials / intermediates according to the general route 5 illustrated in Intermediate 6.

[0103] Route 6: Intermediate 13 (Step 6.a): 5-morpholino-4H-1,2,4-triazol-3-amine N-cyanocarbodithioimino dimethyl ester (5.04 g, 34.4 mmol) was added to a solution of morpholine (3.0 g, 34.44 mmol) in acetonitrile (20 mL), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature, and hydrazine hydrate (1:1) (2.5 mL, 51.7 mmol) was added, followed by stirring at 80 °C for 4 h. The reaction mixture was concentrated under vacuum and ground with acetonitrile to give the title compound (4.92 g, 29.1 mmol, 85% yield) as a white solid.1 HNMR (500 MHz, DMSO- d 6) δ 10.98 (s, 1H), 5.75 (s, 2H), 3.67 – 3.58 (m, 4H), 3.14 – 3.06 (m, 4H); M / Z 170 [M+H] + ESI + , RT = 0.22 (S3).

[0104] Intermediate 14 (Step 6.b): 2-morpholino-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one To a stirred solution of 5-morpholino-4H-1,2,4-triazol-3-amine (500 mg, 2.96 mmol, intermediate 13) in acetonitrile (10 mL), ethyl (2E)-3-ethoxyprop-2-enoate (468.7 mg, 3.25 mmol) and dipotassium carbonate (0.82 mL, 5.91 mmol) were added, and the reaction mixture was heated overnight at 100°C in a pressure vessel. The reaction was cooled to room temperature, and the precipitate was collected by filtration and washed with acetonitrile to give the title compound (55% purity, 1.18 g, 2.94 mmol, 99% yield) as a grayish-white solid. This product contained K₂CO₃ (45% w / w) and was used directly in the next step without further purification. 1 H NMR (500 MHz, DMSO- d 6) δ 7.84 (d, J = 7.4 Hz, 1H), 5.53 (d, J = 7.4 Hz, 1H), 3.67 – 3.61 (m, 4H), 3.27 – 3.22 (m, 4H); M / Z : 222 [M+H] + ESI + , RT = 0.39 (S1).

[0105] The intermediate compounds in Table 3 were synthesized using the corresponding starting materials / intermediates according to the general route 6 illustrated in Intermediate 14.

[0106] Route 7: Intermediate 17: (E)-3-cyclopropyl-3-methoxy-prop-2-enoic acid methyl ester Sulfuric acid (0.20 mL, 3.75 mmol) was added dropwise to a cooled solution of methyl 3-cyclopropyl-3-oxopropionate (10.0 g, 70.4 mmol) and trimethyl orthoformate (20 mL, 182.8 mmol) at 0ºC. The reaction mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was purified directly by silica gel chromatography (0–30% ethyl acetate / heptane) to give the title compound (80% purity, estimated by NMR, 8.5 g, 43.5 mmol, 62% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 5.05 (s, 1H), 3.69 (s, 3H), 3.56 (s,3H), 3.22 – 3.13 (m, 1H), 0.96 – 0.90 (m, 2H), 0.82 – 0.75 (m, 2H); M / Z 157 [M+H] + ESI + , RT = 0.81 (S1).

[0107] The intermediate compounds in Table 4 were synthesized using the corresponding starting materials / intermediates according to the general route 7 illustrated in Intermediate 17.

[0108] Route 8: Intermediate 20: 2-Bromo-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one A solution of 5-bromo-4H-1,2,4-triazol-3-amine (9.0 g, 52.5 mmol) and ethyl (2E)-3-ethoxyprop-2-enoate (8.3 g, 57.7 mmol) in ethanol (60 mL) was reacted with sodium methoxide (5.4 M, in EtOH, 20 mL, 0.11 mol) and stirred at 90°C for 18 h. The reaction mixture was cooled to room temperature and poured into water at 0°C. 5 M HCl aqueous solution was added until a solid precipitate formed. The mixture was stirred at 0°C for 20 min, and then the solid was separated by vacuum filtration. The filtrate was allowed to stand at 0°C for 1 h to allow more of the desired product to precipitate, which was also separated by vacuum filtration. Combining the two solids yielded the title compound (80% purity, 9 g, 33.5 mmol, 64% yield) as a light brown solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ13.20 (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).

[0109] The intermediate compounds in Table 5 were synthesized using the corresponding starting materials / intermediates according to the general route 8 of intermediate 20 examples.

[0110] Route 9: Intermediate 28: 4-(5-chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)morpholine: Phosphorus oxychloride (14 mL, 0.149 mol) was added to a solution of 2-morpholino-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one (3.30 g, 14.9 mmol, intermediate 14) in acetonitrile (47.1 mL), and the mixture was stirred at 100°C for 36 h in a sealed tube. The reaction mixture was cooled to room temperature and poured onto ice. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum to give the title compound (2.17 g, 9.05 mmol, 61% yield) as a brown powder. 1 HNMR (300 MHz, DMSO- d 6)δ 9.10 (d, J = 6.9 Hz, 1H), 7.21 (d, J = 6.9 Hz, 1H), 3.69(t, J = 4.8 Hz, 4H), 3.49 (t, J = 4.8 Hz, 4H). M / Z 240 [M+H] + ESI + , RT = 1.66(S4).

[0111] The intermediate compounds in Table 6 were synthesized using the corresponding starting materials / intermediates according to the general route 9 illustrated in Intermediate 28.

[0112] Route 10: Intermediate 39: 4-(5-chloro-7-methoxy-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)morpholine: Sodium methoxide (0.033 mL, 5.4 M, in MeOH) was added to a solution of 4-(5,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)morpholine (100 mg, 0.365 mmol, intermediate 38) in methanol (4 mL), and the reaction was stirred at room temperature for 2.5 h. The reaction mixture was diluted with water, and the aqueous layer was extracted with dichloromethane. The combined organic layers were passed through a phase separator and concentrated under vacuum to give the title compound (80 mg, 0.166 mmol, 46% yield) as a white solid. 1 HNMR (500 MHz, DMSO- d 6 ) δ 6.93 (s, 1H), 4.19 (s, 3H), 3.73 – 3.66 (m, 4H), 3.49 – 3.44 (m, 4H); M / Z 270 [M+H] + ESI + , RT = 0.52 (S1).

[0113] Route 11: Intermediate 40: (2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl) trifluoromethanesulfonate: A solution of 2-morpholino-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one (intermediate 14) (100 mg, 0.452 mmol) in DCM (2 mL) was reacted with trifluoromethanesulfonyl chloride (0.07 mL, 0.63 mmol) and triethylamine (0.04 mL, 0.54 mmol) at 0°C and stirred at 0°C for 1 h. The reaction mixture was diluted with water, and the aqueous layer was extracted with dichloromethane. 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% ethyl acetate / heptane) to give the title compound (65 mg, 0.184 mmol, 41% yield) as a white solid. 1 HNMR (500 MHz, DMSO- d 6 ) δ 9.38 (d, J = 7.0 Hz, 1H), 7.31 (d, J = 7.0 Hz, 1H), 3.73– 3.68 (m, 4H), 3.56 – 3.50 (m, 4H); M / Z 354 [M+H] + ESI + , RT = 0.81 (S1).

[0114] Route 12: Example 1: 3-Methyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol: To a degassed solution of 4-(5-chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)morpholine (intermediate 28) (200 mg, 0.835 mmol), tripotassium phosphate (354 mg, 1.67 mmol), and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)phenol (intermediate 6) (277 mg, 0.918 mmol) in 1,4-dioxane (11.0 mL) and water (3.6 mL), [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride DCM (136 mg, 0.167 mmol) was added, and the reaction was stirred at 110°C for 4 hours. The reaction was cooled to room temperature and water was added. The aqueous layer was extracted with ethyl acetate. The combined organic phases were dried using a phase separator and concentrated under vacuum. The crude product was purified by silica gel chromatography (0–30% ethyl acetate / DCM) to give the title compound (90 mg, 0.242 mmol, 7% yield) as a grayish-white solid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 10.39 – 10.22 (m, 1H), 9.13 (d, J = 6.8Hz, 1H), 7.17 – 7.11 (m, 2H), 7.10 – 7.07 (m, 1H), 3.76 – 3.70(m, 4H), 3.56 –3.51 (m, 4H), 2.17 (s, 3H); M / Z 380 [M+H] + ESI + , RT = 2.14 (S5).

[0115] The compounds in Table 7 were synthesized using the corresponding starting materials / intermediates according to the general route 12 illustrated in Example 1.

[0116] Route 13: Intermediate 41: 2-(2-bromo-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol To a degassed solution of 2-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 33) (1.55 g, 6.31 mmol), tripotassium phosphate (2.8 g, 13.2 mmol), and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)phenol (intermediate 6) (1.5 g, 4.87 mmol) in 1,4-dioxane (20 mL) and water (2 mL), [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (DCM) (1.0 g, 1.22 mmol) was added, and the reaction was stirred at 50°C for 30 min. The reaction was cooled to room temperature and water was added. The aqueous layer was extracted with ethyl acetate. The combined organic phases were concentrated under vacuum. The crude product was purified by silica gel chromatography (0-50% ethyl acetate / heptane), followed by grinding with ethyl acetate:heptane (1:2) to give the title compound (650 mg, 1.73 mmol, 27% yield) as a grayish-white solid. 1 HNMR (400 MHz, DMSO- d 6 10.44 (s, 1H), 9.43 (d, J = 7.0 Hz, 1H), 7.47 (d, J = 7.0Hz, 1H), 7.18 (s, 1H), 7.11 (s, 1H), 2.18 (s, 3H); M / Z 373 and 375 [M+H] + ESI + ,RT = 3.13 (S2).

[0117] Route 14: Example 21: 3-Methyl-2-[2-[(3S)-3-methylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol: (3) S A solution of 3-methylmorpholine (60.0 mg, 0.593 mmol), 2-(2-bromo-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol (30.0 mg, 0.0764 mmol, intermediate 38), and N-ethyl-N-isopropyl-prop-2-amine (0.0400 mL, 0.229 mmol) was stirred at 100°C for 1 hour, followed by stirring at 150°C for another 3 hours. The crude reaction mixture was purified by silica gel chromatography (0-100% ethyl acetate / heptane) to give the title compound (3.0 mg, 0.008 mmol, 10% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 10.66 (brs, 1H), 8.61 (d, J = 7.0 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 7.10 – 7.07 (m, 2H), 4.36 (m, 1H), 4.04 – 3.97 (m, 1H), 3.96 – 3.89 (m, 1H), 3.82 – 3.77 (m, 2H), 3.71 – 3.60 (m, 1H), 3.53 – 3.41(m, 1H), 2.56 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H); M / Z 394 [M+H] + ESI + , RT = 1.67 (S2).

[0118] The compounds in Table 9 were synthesized using the corresponding starting materials / intermediates according to the general route 14 illustrated in Example 21.

[0119] Route 15: Step 15.a: Methyl 6-deuterium-2-morpholino-5-oxo-4H-[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid 5-morpholino-4H-1,2,4-triazol-3-amine (intermediate 13) (4.00 g, 23.6 mmol) was reacted with methanol- d 4 (25.0 mL) and DMSO- d 6 The suspension in (5 mL) was stirred at room temperature for 18 hours, and then concentrated under vacuum. The residue was redissolved in methanol-d4 (25.0 mL) and stirred at room temperature for 18 hours. This process was repeated a total of 4 times. 1 HNMR monitoring revealed approximately 95% deuterium-proton exchange, and the crude product was directly used in the cyclization step. The residue was dissolved in methanol. d 4 (25.0 mL) was added to dimethyl butyryl-2-acetyldialyte (3.4 mL, 28.7 mmol). The reaction was stirred at 70 °C for 4 hours, then cooled to room temperature. A bright yellow precipitate was formed, which was filtered under vacuum and washed with MeCN (5 mL) to give the title compound (91% purity, determined by LCMS, 800 mg, 2.60 mmol, 11% yield) as a bright yellow solid. 1 H NMR (400MHz, DMSO- d 6 ) δ 13.13 (s, 1H), 3.91 (s, 3H), 3.69 – 3.64 (m, 4H), 3.40 – 3.27(m, 4H); M / Z : 281 [M+H] + ESI + , RT = 1.42 (S2).

[0120] Step 15.b: Methyl 5-chloro-6-deuterium-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid Phosphorus oxychloride (0.91 mL, 9.50 mmol) was slowly added to a suspension of methyl 6-deuterium-2-morpholino-5-oxo-4H-[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylate (500 mg, 1.62 mmol) in ACN (1 mL) at room temperature, and the reaction mixture was stirred at 95ºC for 3 hours. The reaction mixture was cooled to room temperature, and ice-cooled water was slowly added and stirred for 10 minutes, followed by extraction with ethyl acetate. The combined organic extracts were concentrated under vacuum to give the title compound (54% purity, 350 mg, 0.633 mmol, 39% yield) as a light brown solid for use. This material was used directly in the next step. 1 H NMR (400 MHz, DMSO- d 6 ) δ 3.98 (s, 3H), 3.73 – 3.69 (m, 4H), 3.56 – 3.53(m, 4H); M / Z : 299, 301 [M+H] + ESI + , RT = 0.64 (S1).

[0121] Step 15.c: 6-Deuterium-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid Methyl 5-chloro-6-deuterium-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-7-carboxylate (54% purity, 300 mg, 0.542 mmol), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)phenol (intermediate 6) (250 mg, 0.786 mmol), and tripotassium phosphate (270 mg, 1.27 mmol) in 1,4-dioxane (6.0 mL) and water (1.0 mL) were added to a degassed solution of these compounds, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was then cooled to room temperature, and 1 M NaOH aqueous solution was added. After stirring for 5 minutes, the reaction mixture was diluted with ethyl acetate. The phases were separated, and the organic phase was extracted with 1M NaOH aqueous solution. The combined aqueous phase was acidified to pH 4 with 1M HCl aqueous solution and extracted with ethyl acetate. The combined organic phase was concentrated under vacuum and then concentrated again under vacuum through a hydrophobic phase separator. The residue was suspended in ethyl acetate / heptane (1:5), sonicated, and the resulting solid was filtered under vacuum to give the title compound (220 mg, 0.493 mmol, 91% yield) as a yellow solid. 1 HNMR (400 MHz, DMSO- d 6 ) δ 10.28 (s, 1H), 7.11 (s, 1H), 7.07 (s,1H), 3.73 –3.68 (m, 4H), 3.52 – 3.47 (m, 4H), 2.14 (s, 3H); M / Z : 425 [M+H] + ESI + , RT =2.72 (S2).

[0122] Example 42 (Step 15.d): 2-(6-deuter-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol A solution of 6-deuterium-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid (90.0 mg, 0.201 mmol) in concentrated HCl (37%) (5.0 mL, 60.0 mmol) was heated at 150°C for 8 hours and then cooled to 0°C. The mixture was alkalized to pH 14 with 5M aqueous sodium hydroxide solution and then extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and then concentrated under vacuum. The residue was dissolved in dichloromethane, passed through a phase separator, and then concentrated under vacuum. The residue was suspended in ethyl acetate / heptane (1:1), sonicated, and the resulting solid was filtered under vacuum to give the title compound (12 mg, 0.031 mmol, 15% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.11 (s, 1H), 7.12 (s, 1H), 7.07(s,1H), 3.75 – 3.70 (m, 4H), 3.55 – 3.51 (m, 4H), 2.16 (s, 3H); M / Z 381 [M+H] + ESI + , RT = 2.84 (S2).

[0123] Route 16: Step 16.a: 6-Deuterium-7-methyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-ol 5-(morpholin-4-yl)-4H-1,2,4-triazol-3-amine (intermediate 13) (5.0 g, 29.6 mmol) was reacted with methanol- d 4 (25.0 mL) and DMSO- d 6 The suspension in (5 mL) was stirred overnight at room temperature, and then concentrated under vacuum. The residue was redissolved in methanol. d 4 (25.0 mL) and stirred overnight at room temperature. Proton / deuterium exchange was repeated a total of 6 times (monitored by NMR) until approximately 90% deuterium exchange was measured by NMR, yielding the deuterated triazole derivative in 5 mL of DMSO. d 6The suspension was added. Ethyl butyrate (4.0 mL, 34.32 mmol) and the mixture was stirred at 80°C for 3 hours, then cooled to room temperature. Water and ethyl acetate were added, and the phases were separated. The aqueous phase was allowed to stand for 30 minutes, and then the solid precipitate was obtained by vacuum filtration to give the title compound (300 mg, 1.14 mmol, 4% yield, containing 95% deuterium, as determined by NMR) as a white solid. 1 H NMR (400 MHz, DMSO-) d 6 ) δ 12.60 (s, 1H), 3.71 – 3.65 (m, 4H), 3.37 – 3.32 (m, 4H), 2.38 (s, 3H); M / Z : 237 [M+H] + ESI + , RT = 1.36 (S2).

[0124] Example 43 (Step 16.b): 2-(6-deuter-7-methyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol A solution of 6-deuterium-7-methyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidine-5-ol (220 mg, 0.838 mmol) and triethylamine (0.25 mL, 1.79 mmol) in DCM (10 mL) was added dropwise to a solution at room temperature with trifluoromethanesulfonic anhydride (0.30 mL, 1.79 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under vacuum to give a brown powder, which was dissolved in 1,4-dioxane (6.0 mL) and water (1.0 mL). 3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-5-(trifluoromethyl)phenol (intermediate 6) (260 mg, 0.861 mmol), tripotassium phosphate (360 mg, 1.67 mmol), and cyclopentyl(diphenyl)phosphine; palladium dichloride; iron (130 mg, 0.177 mmol) were added, and the mixture was stirred at 80°C for 3 h. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the organic phase was concentrated under vacuum. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / heptane) to the title compound (27 mg, 0.065 mmol, 8% yield, 95% deuterium observed by NMR) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.23 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H), 3.75 – 3.69 (m, 4H), 3.57 – 3.51 (m, 4H), 2.69 (s, 3H), 2.14 (s, 3H); M / Z 395 [M+H] + ESI + , RT =3.03 (S2).

[0125] Route 17: Step 17.a: Methyl 3-(oxetane-3-yl)prop-2-ynyl ester Butyllithium (1.10 mL, 2.5 M, in hexane, 2.75 mmol) was added to a stirred suspension of 3-ethynyloxetane (200 mg, 2.44 mmol) in THF (3.2 mL) at -78 °C, and the suspension was stirred for 30 min. Methyl chloroformate (0.284 mL, 3.68 mmol) was added, and the reaction was heated to room temperature for 1 h. The reaction was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were concentrated under vacuum to give the title compound (570 mg, 2.24 mmol, 92% yield) as an orange oil. This material was used directly in the next reaction. 1 H NMR (400 MHz, DMSO- d 6 ) δ 4.77 (dd, J = 8.6, 5.6 Hz, 2H), 4.56 (dd, J = 6.9, 5.6 Hz, 2H), 4.18 –4.08 (m, 1H), 3.72 (s, 3H).

[0126] Step 17.b: 2-morpholino-7-(oxecyclobutane-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-ol A suspension of 5-(morpholino-4-yl)-4H-1,2,4-triazol-3-amine (intermediate 13) (315 mg, 1.86 mmol) and methyl 3-(oxecyclobutane-3-yl)prop-2-ynyl ester (570 mg, 2.24 mmol) in DMSO (0.50 mL) was stirred at 100°C for 16 hours and then cooled to room temperature. The reaction mixture was purified by reversed-phase column chromatography (10–100% water + 0.1% formic acid to ACN + 0.1% formic acid) to give the title compound (115 mg, 0.373 mmol, 20% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.15 (s, 1H), 4.90 – 4.82 (m, 2H), 4.76 – 4.68 (m, 2H), 4.58 – 4.45 (m, 1H), 3.69 – 3.63 (m, 4H), 3.34 – 3.30 (m, 4H); M / Z :278 [M+H] + ESI + , RT = 1.37 (S2).

[0127] Example 44 (Step 17.c): 3-Methyl-2-[2-morpholino-7-(oxecyclobutane-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol A solution of 2-morpholino-7-(oxetane-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-ol (100 mg, 0.325 mmol) and triethylamine (0.100 mL, 0.717 mmol) in DCM (4.0 mL) was added dropwise at room temperature with trifluoromethanesulfonyl chloride (0.0700 mL, 0.658 mmol) and the reaction was stirred for 30 minutes. The mixture was concentrated under vacuum and dissolved in 1,4-dioxane (2.5 mL) and water (0.40 mL). Tripotassium phosphate (140 mg, 0.650 mmol) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-5-(trifluoromethyl)phenol (intermediate 6) (126 mg, 0.397 mmol) were added, and the reaction mixture was degassed for 2 min. Then, cyclopentyl(diphenyl)phosphine, palladium dichloride, and iron (50.0 mg, 0.0681 mmol) were added, and the mixture was stirred at 50°C for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were concentrated under vacuum, and the crude product was purified by silica gel chromatography (0-100% ethyl acetate / heptane) to give the title compound (8.80 mg, 0.0192 mmol, 6% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ10.22 (s, 1H), 7.26 (s, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 5.03 – 4.95 (m, 2H), 4.91 – 4.81(m, J = 2.7 Hz, 3H), 3.75 – 3.68 (m, 4H), 3.55 – 3.48 (m, 4H), 2.17(s, 3H); M / Z 436 [M+H] + ESI + , RT = 3.03 (S2).

[0128] Example 2: Bioassay The purpose of this embodiment is to evaluate the activity of the compounds synthesized in "Example 1: Chemical Synthesis".

[0129] 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.

[0130] Day 1: THP1 cells were seeded at a density of 18,000 cells per well in differentiation medium in 384-well poly-L-lysine-coated plates containing RPMI 1640 medium (without glutamine and phenol red), 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.

[0131] 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.

[0132] 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).

[0133] 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 (reference inhibitor MCC950 (sodium salt), concentration 10x IC50). 50 (1µg / ml LPS, 50µM Nigerian styracin final concentration), used for the purpose of standardization.

[0134] 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.

[0135] After pretreatment, cells were washed with serum-free growth medium containing 50 µM nigrain. 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, and the cells were incubated at 37°C and 5% CO2 for 2 hours. Finally, the supernatant was collected and stored at -20°C.

[0136] 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 (receptor).

[0137] 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, manifested as a decrease in the HTRF ratio.

[0138] Table 10 shows the THP1 IL-1β release of the compounds in the tested examples.

[0139] While certain embodiments have been illustrated and described by way of example, it should be understood that changes and modifications can be made to them in accordance with common art without departing from the broader aspects of the technology as defined in the following claims.

[0140] The embodiments exemplified herein can be suitably implemented in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted broadly and not in any limiting sense. Furthermore, the terms and expressions used herein are descriptive rather than limiting, and their use is not intended to exclude any equivalents of the shown and described features or portions thereof, but it should be recognized that various modifications can be made within the scope of the claimed technology. Moreover, the phrase “consisting essentially of…” should be understood to include those specifically listed elements as well as other elements that do not materially affect the basic and novel features of the claimed technology. The phrase “consisting of…” does not include any unspecified elements.

[0141] This disclosure is not limited to the specific embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art.

[0142] All publications, patent applications, granted patents and other documents mentioned in this specification are incorporated herein by reference as if each publication, patent application, granted patent or other document were specifically and individually identified and incorporated herein by reference in its entirety. Definitions contained in the referenced text that contradict the definitions in this disclosure are excluded.

[0143] Other embodiments are set forth in the following claims.

Claims

1. Compounds of formula (I): Or its isotope-labeled compounds, wherein: R 1 It can be 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 can be H or CH3, provided that R 2 and R 3 Not all of them are H; R 4 For H, C 1-4 Alkyl, C 3-5 Cycloalkyl, unsubstituted saturated 4- to 6-membered heterocyclic group, OCH3, Cl or F, wherein C 1-4 Alkyl and C 3-5 The cycloalkyl group is optionally substituted with one or more F; or R 3 and R 4 The connection forms -CH2-CH2-CH2- or -CH2-O-CH2-; -X 1 -for-C(R) 5b (R) 5c - or -C(R) 5b (R) 5c CH2-*, where the asterisked bonds are attached to oxygen in formula (I); -X 2 -for-CH(R) 5d - or -CH(R) 5d CH2-*, where the asterisked bonds are attached to oxygen in formula (I); R 5 R 5a R 5b R 5c and R 5d Independently selected from H, F, 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; or R 5 and R 5b They connect, together with the carbon atoms they are attached to, to form a ring T. 1 ;or R 5b and R 5c Linked together, together with the carbon atoms to which they are linked, to form a cyclopropyl ring, wherein the cyclopropyl ring is optionally substituted with one or more F atoms; or R 5 and R 5a The linkage forms a divalent group -CH2-, -CH2CH2-, or -CH2OCH2-, where each hydrogen can be independently replaced by F; or R 5b and R 5d The linkage forms a divalent group -CH2-, -CH2CH2-, or -CH2OCH2-, where each hydrogen can be independently replaced by F; or R 5b R 5a The linkage forms a divalent group -CH2-, where each hydrogen can be independently replaced by F; T 1 It is cyclopropyl or N-methylpyrrolidine, wherein T 1 Optionally replaced by one or more Fs, whether the same or different.

2. The compound according to claim 1 or its isotope-labeled compound, wherein R 1 The components are CF3, CHF2, F, Cl, OCH3, OCHF2, CH3, or CN, with R being preferred. 1 It can be CN, CH3, CF3, OCH3, F or Cl, more preferably CF3.

3. The compound according to claim 1 or 2, or its isotope-labeled compound, wherein R 3 and R 4 Selected to obtain the formulas chosen from (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig): 。 4. The compound according to claim 3 or its isotope-labeled compound, wherein the compound has the formula (Ib), (Ic) or (If), preferably (Ib).

5. The compound according to any one of claims 1 to 4, or an isotope-labeled compound thereof, wherein R 2 R 3 and R 4 The following expressions are selected to obtain the expressions chosen from (Ia'), (Ib'), (Ic'), (Id'), (Ie'), (If'), and (Ig'): 。 6. The compound according to any one of claims 1 to 5, or an isotopically labeled compound thereof, wherein -X 1 -for-C(R) 5b (R) 5c )-.

7. The compound according to any one of claims 1 to 6, or an isotope-labeled compound thereof, wherein -X 2 -for-CH(R) 5d )-.

8. The compound according to any one of claims 1 to 7, or an isotope-labeled compound thereof, wherein R 5 It can be H or CH3.

9. The compound according to any one of claims 1 to 8, or an isotope-labeled compound thereof, wherein R 5a For H.

10. The compound according to any one of claims 1 to 9, or an isotope-labeled compound thereof, wherein R 5b It can be H or CH3.

11. The compound according to any one of claims 1 to 10, or an isotope-labeled compound thereof, wherein R 5c and R 5b For H.

12. The compound according to any one of claims 1 to 11, or an isotope-labeled compound thereof, wherein R 5 R 5a X 1 and X 2 The following formulas are selected to obtain the formulas chosen from (Ih), (Ii), (Ij), (Ik), and (Il): 。 13. The compound according to any one of claims 1 to 12, or an isotope-labeled compound thereof, wherein the compound is 3-Methyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol; 3-Hydroxy-5-methyl-4-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzylnitrile; 5-Methoxy-3-methyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol; 5-Chloro-3-methyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol; 3,5-Dimethyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol; 5-Fluoro-3-methyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol; 3-Methyl-2-(7-methyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-methyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[(2) R [-2-methylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[(2) S [-2-methylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 2-(7-Ethyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(7-Cyclopropyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(11-morpholino-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)-5-(trifluoromethyl)phenol; 5-(difluoromethyl)-3-methyl-2-(2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenol; 3-Methyl-2-[2-[(3 S [-3-methylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[(3 R [-3-methylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 5-Methoxy-3-methyl-2-(11-morpholino-4-oxa-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)phenol; 3-Methyl-2-(11-morpholino-4-oxa-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)-5-(trifluoromethyl)phenol; or 2-(6-deuter-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol.

14. The compound according to any one of claims 1 to 12, or an isotope-labeled compound thereof, wherein the compound is... 3,5-Dimethyl-2-(11-morpholino-4-oxa-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)phenol; 2-(11-morpholino-4-oxa-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)-5-(trifluoromethyl)phenol; 5-Methyl-2-(11-morpholino-4-oxa-1,8,10,12-tetraazatricyclo[7.3.0.02,6]dodec-2(6),7,9,11-tetraen-7-yl)phenol; 2-(7-methoxy-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-(1,4-oxazacycloheptane-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol; 2-[2-(2,2-dimethylmorpholin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 2-[2-(2-cyclopropylmorpholin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 2-[2-(2-ethylmorpholin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 3,5-Dimethyl-2-[2-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 2-[2-[(3 S )-3-(hydroxymethyl)morpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 2-[2-[(3 R [-3-isopropylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 3,5-Dimethyl-2-[2-[(1 S 4 S )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 2-[2-[(3 R )-3-(hydroxymethyl)morpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 3,5-Dimethyl-2-{2-[(1 R 5 S )-8-oxa-3-azabicyclo[3.2.1]oct-3-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl}phenol; 3,5-Dimethyl-2-[2-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 3,5-Dimethyl-2-[2-[2-(trifluoromethyl)morpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 2-[2-[(3 S [-3-isopropylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 3,5-Dimethyl-2-[2-(2,2,6-trimethylmorpholin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 3,5-Dimethyl-2-[2-[(1 R 4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 2-[2-[(2 R 6 R [-2,6-dimethylmorpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-3,5-dimethylphenol; 3,5-Dimethyl-2-[2-(4-oxa-7-azaspiro[2.5]oct-7-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenol; 2-(6-Deuter-7-methyl-2-morpholino-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-3-methyl-5-(trifluoromethyl)phenol; or 3-Methyl-2-[2-morpholino-7-(oxecyclobutane-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-5-(trifluoromethyl)phenol.

15. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 13 or 14, or an isotopically labeled compound thereof, and a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

16. The compound or its isotope-labeled compound according to any one of claims 1 to 13 or claim 14, used as a pharmaceutical.

17. A method of using the compound or its isotopically labeled compound according to any one of claims 1 to 13 or claim 14, or the pharmaceutical composition of claim 15, for treating or preventing one or more diseases or conditions associated with NLRP3.

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