Triazinone derivatives as NLRP3 inhibitors

Abstract

The present invention relates to novel compounds having the general formula (I), 1 , R 2 , R 3 , R 4 and R 5 as described herein), compositions comprising the compounds, and methods of using the compounds. TIFF2025539252000021.tif70161

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to organic compounds useful for the treatment and / or prevention in mammals, in particular compounds that modulate NLRP3 inhibition.

[0002] The present invention relates to novel compounds of formula I [ka] (In the formula, R 1 is H, alkyl, alkoxy, -CN, halo, haloalkyl, haloalkoxy, acetyl, or SF6; R 5 is H or or R 1 and R 5 and the atoms to which they are attached form either a 4-6 membered heterocycle containing a single O heteroatom optionally substituted with 1 or 2 substituents independently selected from halo or alkyl, or R 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered cycloalkyl ring optionally substituted with 1 to 2 substituents independently selected from halo or alkyl; R 2 is H, halo, or alkyl; R 3 is H or alkyl, and R 2 and R 3 and only one of R 4 is an oxetane, alkyl, or -(CH2) n -R 6 and R 6 is hydroxy or methoxy, and n is greater than 1. and pharmaceutically acceptable salts thereof.

[0003] Furthermore, the present invention includes all racemic mixtures, all their corresponding enantiomers and / or optical isomers. [Background technology]

[0004] Background of the Invention The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activity is pathogenic in genetic disorders such as cryopyrin-associated periodic syndromes (CAPS), and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis.

[0005] NLRP3 is an intracellular signaling molecule that senses many pathogen-, environmental, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like proteins containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form large aggregates known as ASC specks. Polymerized ASC then interacts with the cysteine ​​protease caspase-1 to form a complex called the inflammasome. This leads to the activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (pro-IL-1β and pro-IL-18, respectively), thereby activating these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. ASC specks can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18, leading to apoptotic cell death.

[0006] Caspase-1 cleaves pro-IL-1β and pro-IL-18 to their active forms, which are secreted from cells. Active caspase-1 also cleaves gasdermin-D, causing pyroptosis. Through its control of the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high-mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and allowing IL-1α to be released. In human cells, caspase-1 can also regulate the processing and secretion of IL-37. Many other caspase-1 substrates, such as components of the cytoskeleton and glycolytic pathways, may contribute to caspase-1-dependent inflammation.

[0007] NLRP3-dependent ASC specks are released into the extracellular milieu where they can activate caspase-1, induce the processing of caspase-1 substrates, and propagate inflammation.

[0008] Active cytokines derived from NLRP3 inflammasome activation are key drivers of inflammation and interact with other cytokine pathways to shape immune responses to infection and injury. For example, IL-1β signaling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergize with IL-23 to induce IL-17 production by memory CD4+ Th17 cells and γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also act synergistically to induce IFN-γ production from memory T cells and NK cells, which drives Th1 responses.

[0009] The inherited CAPS disorders Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID) are caused by gain-of-function mutations in NLRP3, defining it as a critical component of the inflammatory process. NLRP3 is also involved in the pathogenesis of many complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout, among others.

[0010] The role of NLRP3 in central nervous system diseases is becoming clearer, and lung diseases have also been shown to be affected by NLRP3. NLRP3 has also been implicated in many central nervous system conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, and brain damage due to pneumococcal meningitis (Walsh et al., Nature Reviews, 15:84-97, 2014, and Dempsey et al., Brain. Behav. Immun. 201761:306-316). NLRP3 has also been shown to be involved in many lung diseases, such as chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 184:42-54, 2014 and Kim et al. Am. J Respir Crit Care Med. 2017 196(3):283-97). Furthermore, NLRP3 is involved in the development of liver disease, kidney disease, and aging. Many of these associations are due to NLRP3. - / - Although defined using mice, there are also insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[0011] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits IL-1β production at micromolar concentrations in response to NLRP3 activation, but not in response to NLRC4 or NLRP1 activation. Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), but these agents have limited potency and are nonspecific.

[0012] Current treatments for NLRP3-related diseases include biologic agents that target IL-1. These include the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. These approaches have proven successful in treating CAPS, and these biologic agents are being used in clinical trials for other IL-1β-related diseases.

[0013] There is a need to provide compounds that have improved pharmacological and / or physiological and / or physicochemical properties and / or that provide useful alternatives to known compounds. Summary of the Invention

[0014] Summary of the Invention The present invention relates to novel compounds of formula I [ka] (In the formula, R 1 is H, alkyl, alkoxy, -CN, halo, haloalkyl, haloalkoxy, acetyl, or SF6; R 5 is H or or R 1 and R 5 and the atoms to which they are attached form either a 4-6 membered heterocycle containing a single O heteroatom optionally substituted with 1 or 2 substituents independently selected from halo or alkyl, or R 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered cycloalkyl ring optionally substituted with 1 to 2 substituents independently selected from halo or alkyl; R 2 is H, halo, or alkyl; R 3 is H or alkyl, and R 2 and R 3 and only one of R 4is an oxetane, alkyl, or -(CH2) n -R 6 and R 6 is hydroxy or methoxy, and n is greater than 1. and pharmaceutically acceptable salts thereof.

[0015] The term "alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl refers to a group having 1 to 6 carbon atoms (C 1-6 -alkyl) or 1 to 4 carbon atoms (C 1-4 -alkyl). 1-6 Examples of -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. A particular alkyl group is methyl.

[0016] The term "alkoxy" refers to a group in which R' is C 1-6 represents a group of formula -O-R', which is an alkyl group. 1-6 Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.

[0017] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise specified, cycloalkyl contains 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and octahydropentalenyl. A particular example is cyclobutyl. Another particular example is cyclopentyl.

[0018] The terms "halogen," "halide," and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo. Particular halogens are fluoro and chloro. A preferred halogen is fluoro.

[0019] The term "haloalkyl" refers to C 1-6 -C in which at least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom 1-6 represents an alkyl group. Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl. A particular example is trifluoromethyl.

[0020] The term "haloalkoxy" refers to C 1-6 -C in which at least one hydrogen atom of an alkoxy group is replaced by the same or different halogen atom 1-6 -represents an alkoxy group. Examples of haloalkoxy are difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy. Particular examples are difluoromethoxy and trifluoromethoxy.

[0021] The term "heterocycle" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms containing one, two, or three ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycles are azetidinyl, diazepanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and piperazinyl. Examples of polycyclic saturated heterocycles are azaspiroheptanyl, diazaspiroheptanyl, azaspirooctanyl, diazospirooctanyl, diazaspirononanyl, oxaazaspirooctanyl, and oxadiazaspirononanyl. A particular example of a heterocycle is a saturated furanyl ring.

[0022] The term "hydroxy" refers to an --OH group.

[0023] The term "nitrile" refers to a -C≡N group.

[0024] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids, such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins.The compound of formula I can also exist in the form of a zwitterion.Particularly preferred pharmaceutically acceptable salts of the compound of formula I are salts formed with formic acid and salts formed with hydrochloric acid to produce hydrochloride, dihydrochloride, or trihydrochloride.

[0025] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0026] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0027] The abbreviation ug means microgram and is equivalent to the symbol μg.

[0028] The compounds of formula I may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0029] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0030] Also, one embodiment of the present invention provides compounds according to formula I as described herein and pharmaceutically acceptable salts or esters thereof, particularly compounds according to formula I as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula I as described herein.

[0031] One embodiment of the present invention is R 1 is H, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy.

[0032] One embodiment of the present invention is R 1 is haloalkyl or haloalkoxy.

[0033] One embodiment of the present invention is R 2 is H and R 3 is alkyl.

[0034] One embodiment of the present invention is R 4 is alkyl or -(CH2) n -R 6 and R 6 is hydroxy and n is 2.

[0035] One embodiment of the present invention is R 4 is alkyl.

[0036] One embodiment of the present invention is R 1 and R 5 together with the atom to which they are attached form a 4-5 membered cycloalkyl or a 5 membered heterocycle containing a single O heteroatom.

[0037] One embodiment of the present invention comprises: R 1 is haloalkyl or haloalkoxy; R 5 is H or or R 1 and R 5 together with the atom to which they are attached form a 4- to 5-membered cycloalkyl or a 5-membered heterocycle containing a single O heteroatom; R 2 is H, R 3 is alkyl, R 4 is alkyl or -(CH2) n -R 6 and R 6 is hydroxy and n is 2; Provided herein are compounds according to Formula I, and pharmaceutically acceptable salts thereof.

[0038] One embodiment of the present invention comprises: R 1 is haloalkyl or haloalkoxy; R 5 is H or or R 1 and R 5 together with the atom to which they are attached form a 4- to 5-membered cycloalkyl or a 5-membered heterocycle containing a single O heteroatom; R 2 is H, R 3 is alkyl, R 4 is alkyl, Provided herein are compounds according to Formula I, and pharmaceutically acceptable salts thereof.

[0039] Specific examples of compounds of formula I described herein are: 3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one, formic acid, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one, 3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-4-methyl-1,2,4-triazin-5-one, and pharmaceutically acceptable salts thereof is selected from.

[0040] Other specific examples of compounds of formula I described herein are: 3-(4-hydroxyindan-5-yl)-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxyindan-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxyindan-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[6-(2-hydroxyethyl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-(2-hydroxyethyl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-(2-hydroxyethyl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, and pharmaceutically acceptable salts thereof is selected from.

[0041] Preferred examples of compounds of formula I described herein are: 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-4-methyl-1,2,4-triazin-5-one, and pharmaceutically acceptable salts thereof is selected from.

[0042] Other preferred examples of compounds of formula I described herein are 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one, and pharmaceutically acceptable salts thereof is selected from.

[0043] Another preferred example of a compound of formula I described herein is 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxyindan-5-yl)-4-methyl-1,2,4-triazin-5-one, or a pharmaceutically acceptable salt thereof.

[0044] The most preferred examples of compounds of formula I described herein are 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxyindan-5-yl)-4-methyl-1,2,4-triazin-5-one, and pharmaceutically acceptable salts thereof is selected from.

[0045] Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, a compound of Formula I can be formulated into a galenic dosage form by mixing it at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosages and concentrations used. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably somewhere in the range of about 3 to about 8. In one example, a compound of Formula I is formulated in acetate buffer at pH 5. In another embodiment, the compound of Formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0046] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0047] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0048] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers and additional active agents.

[0049] Typical preparations are prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide a superior presentation of the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0050] The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injection solutions or topical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules, for example.

[0051] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances, and liquid polyols.

[0052] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0053] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0054] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0055] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

[0056] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain still other therapeutically valuable substances.

[0057] The dosage may vary widely and will, of course, be adapted to the individual requirements of each particular case. In general, for oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g., about 300 mg per person), is preferably divided into 1 to 3 individual doses, which may, if appropriate, consist of, for example, equal amounts. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be between 0.1 and 25 mg, may be administered either in a single dose per day or per week, or in multiple doses (2 to 4 times) per day or per week. However, it will be apparent that the upper or lower limits given herein may be exceeded where indicated.

[0058] One embodiment of the present invention is a compound according to formula I described herein for use as a therapeutically active substance.

[0059] One embodiment of the present invention is a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0060] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

[0061] As used herein, the term "NLRP3 inhibition" refers to a complete or partial reduction in the activity level of NLRP3, including, for example, inhibition of active NLRP3 and / or inhibition of NLRP3 activation.

[0062] There is evidence for a role for NLRP3-induced IL-1 and IL-18 in the inflammatory responses associated with or resulting from a number of different disorders (Menu et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

[0063] In one embodiment, the disease, disorder or condition is selected from the following: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) lymphatic symptoms; (xiv) psychological disorders; (xv) graft-versus-host disease; (xvi) allodynia; (xvii) symptoms related to diabetes; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0064] In another embodiment, the disease, disorder or condition is selected from the following: (i) Cancer; (ii) infectious diseases; (iii) central nervous system disorders; (iv) cardiovascular disease; (v) liver disease; (vi) eye disease; or (vii) Skin diseases.

[0065] In a further exemplary embodiment of the invention, the disease, disorder or condition is inflammation. Examples of inflammation that may be treated or prevented include inflammatory responses associated with or resulting from: (i) skin conditions such as contact sensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (ii) articular conditions such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, or Reiter's disease); (iii) muscle conditions such as polymyositis or myasthenia gravis; (iv) gastrointestinal conditions such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), colitis, gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may have effects remote from the gut (e.g., migraine, rhinitis, or eczema); (v) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust-induced asthma, especially chronic or refractory asthma, e.g., late-stage asthma and airway hyperresponsiveness), bronchitis, rhinitis (acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, panlentic rhinitis, rhinitis sicca, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis, e.g., hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, volcanic ash-induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (vi) vascular conditions such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (vii) autoimmune conditions such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease; (viii) ocular conditions such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (ix) neurological conditions such as multiple sclerosis or encephalomyelitis; (x) an infection or infection-related condition such as acquired immune deficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B, or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, hemorrhagic dengue fever, leishmaniasis, streptococcal myositis, mycobacterium tuberculosis (including mycobacterium tuberculosis and HIV co-infection), mycobacterium avium intracellulare, pneumocystis carinii pneumonia, orchitis / epididymitis, Legionnaires' disease, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (xi) renal conditions such as mesangial proliferative glomerulonephritis, renal syndrome, nephritis, glomerulonephritis, obesity-related glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritic syndrome, renal fibrosis including chronic crystalline nephropathy, or renal hypertension; (xii) lymphatic conditions such as Castleman's disease; (xiii) conditions of or involving the immune system, such as hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (xiv) liver conditions such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, hepatic fibrosis, or liver failure; (xv) Cancer, including those mentioned above; (xvi) burns, wounds, trauma, hemorrhage or stroke; (xvii) radiation exposure; (xviii) metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, or pseudogout; and / or (xix) Pain such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.

[0066] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) lymphatic symptoms; (xiv) psychological disorders; (xv) graft-versus-host disease; (xvi) allodynia; (xvii) symptoms related to diabetes; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0067] One embodiment of the present invention is the use of a compound according to formula I as described herein in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0068] One embodiment of the present invention is the use of a compound according to formula I as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0069] One embodiment of the present invention is the use of a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0070] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0071] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0072] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0073] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0074] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder, or condition selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to formula I described herein.

[0075] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder, or condition selected from asthma or COPD, comprising administering an effective amount of a compound according to formula I described herein.

[0076] One embodiment of the present invention relates to a method of inhibiting NLRP3, comprising administering an effective amount of a compound according to Formula I described herein.

[0077] Also, one embodiment of the present invention is a compound of formula I as described herein when prepared according to any one of the processes described.

[0078] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to Formula I described herein and a therapeutically inert carrier. [Brief explanation of the drawings]

[0079] [Figure 1] Voltage Pattern DETAILED DESCRIPTION OF THE INVENTION

[0080] Assay procedure NLRP3 and pyroptosis It is well established that activation of NLRP3 leads to cell pyroptosis, a hallmark of which plays a key role in the development of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, inhibitors of NLRP3 are expected to block pyroptosis and the release of pro-inflammatory cytokines (e.g., IL-1β) from cells.

[0081] THP-1 cells: culture and preparation THP-1 cells (ATCC No. TIB-202) were grown in RPMI containing L-glutamine (Gibco No. 11835) supplemented with 1 mM sodium pyruvate (Sigma No. S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma No. P4333) in 10% fetal bovine serum (FBS) (Sigma No. F0804). Cells were passaged periodically until confluent (approximately 10 6 The THP-1 cells were grown to a concentration of 625,000 cells / ml. On the day of the experiment, the THP-1 cells were harvested and resuspended in RPMI medium (without FBS). The cells were then counted, and viability (>90%) was confirmed using trypan blue (Sigma #T8154). Appropriate dilutions were made to obtain a concentration of 625,000 cells / ml. LPS (Sigma #L4524) was added to this diluted cell solution to obtain a final assay concentration (FAC) of 1 μg / ml. 40 μl of the final preparation was dispensed into each well of a 96-well plate. The plates prepared in this way were used for compound screening.

[0082] THP-1 cell pyroptosis assay For compound screening, the following method stepwise assay was followed. 1. Seed THP-1 cells (25,000 cells / well) in 40 μl of RPMI medium (without FBS) containing 1.0 μg / ml LPS in a 96-well black-walled, clear-bottom cell culture plate coated with poly-D-lysine (VWR No. 734-0317). 2.5 μl of compound (8-point half-log dilutions at the highest dose of 10 μM) or vehicle (DMSO 0.1% FAC) is added to the appropriate wells. 3. Incubate at 37°C, 5% CO2 for 3 hours. Add 4.5 μl of nigericin (Sigma No. N7143) (FAC 5 μM) to all wells 5. Incubate at 37°C, 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plate at 300 x g for 3 minutes and remove the supernatant. 7. 50 μl of resazurin (Sigma #R7017) (100 μM resazurin in RPMI medium without FBS) is then added and the plate is incubated at 37°C and 5% CO for a further 1-2 hours. 8. The plate was read on an Envision reader at Ex 560nm and Em 590nm. 9.IC 50 Fit the data to a nonlinear regression equation (log inhibitor vs. response variable slope, 4 parameters)

[0083] The results of the pyroptosis assay were compared with those of THP IC 50 These are summarized in Table 1 below.

[0084] Human whole blood IL-1β release assay For systemic delivery, the ability of a compound to inhibit NLRP3 when present in the bloodstream is crucial. Therefore, we investigated the NLRP3 inhibitory activity of a number of compounds in human whole blood according to the following protocol.

[0085] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor pool. 1. Plate out 80 μl of whole blood containing 1 μg / ml LPS into a 96-well clear-bottom cell culture plate (Corning #3585). 2. Add 10 μl of compound (8-point half-log dilutions at the highest dose of 10 μM) or vehicle (FAC in DMSO 0.1%) to the appropriate wells. 3. Incubate at 37°C, 5% CO2 for 3 hours. 4. Add 10 μl of nigericin (Sigma #N7143) (10 μM FAC) to all wells 5. Incubate at 37°C, 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plate at 300 x g for 5 minutes to pellet the cells, remove 20 μl of the supernatant and add to a 96-well v-bottom plate for IL-1β analysis (Note: These plates containing supernatant can be stored at -80°C for analysis at a later date). 7. IL-1β was measured according to the manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000). 8.IC 50 Fit the data to a nonlinear regression equation (log inhibitor vs. response variable slope, 4 parameters)

[0086] Human whole blood assay results HWB IC 50 These are summarized in Table 1 below.

[0087] hERG screening assay During the small molecule drug development process, cardiac arrhythmias are one of the most frequent adverse side effects leading to drug failure. Such failures are often related to the drug's ability to inhibit the human ether-a-go-go-related gene (hERG) cardiac potassium channel. Therefore, no or low inhibition of the hERG cardiac potassium channel would be beneficial.

[0088] cell The CHO-crelox hERG cell line (ATCC reference number PTA-6812, female Chinese hamster cells) was generated and validated at Roche. Ready-to-use frozen instant CHO-hERG cells were cryopreserved at Evotec (Germany) and used directly in the experiments.

[0089] Experimental solution The extracellular solution contained (in mM): NaCl 150; KCl 4; CaCl 1; MgCl 1; HEPES 10; pH 7.2-7.4 with NaOH, osmolality 290-330 mOsm. The internal solution contained (in mM): KCl 10; KF 100; NaCl 10; HEPES 10; EGTA 20; pH 7.0-7.4 with KOH, osmolality 260-300 mOsm.

[0090] electrophysiology The effects of compounds on hERG K+-current parameters will be evaluated at two concentrations in at least four cells.

[0091] hERG studies are performed using the automated patch clamp system SynchroPatch® 384 (Nanion Technologies GmbH, Germany). K+ currents are measured using the patch voltage clamp technique in the whole-cell configuration at 35-37°C.

[0092] Cells were held at a resting voltage of -80 mV and stimulated with the voltage pattern shown in Figure 1 (outward K at 35–37 °C). + The pulse pattern used to elicit the current) activated hERG channels at a stimulation frequency of 0.1 Hz (6 bpm) to conduct outward IK hERG currents.

[0093] Data analysis The amplitude of the IKhERG was recorded at each drug concentration and compared to vehicle control values ​​(set at 100%) to define fractional blocks. The concentration-response data were fitted with the following relationship: [Table 1]

[0094] Concentration-response curves were fitted by nonlinear regression analysis using the EworkBook suite (ID Business Solutions Ltd, UK). Data fitting was performed using a four-parameter logistic model (fit = (A + (B / (1 + ((x / C)^D)))), where A = 0 and B = 100).

[0095] The results of the hERG assay were analyzed using the hERG IC 20 The results are summarized in Table 2 below.

[0096] Transcellular P-gp assay: A typical assay uses transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human P-gp or mouse P-gp cultured on 96-well semi-permeable filter membrane plates, where these cells form a polarized monolayer with tight junctions, which act as a barrier between the apical and basolateral compartments.

[0097] P-gp is expressed in the apical membrane of the monolayer.

[0098] The adhesion of the cell monolayer and the functional activity of P-gp are confirmed by the addition of the cell-impermeable marker Lucifer Yellow and the reference P-gp substrate Edoxaban, respectively.

[0099] PAMPA: PAMPA (Parallel Artificial Membrane Permeability Assay) is a first-order selective permeability screen for drug candidates. The PAMPA assay uses artificial phospholipid membranes to mimic transcellular absorption conditions. The assay determines permeability values ​​that can be used for compound optimization and ranking purposes and as input parameters for in silico models predicting intestinal absorption.

[0100] The donor concentration is measured at t-start (baseline) and compared to the donor and acceptor concentrations after a certain time period (t-end), and the extent of compound crossing the membrane is calculated.

[0101] Microsomal stability: Incubations with 1 μM test compound in microsomes (0.5 mg / mL) and the cofactor NADPH are performed in 96-well plates at 37°C using a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system. After a 10-minute preincubation step between microsomes and test compound, the enzymatic reaction is initiated by the addition of the cofactor. Aliquots of the incubation are removed at 1, 3, 6, 9, 15, 25, 35, and 45 minutes and quenched with 1:3 (v / v) acetonitrile containing an internal standard. Samples are then cooled and centrifuged, after which the supernatant is analyzed by LC-MS / MS2.

[0102] Metabolic stability in hepatocytes: Assay Description: Biological materials. Obtain cryopreserved hepatocytes [mouse, rat, rabbit, monkey, human (mixed sex)]. Hepatocyte viability after reconstitution is at least 80% throughout the study. Obtain ready-to-use rat / human HepatoPac® cultures [long-term hepatocyte co-cultures; pooled (human male n=5, female n=5)], stromal mouse fibroblasts (negative control; pooled), incubation plates, application medium, and maintenance medium.

[0103] Metabolism by Suspension Hepatocytes. Primary pooled cryopreserved hepatocytes were reconstituted with prewarmed William's E medium containing 10% FCS, 0.05 mg / mL streptomycin, 50 U / mL penicillin, and 0.4 mM L-glutamine, as well as 0.01 mg / mL gentamicin, 0.048 mg / mL hydrocortisone, and 0.004 mg / mL insulin to a final suspension density of 1 × 10 cells / mL. Incubations were performed automatically using a Liquid Handling System (Tecan) equipped with a CO incubator with an orbital shaker. After adding test compound (e.g., 1 μM) to the wells (1 × 10 cells / well), the 96-well hepatocyte suspension culture plate was incubated at 37 °C in 5% CO. Samples were quenched at the designated time points by adding acetonitrile (containing the internal standard) to the incubation wells for up to 2 hours.

[0104] Incubations of test substances (e.g., 1 μM, 0.1% v / v DMSO) performed in HepatoPac® metabolic suspension assays are performed in 96-well plates containing either cocultures of adherent hepatocytes with mouse fibroblast control cells or control cells alone (5% CO2 atmosphere, 37°C). The incubation medium for human HepatoPac® is identical to that used in suspension hepatocytes. At designated time points (2, 18, 26, 48, 72, and 96 hours), all wells are quenched with ice-cold acetonitrile containing an internal standard.

[0105] The samples are then appropriately centrifuged and the supernatants are analyzed by LC-MS / MS. Incubations are performed in n=1 or 2. [Table 2] [Table 3]

[0106] The invention will now be illustrated by the following examples, which have no limiting character.

[0107] Where preparations are obtained as mixtures of enantiomers or diastereoisomers, the pure enantiomers or diastereoisomers may be obtained by the methods described herein or by methods known to those skilled in the art, such as, for example, chiral chromatography or crystallization.

[0108] Experimental Method Abbreviation: [Table 4] [Example]

[0109] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen atmosphere.

[0110] Synthesis of intermediates: Intermediate 1: 3-chloro-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one [ka]

[0111] Step A: 2-[(4-methoxyphenyl)methyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazine-3,5-dione A solution of 6-bromo-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione (1.66 g, 4.84 mmol, 1.1 equiv.), commercially available 6-methyl-1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine, dihydrochloride salt (CAS no. 2126160-15-2, 1.10 g, 4.39 mmol, 1.0 equiv.), and cesium carbonate (7.14 g, 21.9 mmol, 5.0 equiv.) in MeCN (20 mL) and water (80.0 μL, 4.44 mmol, 1.01 equiv.) was sparged (sonicated for 5 min with N bubbling). Palladium(II) acetate (40.0 mg, 0.18 mmol, 0.04 equiv.) and Xantphos (103 mg, 0.18 mmol, 0.04 equiv.) in MeCN (20 mL) were then added, and the reaction mixture was heated to 50° C. for 1 h. After this time, the reaction temperature was increased to 85° C. and stirred at this temperature for 18 h. The reaction mixture was cooled, filtered through Celite, rinsed with EtOAc, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (40 g cartridge, 0-10% MeOH [0.7 M NH]: EtOAc) to afford the title compound (702 mg, 38%) as an orange solid. LCMS: m / z 386.3 [M+H] + ,ESI pos.

[0112] Step B: 4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-2H-1,2,4-triazine-3,5-dione To a solution of 2-[(4-methoxyphenyl)methyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazine-3,5-dione (Step A) (603 mg, 1.56 mmol, 1.0 equiv.) in DCM (3 mL) and MeCN (1.5 mL) was added trifluoromethanesulfonic acid (360 μL, 4.07 mmol, 2.6 equiv.). The reaction mixture was heated to 35 °C and stirred for 18 h. The reaction mixture was loaded onto silica and purified by silica gel chromatography (40 g cartridge, 0-15% MeOH [0.7 M NH]:ethyl acetate) to afford the title compound (407 mg, 98% yield) as an orange solid. LCMS: m / z 266.2 [M+H] + ,ESI pos.

[0113] Step C: 3-chloro-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one The above 4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-2H-1,2,4-triazine-3,5-dione (Step B) (503 mg, 1.90 mmol, 1.0 equiv) was added to a stirred solution of phosphorus oxychloride (5.0 mL, 53.6 mmol, 28.3 equiv) and the reaction was heated to 100° C. for 16 h. The reaction was diluted with additional phosphorus oxychloride (5.0 mL, 53.6 mmol, 28.3 equiv) and heated to 100° C. for an additional 24 h. The reaction mixture was cooled and concentrated in vacuo, and the resulting brown oil was then dissolved in MeCN (ca. 30 mL) and added portionwise to a vigorously stirred solution of EtOAc (50 mL) and KPO (50% aqueous solution, 100 mL). The pH of the aqueous solution was then adjusted to approximately pH 12 by portionwise addition of solid KPO, and the organic layer was separated. The aqueous phase was extracted with EtOAc (2 x 50 mL), and the combined organic layers were dried (MgSO), filtered, and concentrated in vacuo to give the title compound (414 mg, 73%) as a pale yellow solid. LCMS: m / z 284.2 / 286.2 [M+H] + ,ESI pos.

[0114] Intermediate 2: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol [ka] A mixture of 3-bromobicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (317 mg, 1.59 mmol, 1.0 equiv), bis(pinacolato)diboron (2028.8 mg, 7.99 mmol, 5.02 equiv), Pd(dppf)Cl.DCM complex (158.5 mg, 0.19 mmol, 0.12 equiv), and potassium acetate (475.5 mg, 4.85 mmol, 3.04 equiv) in 1,4-dioxane (15 mL) was degassed with N for 5 min, then heated to 90 °C and stirred for 2 h. The reaction was cooled to room temperature, then concentrated in vacuo and purified by column chromatography on silica gel (40 g cartridge, 0–100% EtOAc / isohexane) to afford the title compound (144.2 mg, 14% yield) as a white solid. A further batch of the title compound (366 mg, 25% yield) was also isolated as a white solid. 1 H NMR(500MHz,DMSO)δ8.55(s,1H),7.36(d,1H),6.58(d,1H),3.12-2.97(m,4H),1.28(s,12H).LCMS m / z 247.7[M+H] + ESI pos.

[0115] Intermediate 3: 2-[4-(difluoromethoxy)-2-methoxy-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step A: 1-Bromo-4-(difluoromethoxy)-2-methoxy-benzene A solution of commercially available 4-bromo-3-methoxyphenol (CAS No. 102127-34-4, 2.0 g, 9.85 mmol, 1.0 equiv.), cesium carbonate (16.05 g, 49.3 mmol, 5.0 equiv.), and sodium chlorodifluoroacetate (4.51 g, 29.6 mmol, 3.0 equiv.) in DMF (50 mL) and water (5 mL) was placed under a nitrogen atmosphere and stirred at 90°C for 16 hours. Sodium chlorodifluoroacetate (4.51 g, 29.6 mmol, 3.0 equiv.) was added to the reaction mixture, which was heated at 90°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with DCM (20 mL) and 10% aqueous LiCl (200 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 x 20 mL), and then the combined organic layers were concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g cartridge, 0-50% (EtOAc / isohexane)) to afford the title compound (847 mg, 30% yield) as a clear, colourless oil. 1 H NMR (500MHz, CDCl3) δ7.50(d,1H),6.68(d,1H),6.65-6.33(m,2H),3.89(s,3H).

[0116] Step B: 2-[4-(difluoromethoxy)-2-methoxy-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A solution of 1-bromo-4-(difluoromethoxy)-2-methoxy-benzene (Step A) (2.05 g, 8.10 mmol, 1.0 equiv.), bis(pinacolato)diboron (2.67 g, 10.5 mmol, 1.3 equiv.), potassium acetate (2.67 g, 27.2 mmol, 3.35 equiv.), Xphos (82.0 mg, 0.17 mmol, 0.02 equiv.), and Xphos Pd G3 (410.0 mg, 0.48 mmol, 0.06 equiv.) in isopropyl acetate (50 mL) was heated to 90 °C under a nitrogen atmosphere and stirred at this temperature for 16 h. The reaction mixture was cooled to room temperature and diluted with water (50 mL) and DCM (100 mL), after which the layers were separated. The aqueous layer was extracted with DCM (2 × 100 mL), and the combined organic layers were concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-50% (EtOAc / isohexane)) to afford the title compound (1.65 g, 58% yield) as a clear brown oil. 1 H NMR(500MHz,DMSO)δ7.57(d,1H),7.32(t,1H),6.76-6.68(m,2H),3.75(s,3H),1.26(s,12H).

[0117] Intermediate 4: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol [ka] Step A: 5-Bromo-2,3-dihydrobenzofuran-4-ol To a solution of 2,3-dihydrobenzofuran-4-ol (CAS number 144822-82-2, 2.00 g, 14.7 mmol, 1 equiv.) in methanol (40 mL) was added pyridine tribromide (4.70 g, 14.7 mmol, 1 equiv.) at -40 °C. The resulting mixture was stirred at -40 °C for 0.5 h, then warmed to 20 °C and stirred for 16 h. After completion of the reaction, the reaction mixture was dissolved in EtOAc (100 mL). The organic layer was washed with 1N hydrochloric acid (100 mL × 2), followed by brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EtOAc = 15:1 to 10:1) to afford the title compound (1.90 g, 60% yield) as a yellow solid. LCMS: m / z 212.8 [M H ] - ,ESI neg.

[0118] Step B: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol To a solution of the above 5-bromo-2,3-dihydrobenzofuran-4-ol (58.4 g, 271 mmol, 1.00 equiv.) in dioxane (600 mL), B2Pin2 (69.0 g, 271 mmol, 1.00 equiv.), KOAc (58.6 g, 597 mmol, 2.20 equiv.), and Pd(PPh3)2Cl2 (9.94 g, 13.6 mmol, 0.05 equiv.) were added. The mixture was then stirred at 90 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give a yellow solid. The target (9.72 g, 13% yield, 97% purity) was obtained as a yellow solid. 1 H NMR (400MHz, CDCl3): δ=8.01(s,1H),7.44(d,1H),6.41(d,1H),4.62(t,2H),3.17(t,2H),1.36(s,12H).

[0119] Synthesis of Examples Example 1: 3-[2-Hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one [ka] To a stirred solution of the above 3-chloro-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one intermediate 1 (206 mg, 0.73 mmol, 1.0 equiv.), commercially available [2-hydroxy-4-(trifluoromethoxy)phenyl]boronic acid (CAS number 1309768-22-6, 178 mg, 0.80 mmol, 1.10 equiv.) in 1,4-dioxane (3 mL) and saturated aqueous sodium carbonate (750 μL, sparged (N bubbling by sonication) for 2 min), 2-hydroxy-4-(trifluoromethoxy)phenyl]boronic acid (CAS number 1309768-22-6, 178 mg, 0.80 mmol, 1.10 equiv.) was added 2-hydroxy-4-(trifluoromethoxy)phenyl (CAS number 1309768-22-6) and the reaction mixture was heated to 80 °C and stirred for 6 h. The reaction was cooled and degassed, and additional saturated aqueous sodium carbonate (250 μL, 2.67 mmol, 3.67 equiv) and xphos Pd g3 (35.0 mg, 0.04 mmol, 0.06 equiv) were added, and the reaction was heated to 80° C. and stirred for an additional 18 h. The reaction mixture was concentrated and loaded onto some Celite, then added to a plug of Celite and rinsed with EtOAc (100 mL). The solvent was removed, and the crude sample was dissolved in DMSO, filtered, and purified using a Waters XBridge BEH C 18 ODB preparative column, 130Å, 5 μm, 30 mm x 100 mm, flow rate 40 mL / min -1Purification was performed by reversed-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) eluting with 0.3% ammonia in a water-MeCN gradient over 12.5 min using UV across all wavelengths with PDA, QDa and ELS detectors. The at-column dilution pump was at 2 mL min throughout the method. -1 of methanol, which contained the following MeCN percentages: Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, ramp from 5% MeCN to 30% MeCN; 10.5-10.6 min, ramp from 30% MeCN to 100% MeCN; 10.6-12.5 min, hold at 100% MeCN. Clean fractions were combined and evaporated to give the title compound (86 mg, 29% yield) as a pale yellow solid. LCMS m / z 426.2 [M+H] + ,ESI pos.

[0120] Example 1 Chiral Separation: Example 1 (80.6 mg) was dissolved in MeOH (3 mL), filtered, and then separated by chiral SFC on a Waters prep 100 using PDA and QDA detectors at 40 °C and 120 bar. The column was a Lux® 5 μM Amylose-1 LC column 250 × 21.2 mm, AXIA™ Packed (Phenomenex®), 30% ethanol (0.4% triethylamine), 70% CO2 at a flow rate of 65 mL / min. Clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residue was redissolved in methanol, transferred to a final vial, and evaporated on a Biotage V10. The sample was then further dried overnight in a vacuum oven at 30 °C / 5 mbar to give both enantiomers 1A (30.0 mg, 9.23% yield) and 1B (29.8 mg, 9.17% yield) as colorless glasses with arbitrarily assigned stereochemistry.

[0121] Enantiomer 1A: 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one 1 H NMR (500 MHz, DMSO, 353.15 Kelvin) δ 7.40 (d, 1H), 6.88-6.83 (m, 2H), 4.72-4.61 (m, 1H), 3.86-3.78 (m, 1H), 3.75-3.65 (m, 1H), 3.17 (s, 3H), 2.94 (ddd, 1H), 2.48-2.44 (m, 1H), 2.35-2.28 (m, 1H), 2.17 (s, 3H), 2.07 (td, 1H), 2.03-1.77 (m, 4H), 1.67 (dq, 1H). Note: Phenol has been replaced; LCMS m / z 426.4 [M+H] + ESI pos.

[0122] Enantiomer 1B: 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one 1 H NMR (500 MHz, DMSO, 353.15 Kelvin) δ 7.40 (d, 1H), 6.88-6.83 (m, 2H), 4.72-4.61 (m, 1H), 3.86-3.78 (m, 1H), 3.75-3.65 (m, 1H), 3.17 (s, 3H), 2.94 (ddd, 1H), 2.48-2.44 (m, 1H), 2.35-2.28 (m, 1H), 2.17 (s, 3H), 2.07 (td, 1H), 2.03-1.77 (m, 4H), 1.67 (dq, 1H). Note: Phenol has been replaced; LCMS m / z 426.4 [M+H] + ESI pos.

[0123] Examples 2A and 2B: Enantiomer 2A and Enantiomer 2B of 3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one [ka] To a stirred solution of the above 3-chloro-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one intermediate 1 (206 mg, 0.73 mmol, 1.0 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol intermediate 4 (209.3 mg, 0.8 mmol, 1.1 equiv) in 1,4-dioxane (3 mL) and saturated aqueous sodium carbonate (750.0 μL) sparged (N bubbling with sonication) for 2 minutes, Xphos Pd g3 (32.0 mg, 0.04 mmol, 0.05 equiv) was added and the reaction was stirred at 80° C. for 20 hours. The reaction mixture was concentrated and loaded onto some Celite, then added to a plug of Celite and rinsed with EtOAc (100 mL). The solvent was removed and the crude sample was dissolved in DMSO (4.6 mL), filtered, and purified using a Waters XBridge BEH C 18 Purification was performed by reverse-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organizer, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on an ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, at a flow rate of 40 mL min eluting with a 0.3% ammonia in water-MeCN gradient over 12.5 min using UV across all wavelengths with PDA, QDa, and ELS detectors. The at-column dilution pump was set to 2 mL min throughout the method. -1of methanol, which contained the following MeCN percentages. Gradient information: 0.0–0.5 min, 5% MeCN; 0.5–10.5 min, ramp from 5% MeCN to 30% MeCN; 10.5–10.6 min, ramp from 30% MeCN to 100% MeCN; 10.6–12.5 min, hold at 100% MeCN. Clean fractions were evaporated in a Genevac, then dissolved in MeOH (5 mL) with sonication, filtered, and then separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210–400 nm, 40 °C, 120 bar. The column was a Phenomenex Lux A1 10 × 250 mm, 5 μm, 60% MeOH (0.2% DEA), 40% CO₂, flow rate 15 mL / min. Clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residue was redissolved in methanol, transferred to a final vial, and evaporated on a Biotage V10. The sample was then further dried in a vacuum oven at 30°C / 5 mbar over the weekend to give both enantiomers 2A (13.9 mg, 4.74%) and 2B (14.2 mg, 5%) as light brown lyophilized solids with arbitrarily assigned stereochemistry.

[0124] Enantiomer 2A: 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one 1 H NMR (500 MHz, DMSO) δ 7.02 (d, 1H), 6.35 (d, 1H), 4.70-4.63 (m, 1H), 4.58 (t, 2H), 3.85-3.77 (m, 1H), 3.74-3.63 (m, 1H), 3.18 (s, 3H), 3.15 (t, 2H), 2.96-2.91 (m, 1H), 2.48-2.44 (m, 1H), 2.34-2.27 (m, 1H), 2.17 (s, 3H), 2.07 (td, 1H), 2.02-1.78 (m, 4H), 1.70-1.63 (m, 1H). Note: Phenol was replaced. LCMS m / z 384.2 [M+H]+ ESI pos.

[0125] Enantiomer 2B: 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one 1 H NMR (500 MHz, DMSO) δ 6.99 (d, 1H), 6.29 (d, 1H), 4.69-4.62 (m, 1H), 4.55 (t, 2H), 3.84-3.77 (m, 1H), 3.72-3.64 (m, 1H), 3.19 (s, 3H), 3.12 (t, 2H), 2.96-2.91 (m, 1H), 2.49-2.43 (m, 1H), 2.35-2.27 (m, 1H), 2.16 (s, 3H), 2.07 (td, 1H), 2.02-1.76 (m, 4H), 1.69-1.64 (m, 1H). Note: Phenol was replaced. LCMS m / z 384.2 [M+H] + ESI pos.

[0126] Example 3: 3-[4-(Difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one [ka] Step A: 3-[4-(difluoromethoxy)-2-methoxy-phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one [ka] To a stirred solution of the above 3-chloro-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one intermediate 1 (294 mg, 1.04 mmol, 1.0 equiv.), 2-[4-(difluoromethoxy)-2-methoxy-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane intermediate 3 (377 mg, 1.26 mmol, 1.21 equiv.) in 1,4-dioxane (5 mL) and saturated aqueous sodium carbonate (1.0 mL, 10.7 mmol, 10.3 equiv.) sparged (sonicated N bubbling) for 2 min was added 1,2,4-triazin-5-one intermediate 1 (294 mg, 1.04 mmol, 1.0 equiv.), 2-[4-(difluoromethoxy)-2-methoxy-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane intermediate 3 (377 mg, 1.26 mmol, 1.21 equiv.). g3 (45.0 mg, 0.05 mmol, 0.05 equiv) was added and the reaction was heated to 80° C. and left stirring for 2.5 h. The reaction mixture was concentrated, loaded onto Celite, and purified by column reversed-phase chromatography (C 18 , 40 g, 20-100% MeCN:10 mM aqueous ammonium bicarbonate solution) to give the title compound (276 mg, 62% yield) as a pale yellow solid. LCMS m / z 421.8 [M+H] + ,ESI pos.

[0127] Step B: 3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one 3-[4-(Difluoromethoxy)-2-methoxy-phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one (Step A) (296 mg, 0.7 mmol, 1.0 equiv.), potassium carbonate (292 mg, 2.11 mmol, 3.01 equiv.), and NMP (3 mL) were placed in a microwave vial, sonicated, and sealed. Benzenethiol (76.0 μL, 0.74 mmol, 1.06 equiv.) was added, and the reaction mixture was irradiated in a biotage microwave at 120 °C for 65 min. The reaction mixture was filtered and then loaded onto a basic RP column (C ) eluting at 35% CO₂. 18After direct addition to a 43 g cartridge (10-100%) and concentration to dryness, the title compound was obtained in two fractions: the first fraction (114 mg, 39% yield) as a light brown solid, and the second fraction (100 mg, 34% yield) as a white solid.

[0128] Example 3 Chiral Separation: Example 3 (190.1 mg) was dissolved at 19 mg / mL in DCM / DMSO / MeOH with sonication, filtered, and then separated by chiral SFC on a Sepiatec with UV detection by DAD at 220 nm, 40°C, 120 bar. The column was a Chiralpak IG 10 x 250 mm, 5 µm, 30% MeOH (0.5% DEA), 70% CO2 at a flow rate of 20 mL / min. Clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rocket evaporator at 40°C. The residue was redissolved in methanol, transferred to a final vial, and evaporated on a Biotage V10. The sample was then further dried in a vacuum oven at 30 °C / 5 mbar overnight to give both enantiomer 3A (64.6 mg, 22% yield) and enantiomer 3B (66.2 mg, 23% yield) as light brown solids with arbitrarily assigned stereochemistry.

[0129] Enantiomer 3A: 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one 1H NMR (500MHz, DMSO, 353.15 Kelvin) δ10.31(s,1H),7.32(d,1H),7.18(t,1H),6.75-6.68(m,2H),4.70-4.61(m,1H),3.86-3.78(m,1H),3.73-3 .64(m,1H),3.17(s,3H),2.97-2.89(m,1H),2.48-2.43(m,1H),2.35-2.26(m,1H),2.17(s,3H),2.11-1.77(m,5H),1.70-1.63(m,1H);LCMS m / z 408.3[M+H] + ESI pos.

[0130] Enantiomer 3B: 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one 1 H NMR (500 MHz, DMSO, 353.15 Kelvin) δ 7.29 (d, 1H), 7.16 (t, 1H), 6.70-6.61 (m, 2H), 4.71-4.63 (m, 1H), 3.85-3.78 (m, 1H), 3.72-3.65 (m, 1H), 3.18 (s, 3H), 2.98-2.90 (m, 1H), 2.48-2.44 (m, 1H), 2.34-2.27 (m, 1H), 2.16 (s, 3H), 2.10-1.77 (m, 5H), 1.70-1.64 (m, 1H). Note: Phenol protons have been exchanged; LCMS m / z 408.2 [M+H] + ESI pos.

[0131] Examples 4A and 4B: Enantiomer 4A and Enantiomer 4B of 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one [ka] To a stirred solution of the above 3-chloro-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one intermediate 1 (140.0 mg, 0.49 mmol, 1.0 equiv.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (112 mg, 0.54 mmol, 1.1 equiv.) in 1,4-dioxane (2.5 mL) and saturated aqueous sodium carbonate solution (500 μL) sparged (N bubbling with sonication) for 2 min, xphos Pd g3 (21.0 mg, 0.02 mmol, 0.05 equiv.) was added and the reaction was heated to 80 °C and left stirring for 2 h. The reaction mixture was cooled to room temperature, sparged, and additional xphos Pd G3 (11.0 mg, 0.01 mmol, 0.03 equiv) was added and heated at 80 °C for an additional 2 h. The sample was cooled to room temperature, sparged, and additional saturated aqueous sodium carbonate (250 μL), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (51.0 mg, 0.25 mmol, 0.5 equiv), and xphos Pd G3 (11.0 mg, 0.01 mmol, 0.03 equiv) were added, and the reaction was heated at 80 °C for an additional 2 h. The reaction mixture was concentrated and loaded onto Celite, then added to a plug of Celite and rinsed with EtOAc (100 mL). The solvent was removed, and the crude sample (345 mg) was dissolved in DMSO (1.3 mL), filtered, and purified using Waters X-Select CSH C 18Purification was performed by reverse-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organizer, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) using a 130 Å, 5 μm, 30 mm × 100 mm ODB preparative column at a flow rate of 40 mL min eluting with a 0.1% formic acid in water-MeCN gradient over 8.5 min using UV across all wavelengths with PDA, QDa, and ELS detectors. An at-column dilution pump provided 2 mL min throughout the method, which is included in the MeCN percentages below. Gradient information: 0.0–0.5 min, 10% MeCN; 0.5–5.5 min, ramp from 10% MeCN to 40% MeCN; 5.5–5.6 min, ramp from 40% MeCN to 100% MeCN; 5.6–8.5 min, hold at 100% MeCN. Clean fractions were evaporated in a Genevac, and the residue was then dissolved in MeOH (2 mL) with sonication, filtered, and then separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210–400 nm, 40 °C, and 120 bar. The column was an IG 10 × 250 mm, 5 μm, 20% EtOH (0.5% DEA), 80% CO2, flow rate 15 mL / min. Clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residue was redissolved in methanol, transferred to a final vial, and evaporated on a Biotage V10. The sample was then further dried in a vacuum oven at 30°C / 5 mbar over the weekend to give both enantiomers 4A (15.9 mg, 8% yield) and 4B (17.1 mg, 8% yield) as light brown lyophilized solids with arbitrarily assigned stereochemistry.

[0132] Enantiomer 4A: 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one 1 H NMR (500 MHz, DMSO, 353.15 Kelvin) δ 7.52 (d, 1H), 7.31-7.18 (m, 2H), 4.71-4.64 (m, 1H), 3.86-3.80 (m, 1H), 3.75-3.66 (m, 1H), 3.17 (s, 3H), 2.99-2.91 (m, 1H), 2.48-2.44 (m, 1H), 2.37-2.27 (m, 1H), 2.17 (s, 3H), 2.12-2.02 (m, 1H), 2.02-1.77 (m, 4H), 1.71-1.63 (m, 1H). Note: Phenol protons have been exchanged. LCMS m / z 410.2 [M+H] + ESI pos.

[0133] Enantiomer 4B: 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one 1 H NMR (400 MHz, DMSO, 363.15 Kelvin) δ 10.34 (s, 1H), 7.52 (d, 1H), 7.24-7.19 (m, 2H), 4.72-4.62 (m, 1H), 3.89-3.80 (m, 1H), 3.77-3.65 (m, 1H), 3.18 (s, 3H), 2.98-2.91 (m, 1H), 2.48-2.44 (m, 1H), 2.38-2.27 (m, 1H), 2.18 (s, 3H), 2.13-1.78 (m, 5H), 1.72-1.64 (m, 1H). Note: Phenol protons have exchanged. One proton is partially obscured by the water peak. LCMS m / z 410.2 [M+H] + ESI pos.

[0134] Examples 5A and 5B: Enantiomer 5A and Enantiomer 5B of 3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one [ka] 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol Intermediate 2 (0.15 g, 0.61 mmol, 1.1 equiv), 3-chloro-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one Intermediate 1 (157.0 mg, 0.55 mmol, 1.0 equiv), meCgPPh Pd in ​​1,4-dioxane (4 mL) and water (1 mL). A mixture of G3 (CAS no. 2230788-58-4, 18.3 mg, 0.03 mmol, 0.05 equiv) and potassium carbonate (0.23 g, 1.66 mmol, 3.0 equiv) was degassed with nitrogen for 5 minutes, and then the reaction was heated to 90 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (24 g cartridge, 0-10% (0.7 M NH3) MeOH / DCM) and then purified by C 18The residue was purified by RP chromatography on a 4 g cartridge (0-20% MeCN / HO (0.1% formic acid)) to give an off-white solid (17.7 mg). The white solid was dissolved in MeOH (1 mL) with sonication, filtered, and then separated by chiral SFC on a Waters prep 15 with UV detection by DAD at 210-400 nm, 40 °C, and 120 bar. The column was an A1 10 x 250 mm, 5 μm, with a flow rate of 15 mL / min in 40% MeOH (neutral) 60% CO. Clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residue was redissolved in methanol, transferred to a final vial, and evaporated on a Biotage V10. The sample was then further dried in a vacuum oven at 30°C / 5 mbar over the weekend to give both enantiomers 5A (5.8 mg, 3%) and 5B (5.3 mg, 3%) as off-white solids with arbitrarily assigned stereochemistry.

[0135] Enantiomer 5A: 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-4-methyl-1,2,4-triazin-5-one 1 H NMR (500 MHz, DMSO) δ 7.08 (d, 1H), 6.65 (d, 1H), 4.76-4.56 (m, 1H), 3.85-3.70 (m, 1H), 3.68-3.58 (m, 1H), 3.14 (s, 3H), 3.10-3.03 (m, 4H), 2.90 (dd, 1H), 2.48-2.43 (m, 1H), 2.34-2.23 (m, 1H), 2.14 (s, 3H), 2.06-1.74 (m, 5H), 1.69-1.62 (m, 1H). One exchangeable proton was not observed. LCMS m / z 368.2 [M+H] + ESI pos.

[0136] Enantiomer 5B: 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-4-methyl-1,2,4-triazin-5-one 1 H NMR (500 MHz, DMSO) δ 7.07 (d, 1H), 6.63 (d, 1H), 4.80-4.56 (m, 1H), 3.85-3.68 (m, 1H), 3.68-3.57 (m, 1H), 3.14 (s, 3H), 3.11-3.01 (m, 4H), 2.90 (dd, 1H), 2.48-2.42 (m, 1H), 2.34-2.25 (m, 1H), 2.14 (s, 3H), 2.07-1.74 (m, 5H), 1.69-1.59 (m, 1H). One exchangeable proton was not observed. LCMS m / z 368.2 [M+H] + ESI pos.

[0137] Example 6: 3-(4-hydroxyindan-5-yl)-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one [ka] A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-4-ol (CAS number 2795101-92-5, 287.1 mg, 1.1 mmol), 3-chloro-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one Intermediate 1 (232.0 mg, 0.74 mmol, 1.0 equiv), XPhos Pd G3 (62.4 mg, 0.07 mmol, 0.1 equiv) and potassium carbonate (305.1 mg, 2.21 mmol, 3.0 equiv) in MeCN (4 mL) and water (1 mL) was degassed with nitrogen for 5 minutes, and then the reaction was heated to 80 °C for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (40 g cartridge, 0-10% (0.7 M NH3) MeOH / DCM) to afford the title compound (93.3 mg, 30% yield) as an off-white solid. LCMS m / z 382.3 [M+H] + ESI pos.

[0138] Example 6 Chiral Separation: Example 6 (71.5 mg) was dissolved in MeOH, filtered, and then separated by chiral SFC on a Waters prep100 using PDA and QDa detectors at 40 °C and 120 bar. The column was Lux Amylose-1, 5 μM, 21 mm × 250 mm, 65% MeOH (0.5% DEA), 35% CO2 at a flow rate of 65 mL / min. Clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residue was redissolved in methanol, transferred to a final vial, and evaporated on a Biotage V10. The sample was then further dried overnight in a vacuum oven at 30 °C / 5 mbar to give Enantiomer 6A and Enantiomer 6B as yellowish glasses. The sample was then coevaporated with MeCN followed by MeOH to remove traces of DEA and dried in a desiccator to give both enantiomer 6A (31.6 mg, 11% yield) and enantiomer 6B (23.7 mg, 8% yield) as off-white solids with arbitrarily assigned stereochemistry.

[0139] Enantiomer 6A: 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxyindan-5-yl)-4-methyl-1,2,4-triazin-5-one 1 H NMR(500MHz,DMSO)δ9.31(s,1H),7.03(d,1H),6.80(d,1H),4.77-4.54(m,1H),3.87-3.70(m,1H),3.70-3.57(m,1H),3.12(s,3H) ),2.95-2.86(m,3H),2.83(t,2H),2.49-2.42(m,1H),2.34-2.25(m,1H),2.14(s,3H),2.07-1.76(m,7H),1.70-1.63(m,1H).LCMS m / z 382.2[M+H] + ESI pos.

[0140] Enantiomer 6B: 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxyindan-5-yl)-4-methyl-1,2,4-triazin-5-one 1 H NMR(500MHz,DMSO)δ9.28(s,1H),7.03(d,1H),6.81(d,1H),4.82-4.49(m,1H),3.88-3.69(m,1H),3.69-3.51(m,1H),3.12(s,3H) ),2.96-2.86(m,3H),2.83(t,2H),2.49-2.42(m,1H),2.34-2.25(m,1H),2.14(s,3H),2.07-1.76(m,7H),1.69-1.62(m,1H).LCMS m / z 382.3[M+H] + ESI pos.

[0141] Example 7: 6-[6-(2-hydroxyethyl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one [ka]

[0142] Step A: tert-Butyl pyrrolo[2,3-c]pyridine-1-carboxylate A solution of 6-azaindole (10.0 g, 84.7 mmol, 1.0 equiv.) and di-t-butyl dicarbonate (27.8 g, 127.24 mmol, 1.5 equiv.) in THF (240 mL) and triethylamine (20.0 mL, 143.49 mmol, 1.7 equiv.) was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo to give the title compound (34.1 g, quantitative) as a pale orange oil. LCMS: m / z 162.5 [M-tBu+H] + ,ESI pos.

[0143] Step B: tert-Butyl 2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine-1-carboxylate A solution of tert-butyl pyrrolo[2,3-c]pyridine-1-carboxylate (34.1 g, 84.37 mmol, 1.0 equiv.) and Rh / C Form 20D (5.2 g, 2.53 mmol, 0.03 equiv.) in ethanol (120 mL) and acetic acid (30 mL) was placed under a hydrogen atmosphere and stirred under hydrogen at 50 °C and 5 bar pressure for 2 days. The reaction mixture was filtered through a plug of Celite, and the plug was rinsed with ethanol (2 × 50 mL). The filtrate was diluted with toluene (100 mL) and concentrated to an oil, which was azeotroped with additional toluene (2 × 100 mL). The reaction mixture was diluted with a mixture of chloroform:iPrOH (9:1, 100 mL), and 2 M NaOH was added until a pH of 8–9 was achieved (approximately 100 mL). The separated aqueous layer was further extracted with the solvent mixture (2 × 100 mL). The combined extracts were dried (Na2SO4), filtered and concentrated to give the title compound (20.6 g, 91% yield) as a viscous yellow oil. LCMS: m / z 171.5 [M-tBu+H] + ,ESI pos.

[0144] Step C: tert-Butyl 6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-carboxylate To a stirred suspension of tert-butyl 2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine-1-carboxylate (9.2 g, 34.55 mmol, 1.0 equiv.) and potassium carbonate (10.6 g, 76.6 mmol, 2.22 equiv.) in MeCN (150 mL), benzyl bromide (4.3 mL, 36.2 mmol, 1.05 equiv.) was added dropwise, and the reaction was allowed to stir at room temperature for 2.5 hours. Benzyl bromide (1.2 mL, 10.09 mmol, 0.29 equiv.) was added, and the reaction was allowed to stir for approximately 16 hours. The reaction mixture was diluted with EtOAc (250 mL) and water (250 mL), and the phases were separated. The aqueous layer was extracted again with EtOAc (3 x 100 mL), and the combined organic layers were washed with NaHCO3 (2 x 100 mL), dried over MgSO4, and concentrated in vacuo to give the title compound (13.5 g, quantitative). Approximately 1 g was purified by column chromatography on silica gel (40 g cartridge, 0-10% MeOH (0.7 M NH3) / DCM) to give the title compound (827 mg) as an off-white solid. LCMS m / z 317.3 [M+H] + ESI pos.

[0145] Step D: 6-benzyl-1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine, dihydrochloride tert-Butyl 6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-carboxylate (827.0 mg, 2.61 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and 4 M hydrochloric acid in dioxane (2.6 mL, 10.4 mmol, 3.98 equiv.) was added dropwise. The reaction mixture was stirred at room temperature for approximately 16 hours. The reaction mixture was concentrated in vacuo and then dried in a vacuum oven at 50° C. for 1 day to afford the title compound (870.0 mg, 86% yield) as a pale yellow waxy solid. LCMS m / z 217.2 [M+H] + ESI pos.

[0146] Step E: 6-(6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione A mixture of 6-benzyl-1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine dihydrochloride (870.0 mg, 3.01 mmol, 1.0 equiv.), 6-bromo-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione (1.19 g, 3.65 mmol, 1.21 equiv.), and CsCO (7.82 g, 24.0 mmol, 7.98 equiv.) in MeCN (14 mL) was sparged (N bubbling and sonication for 2 min). Pd(OAc) (54.0 mg, 0.24 mmol, 0.08 equiv.) and Xanthos (140.0 mg, 0.24 mmol, 0.08 equiv.) were added, and the mixture was heated to 50 °C and stirred for 1 h. The reaction was then heated to 80°C and stirred for approximately 18 hours. The reaction mixture was cooled to room temperature, then filtered, and the precipitate was washed with MeCN (2 x 50 mL). The filtrate was concentrated in vacuo, and the resulting residue was dissolved in EtOAc (100 mL) and HCl (100 mL, 1M aqueous solution). The aqueous layer was separated, and the organic layer was washed with HCl (2 x 100 mL, 1M aqueous solution). The aqueous phases were combined, and the pH was adjusted to approximately 9-10 by the addition of solid NaOH. The aqueous material was extracted with EtOAc (3 x 100 mL), and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (40 g cartridge, 0-10% MeOH (0.7 M NH3) / DCM) to afford the title compound (697.0 mg, 48% yield) as a viscous dark red oil. LCMS m / z 462.3 [M+H] + ESI pos.

[0147] Step F: 6-(6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-4-methyl-2H-1,2,4-triazine-3,5-dione Trifluoromethanesulfonic acid (320.0 μL, 3.62 mmol, 2.52 equiv) was added dropwise to a stirred solution of 6-(6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione (697.0 mg, 1.43 mmol, 1.0 equiv) in DCM (8 mL) and MeCN (4 mL) at room temperature. The reaction was heated to 35° C. and stirred for 22 hours. The reaction was diluted with HO (100 mL) and DCM (100 mL) and transferred to a separatory funnel. The separated organic layer was further extracted with 1 M aqueous HCl (100 mL). The aqueous layers were combined in a vigorously stirred Erlenmeyer flask, cooled to 0°C, and basified with tribasic sodium phosphate until a pH of approximately 8-9 was achieved. The mixture was again transferred to a separatory funnel and diluted with DCM (200 mL). The separated aqueous layer was further extracted with DCM (2 x 100 mL), and the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (420.0 mg, 84% yield) as an off-white solid. LCMS m / z 341.8 [M+H] + ESI pos.

[0148] Step G: 6-(6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-3-chloro-4-methyl-1,2,4-triazin-5-one Phosphorus oxychloride (5.0 mL, 53.64 mmol, 43.6 equiv.) was added to 6-(6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-4-methyl-2H-1,2,4-triazine-3,5-dione (420.0 mg, 1.23 mmol, 1.0 equiv.), and the solution was stirred at 105° C. The resulting brown, opaque solution was vigorously stirred for 3 days. The reaction mixture was concentrated in vacuo, and the resulting brown oil was then dissolved in MeCN (approximately 10 mL) and added portionwise to a vigorously stirred solution of EtOAc (50 mL) and KPO (25 wt. % aqueous solution, 50 mL). The pH was monitored during the addition to ensure the aqueous remained basic (approximately pH 8). The pH of the aqueous solution was then adjusted to approximately pH 12 by portionwise addition of solid K3PO4, and the organic material was separated. The aqueous material was again extracted with EtOAc (2 x 100 mL), and the combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (24 g cartridge, 0-10% MeOH (0.7 M NH3) / DCM) to afford the title compound (413.0 mg, 90% yield) as a light brown solid. LCMS m / z 360.2 / 362.1 [M+H] + ESI pos.

[0149] Step H: 6-(6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-3-[2-benzyloxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one A mixture of [2-benzyloxy-4-(trifluoromethoxy)phenyl]boronic acid (314.0 mg, 1.01 mmol, 1.21 equiv.), 6-(6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-3-chloro-4-methyl-1,2,4-triazin-5-one (299.0 mg, 0.83 mmol, 1.0 equiv.), and sodium bicarbonate (222.0 mg, 2.64 mmol, 3.18 equiv.) in water (4 mL) and MeCN (4 mL) was degassed for 5 minutes. XPhos Pd G3 (75.0 mg, 0.09 mmol, 0.11 equiv.) was added, and the reaction mixture was heated at 85 °C for 3 hours. The reaction was cooled to room temperature, filtered through Celite, and concentrated in vacuo. The reaction was diluted with EtOAc (100 mL) and 1 M aqueous HCl (100 mL) and transferred to a separatory funnel. The separated organic layer was further extracted with 1 M aqueous HCl (100 mL). The aqueous layers were combined in a vigorously stirred Erlenmeyer flask, cooled to 0 °C, and basified with NaOH until a pH of approximately 8-9 was achieved. The mixture was again transferred to a separatory funnel and diluted with DCM (200 mL). The separated aqueous layer was further extracted with DCM (2 × 100 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (423.0 mg, 75% yield) as a pale yellow solid. LCMS m / z 592.2 [M+H] + ESI pos.

[0150] Step I: 6-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridin-1-yl)-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one Pd / C (form 39) (190.0 mg, 0.18 mmol, 0.25 equiv.) and Pd / C (form 87) (380.0 mg, 0.18 mmol, 0.25 equiv.) were added to a stirred solution of 6-(6-benzyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-3-[2-benzyloxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one (423.0 mg, 0.71 mmol, 1.0 equiv.) in 1,4-dioxane (7 mL). The hydrogenation vessel was placed under a hydrogen gas atmosphere (2 bar) at 50 °C and vigorously stirred for 4 h. The reaction was filtered through a plug of Celite, rinsed with dioxane, then MeOH, and concentrated to dryness to give the title compound (246.0 mg, 80% yield) as a pale yellow solid. LCMS m / z 412.2 [M+H] + ESI pos.

[0151] Step J: 6-[6-(2-hydroxyethyl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one 2-Iodoethanol (19.8 mg, 0.12 mmol, 0.95 equiv) in DMF (215 µL) was added dropwise to a stirred solution of 6-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridin-1-yl)-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one (50.0 mg, 0.12 mmol, 1.0 equiv) and DIPEA (32.0 µL, 0.18 mmol, 1.51 equiv) in DMF (230 µL) at room temperature, and the reaction mixture was stirred for 48 h. The reaction mixture was transferred to a separatory funnel and diluted with EtOAc (25 mL) and 1 M aqueous HCl (25 mL). The separated organic layer was further extracted with 1 M aqueous HCl (25 mL). The combined aqueous layers were washed with EtOAc (25 mL). The aqueous layer was basified with saturated aqueous NaHCO3 until a pH of approximately 8 was achieved, then extracted with DCM (3 x 25 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (4 g cartridge, 0-10% MeOH (0.7 M NH3) / DCM) to give the title compound (25.7 mg, 46% yield) as a white solid. LCMS m / z 456.3 [M+H] + ESI pos.

[0152] Chiral Separation of Example 7: Example 7 (24 mg) was dissolved at 8 mg / mL in 2 mL of MeOH and 1 mL of DCM with sonication and heating, filtered, and then separated by chiral SFC on a Waters Prep 100 using PDA and QDA detectors at 40 °C and 120 bar. The column was a ChiralpaK IC, 21 × 250 mm, 5 μm, 30% MeOH (0.3% DEA), 70% CO at a flow rate of 65 mL / min. Clean fractions were pooled, rinsed with methanol, and concentrated to dryness using a rotary evaporator. The residue was redissolved in methanol, transferred to a final vial, and evaporated on a Biotage V10 to give both Example 7A (1.3 mg, 2% yield) and Example 7B (5.2 mg, 9% yield) as off-white solids with arbitrarily assigned stereochemistry.

[0153] Example 7A: 6-[(3aS,7aR)-6-(2-hydroxyethyl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one 1 H NMR (500 MHz, DMSO) δ 7.40 (d, 1H), 6.95-6.77 (m, 2H), 4.79-4.52 (m, 1H), 4.41-4.28 (m, 1H), 3.90-3.56 (m, 2H), 3.47 (t, 2H), 3.14 (s, 3H), 3.07-2.99 (m, 1H), 2.66-2.56 (m, 1H), 2.38 (t, 2H), 2.34-2.24 (m, 1H), 2.20-2.08 (m, 1H), 2.05-1.75 (m, 4H), 1.69-1.60 (m, 1H). One exchangeable proton was not observed. LCMS m / z 456.3 [M+H] + ESI pos.

[0154] Example 7B: 6-[(3aR,7aS)-6-(2-hydroxyethyl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one 1 H NMR (500 MHz, DMSO) δ 7.27 (d, 1H), 6.73-6.48 (m, 2H), 4.79-4.55 (m, 1H), 4.48-4.19 (m, 1H), 3.81-3.69 (m, 1H), 3.67-3.58 (m, 1H), 3.46 (t, 2H), 3.18 (s, 3H), 3.05-2.99 (m, 1H), 2.62-2.56 (m, 1H), 2.37 (t, 2H), 2.34-2.24 (m, 1H), 2.19-2.09 (m, 1H), 2.04-1.73 (m, 4H), 1.69-1.60 (m, 1H). One exchangeable proton was not observed. LCMS m / z 456.3 [M+H] + ESI pos.

[0155] Example A The compounds of formula I can be used in a manner known per se as active ingredient to produce tablets of the following composition:

[0156] Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0157] Example B The compound of formula I can be used in a manner known per se as the active ingredient to produce capsules of the following composition:

[0158] Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Compounds of Formula I 【Chemistry 1】 (In the formula, R １ is H, alkyl, alkoxy, —CN, halo, haloalkyl, haloalkoxy, acetyl, or SF ６ and R ５ is H or Or, R １ and R ５ and the atoms to which they are attached form either a 4-6 membered heterocycle containing a single O heteroatom optionally substituted with 1 or 2 substituents independently selected from halo or alkyl, or R １ and R ５ and the atoms to which they are attached form a 4- to 6-membered cycloalkyl ring optionally substituted with 1 to 2 substituents independently selected from halo or alkyl; R ２ is H, halo or alkyl, and R ３ is H or alkyl, and R ２ and R ３ and only one of R ４ is an oxetane, alkyl, or -(CH ２ ) ｎ -R ６ and R ６ is hydroxy or methoxy, and n is greater than 1. and pharmaceutically acceptable salts thereof.

2. R １ The compound of claim 1 , wherein is haloalkyl or haloalkoxy.

3. R ２ is H and R ３ 3. The compound of claim 1 or 2, wherein is alkyl.

4. R ４ is alkyl or -(CH ２ ) ｎ -R ６ and R ６ The compound of any one of claims 1 to 3, wherein is hydroxy and n is 2.

5. R ４ The compound according to any one of claims 1 to 4, wherein is alkyl.

6. R １ is haloalkyl or haloalkoxy; R ５ is H or Or, R １ and R ５ together with the atom to which they are attached form a 4- to 5-membered cycloalkyl or a 5-membered heterocycle containing a single O heteroatom; R ２ is H, R ３ is alkyl, R ４ is alkyl or -(CH ２ ) ｎ -R ６ and R ６ is hydroxy and n is 2; 10. The compound of claim 1, and pharmaceutically acceptable salts thereof.

7. R １ is haloalkyl or haloalkoxy; R ５ is H or Or, R １ and R ５ together with the atom to which they are attached form a 4- to 5-membered cycloalkyl or a 5-membered heterocycle containing a single O heteroatom; R ２ is H, R ３ is alkyl, R ４ is alkyl, 10. The compound of claim 1, and pharmaceutically acceptable salts thereof.

8. 3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one, formic acid, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one, 3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-4-methyl-1,2,4-triazin-5-one, and pharmaceutically acceptable salts thereof The compound according to any one of claims 1 to 7, selected from:

9. 3-(4-hydroxyindan-5-yl)-4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxyindan-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxyindan-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[6-(2-hydroxyethyl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-(2-hydroxyethyl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-(2-hydroxyethyl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, and pharmaceutically acceptable salts thereof The compound according to any one of claims 1 to 7, selected from:

10. 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-4-methyl-1,2,4-triazin-5-one, and pharmaceutically acceptable salts thereof The compound according to any one of claims 1 to 8, selected from:

11. 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one, and pharmaceutically acceptable salts thereof The compound according to any one of claims 1 to 8, selected from:

12. The compound according to any one of claims 1 to 7 or claim 9, which is 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxyindan-5-yl)-4-methyl-1,2,4-triazin-5-one, or a pharmaceutically acceptable salt thereof.

13. 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-4-methyl-1,2,4-triazin-5-one, 6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-3-(4-hydroxyindan-5-yl)-4-methyl-1,2,4-triazin-5-one, and pharmaceutically acceptable salts thereof The compound according to any one of claims 1 to 12, selected from:

14. A compound according to any one of claims 1 to 13 for use as a therapeutically active substance.

15. 14. A compound according to any one of claims 1 to 13 for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a therapeutically inert carrier.

17. 14. Use of a compound according to any one of claims 1 to 13 for the treatment or prevention of a disease, disorder or condition, wherein said disease, disorder or condition is responsive to NLRP3 inhibition.

18. A compound according to any one of claims 1 to 13 for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

19. A compound according to any one of claims 1 to 13 for the treatment or prevention of a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

20. 14. Use of a compound according to any one of claims 1 to 13 in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

21. 14. Use of a compound according to any one of claims 1 to 13 in the treatment or prevention of a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

22. 14. Use of a compound according to any one of claims 1 to 13 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

23. Use of a compound according to any one of claims 1 to 13 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

24. 14. A method of inhibiting NLRP3, comprising administering an effective amount of a compound according to any one of claims 1 to 13 to inhibit NLRP3.

25. 14. A method for the treatment or prevention of a disease, disorder or condition, said method comprising administering an effective amount of a compound according to any one of claims 1 to 13, wherein said disease, disorder or condition is selected from asthma or COPD.

26. 14. A method for the treatment or prevention of a disease, disorder or condition, said method comprising administering an effective amount of a compound according to any one of claims 1 to 13, wherein said disease, disorder or condition is selected from Parkinson's disease or Alzheimer's disease.

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