NLRP3 inhibitors

Abstract

The present invention relates to compounds of the general formula Ib TIFF2024517917000065.tif53169 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and Z are as described herein. The present invention relates to novel compounds having the formula:

Description

[Technical field]

[0001] FIELD OF THEINVENTION 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 a compound of formula Ib [ka] (In the formula, R 1 is H, acetyl, SF5, halo, alkyl, haloalkyl, haloalkoxy or nitrile; R 5 Is H? Or R 1 and R 5 and the atoms to which they are attached form 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 3-6 membered cycloalkyl ring optionally substituted with 1-2 substituents independently selected from halo or alkyl; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; R 3 is H, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; Z is -O- or -NH-; R 4 is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -COH, cycloalkylalkyl, or cycloalkyl optionally substituted with halo; or R4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or R 4 is arylalkyl or heteroarylalkyl, and the arylalkyl or heteroarylalkyl has 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH. The present invention provides novel compounds of the formula:

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

[0004] 2. Background of the Invention The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of inflammatory processes and its aberrant activity is pathogenic in genetic disorders such as cryopyrin-associated periodic syndromes (CAPS), as well as 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-derived, environmental, and host-derived factors. Upon activation, NLRP3 binds to the apoptosis-associated speckle protein, which contains 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 proinflammatory cytokines IL-1β and IL-18 (termed 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 to trigger apoptotic cell death.

[0006] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted from cells. Active caspase-1 also cleaves gasdermin-D, leading to 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, allowing IL-1α to be liberated. In human cells, caspase-1 can also control the processing and secretion of IL-37. Many other caspase-1 substrates, such as components of the cytoskeleton and glycolytic pathways, can contribute to caspase-1-dependent inflammation.

[0007] NLRP3-dependent ASC specks are released into the extracellular milieu where they can activate caspase-1, induce 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 secretion of the proinflammatory 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 that drive 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, thus defining it as a key component of the inflammatory process. NLRP3 has also been implicated in the pathogenesis of many complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout, among others.

[0010] A role for NLRP3 in diseases of the central nervous system has emerged for diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Lung diseases have also been shown to be influenced by NLRP3. In addition, NLRP3 plays a role in the development of liver disease, kidney disease, and aging. Many of these associations may be due to the involvement of NLRP3. - / - Although defined in 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 activation of NLRP3, but not NLRC4 or NLRP1. Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethylsulfoxide (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 are 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 which have improved pharmacological and / or physiological and / or physicochemical properties and / or which represent useful alternatives to known compounds. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows voltage patterns in hERG testing. Summary of the Invention

[0015] The present invention relates to a compound of formula Ib [ka] (In the formula, R 1 is H, acetyl, SF5, halo, alkyl, haloalkyl, haloalkoxy or nitrile; R 5 Is H? Or R 1 and R 5and the atoms to which they are attached form 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 3-6 membered cycloalkyl ring optionally substituted with 1-2 substituents independently selected from halo or alkyl; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; R 3 is H, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; Z is -O- or -NH-; R 4 is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -COH, cycloalkylalkyl, or cycloalkyl optionally substituted with halo; or R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or R 4 is arylalkyl or heteroarylalkyl, and the arylalkyl or heteroarylalkyl has 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH. The present invention provides novel compounds of the formula:

[0016] The term "alkyl" refers to a monovalent linear or branched 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. Particular alkyl groups include methyl, ethyl, propyl, and butyl. When an alkyl residue having a particular number of carbons is named, all geometric isomers having that number of carbons can be included. Thus, for example, "butyl" can include n-butyl, sec-butyl, isobutyl, and t-butyl, and "propyl" can include n-propyl and isopropyl.

[0017] The term "alkoxy" refers to a group in which R' is C 1-6 represents a group of the 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. Particular examples are methoxy and ethoxy.

[0018] The term "acetyl" refers to a group of formula -C(=O)-R', where R' is an alkyl group. Examples of acetyl include -C(=O)CH3.

[0019] The term "aryl", alone or in combination with other groups, refers to a monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic or bicyclic aromatic ring. A preferred aryl is phenyl. Aryl may be unsubstituted or substituted as described herein.

[0020] The term "arylalkyl" refers to an alkyl group in which one of the alkyl group's hydrogen atoms is replaced by an aryl group. An example of an arylalkyl group is phenylalkyl, specifically phenylmethyl.

[0021] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise stated, a cycloalkyl contains 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, a cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. In other embodiments, a cycloalkyl contains one or more double bonds (e.g., a cycloalkyl fused to an aryl or heteroaryl ring, or a non-aromatic monocyclic hydrocarbon containing one or two double bonds). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, spiro[3.3]heptanyl, and the like. Bicyclic means a ring system consisting of two saturated carbocyclic rings with two shared carbon atoms. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, or cycloheptyl. Particular examples are cyclopropyl and cyclobutyl.

[0022] The term "cycloalkylalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl and hydroxycyclopropylmethyl. A particular example is cyclopropylmethyl.

[0023] The terms "halogen", "halide" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo or iodo. Particular halogens are fluoro and chloro.

[0024] The term "haloalkyl" means C 1-6 - at least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom 1-6-represents an alkyl group. Particular examples are fluoromethyl, difluoromethyl and trifluoromethyl.

[0025] The term "haloalkoxy" means 1-6 - 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. A preferred example is trifluoromethoxy.

[0026] The term "heteroaryl", alone or in combination with other groups, refers to a monovalent aromatic containing 1 to 4 ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C. Preferably, the monocyclic heteroaryl has 1 or 2 heteroatoms. Five- or six-membered heteroaryls are preferred. Examples of heteroaryl moieties include, but are not limited to, pyridyl, pyrazinyl, and thienyl. Heteroaryls may be unsubstituted or substituted as described herein.

[0027] The term "heteroarylalkyl" refers to an alkyl group in which one of the alkyl group's hydrogen atoms has been replaced by a heteroaryl group. Examples of heteroarylalkyl groups include pyridinylalkyl.

[0028] The term "heterocycle" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 10 ring atoms, or 3 to 8 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycles are oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, or piperazinyl. Examples of partially unsaturated heterocycles are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. Particular examples of heterocycles are octahydroindolizinyl, azabicyclo[2.2.1]heptan-6-yl, azabicyclo[3.2.1]octan-2-yl, piperidinyl or furanyl. Preferred examples are furanyl and piperidinyl.

[0029] The term "hydroxy" refers to an --OH group.

[0030] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, and dihydroxypropyl.

[0031] The term "nitrile" or "cyano" refers to the group --C.ident.N.

[0032] The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. Salts are formed with inorganic acids, such as 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, N-acetylcysteine. In addition, these salts can be prepared from the addition of inorganic or organic bases to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, 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, polyamine resins. Compounds of formula Ib may also exist in zwitterionic form. Particularly preferred pharma- ceutically acceptable salts of compounds of formula Ib are salts formed with formic acid, acetic acid, trifluoroacetic acid, and with hydrochloric acid to give hydrochloride, dihydrochloride, or trihydrochloride.

[0033] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0034] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0035] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0036] The compounds of formula Ib 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.

[0037] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0038] An embodiment of the present invention also provides compounds according to formula I as described herein and pharma- ceutically acceptable salts or esters thereof, particularly compounds according to formula Ib as described herein and pharma- ceutically acceptable salts thereof, more particularly compounds according to formula Ib as described herein.

[0039] One embodiment of the present invention is 1 is acetyl, SF5, halo, haloalkyl, haloalkoxy or nitrile.

[0040] One embodiment of the present invention is 1 is halo, haloalkyl or haloalkoxy.

[0041] One embodiment of the present invention is 1 is haloalkoxy.

[0042] One embodiment of the present invention is 1 is H, halo, alkyl, haloalkyl, or haloalkoxy.

[0043] One embodiment of the present invention is 1 is Cl, OCF3, CF3, or CH3.

[0044] One embodiment of the present invention is 1 is Cl or CF.

[0045] One embodiment of the present invention is 1 is CF3.

[0046] One embodiment of the present invention is 2 is H, halo, alkyl, haloalkyl, or cycloalkyl, wherein cycloalkyl is optionally substituted with halo.

[0047] One embodiment of the present invention is 2 is H, halo, alkyl or haloalkyl.

[0048] One embodiment of the present invention is 2 is H or alkyl.

[0049] One embodiment of the present invention is 2 is H.

[0050] One embodiment of the present invention is 3 is H, alkyl, haloalkyl, or cycloalkyl, wherein cycloalkyl is optionally substituted with halo.

[0051] One embodiment of the present invention is 3 is H, alkyl or haloalkyl.

[0052] One embodiment of the present invention is 3 is alkyl.

[0053] One embodiment of the present invention is4 is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, or cycloalkylalkyl; or R 4 is cycloalkyl optionally substituted with two substituents independently selected from alkyl, and -OH; or R 4 is an arylalkyl substituted with OH.

[0054] One embodiment of the present invention is 4 is a heterocycle optionally substituted with alkyl.

[0055] One embodiment of the present invention is 4 is an alkyl substituted pyrrolidine, furan, piperidine, or pyran ring.

[0056] One embodiment of the present invention is 4 is an alkyl substituted pyrrolidine or piperidine ring.

[0057] One embodiment of the present invention is 4 is an alkyl substituted piperidine ring.

[0058] One embodiment of the present invention is 4 is tert-butylpiperidine.

[0059] One embodiment of the present invention is 4 is ethylpiperidine.

[0060] One embodiment of the present invention provides a compound according to formula Ib described herein, wherein Z is -NH-.

[0061] One embodiment of the present invention is5 is H or R 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and compounds according to formula Ib as described herein, wherein the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring.

[0062] One embodiment of the present invention is 5 is H or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O atom, according to formula Ib as described herein.

[0063] One embodiment of the present invention is 5 is H.

[0064] One embodiment of the present invention is 1 and R 5 and the atoms to which they are attached form 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 3-6 membered cycloalkyl ring, optionally substituted with 1 or 2 substituents independently selected from halo or alkyl.

[0065] One embodiment of the present invention is 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and compounds according to formula Ib as described herein, wherein the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring.

[0066] One embodiment of the present invention is1 and R 5 and compounds according to formula Ib as described herein, wherein the atoms to which they are attached form a 5-membered heterocycle containing a single O heteroatom.

[0067] One embodiment of the present invention comprises: R 1 is acetyl, SF5, halo, haloalkyl, haloalkoxy or nitrile; R 5 Is H? Or R 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R 2 is H or alkyl; R 3 is H, alkyl or cycloalkyl; Z is -NH-; R 4 is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, or cycloalkylalkyl; or R 4 is cycloalkyl optionally substituted with two substituents independently selected from alkyl and -OH; or R 4 is arylalkyl substituted with OH; Provided herein are compounds according to formula Ib, and pharma- ceutically acceptable salts.

[0068] One embodiment of the present invention comprises: R 1 is acetyl, SF5, halo, haloalkyl, haloalkoxy or nitrile; R 5 Is H? Or R 1 and R 5and the atoms to which they are attached form a 5-membered heterocycle containing a single O, R 2 is H or alkyl; R 3 is H, alkyl or cycloalkyl; Z is -NH-; R 4 is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, or cycloalkylalkyl; or R 4 is cycloalkyl optionally substituted with two substituents independently selected from alkyl and -OH; or R 4 is arylalkyl substituted with OH; Provided herein are compounds according to formula Ib, and pharma- ceutically acceptable salts.

[0069] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, or haloalkoxy; R 5 Is H? Or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O, R 2 Is H? R 3 is alkyl; Z is -NH-; R 4 is a piperidyl ring optionally substituted with alkyl; Provided herein are compounds according to formula Ib, and pharma- ceutically acceptable salts.

[0070] One embodiment of the present invention comprises: R 1 is haloalkoxy; R 5 Is H? R 2 Is H? R 3 is alkyl; Z is -NH-; R 4 is a piperidyl ring optionally substituted with alkyl; Provided herein are compounds according to formula Ib, and pharma- ceutically acceptable salts.

[0071] One embodiment of the present invention comprises: R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, or nitrile; R 5 Is H? Or R 1 and R 5 and the atoms to which they are attached form 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 3- to 6-membered cycloalkyl ring having 1 or 2 substituents independently selected from halo or alkyl; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; R 3 is H, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; Z is -O- or -NH-; R 4 is a heterocycle optionally substituted with 1 to 2 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -COH, or cycloalkyl optionally substituted with halo; or R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or R 4 is arylalkyl or heteroarylalkyl, wherein the arylalkyl or heteroarylalkyl optionally bears up to three substituents independently selected from alkyl, halo, haloalkyl, and -OH; Provided herein are compounds according to formula Ib, and pharma- ceutically acceptable salts thereof.

[0072] One embodiment of the present invention comprises: R 1 and R 5 and the atoms to which they are attached form 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 atom to which they are attached forms a 3- to 6-membered cycloalkyl optionally substituted with 1 or 2 substituents independently selected from halo or alkyl; R 2 but H; R 3 is methyl; Z is -NH-; R 4 is an alkyl substituted piperidine ring; Provided herein are compounds according to formula Ib, and pharma- ceutically acceptable salts thereof.

[0073] One embodiment of the present invention comprises: R 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered cycloalkyl ring: R 2 but H; R 3 is methyl; Z is -NH-; R 4is an alkyl substituted piperidine ring; Provided herein are compounds according to formula Ib, and pharma- ceutically acceptable salts thereof.

[0074] Specific examples of compounds of formula Ib described herein are 6-((1-ethylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-3-piperidyl]amino]-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[(8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino]-1,2,4-triazin-5-one; (R)-6-((1-(cyclopropylmethyl)piperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one; (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one; 6-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-1-propyl-3-piperidyl]amino]-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[(1,5,5-trimethyl-3-piperidyl)amino]-1,2,4-triazin-5-one; (R)-6-((1-cyclopropylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one; 6-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one; 6-[(1-tert-butyl-3-piperidyl)amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-(2-Azabicyclo[2.2.1]heptan-6-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R,5S)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R,5R)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(5S)-5-Fluoro-1-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R)-6,6-dimethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[(3-hydroxyphenyl)methylamino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 4-Cyclopropyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-fluoro-2-hydroxy-phenyl)-4-methyl-1,2,4-triazin-5-one; 4-Ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-1,2,4-triazin-5-one; 3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 3-[4-(1,1-difluoroethyl)-2-hydroxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 3-(4-acetyl-2-hydroxy-phenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; (M or P)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; (P or M)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(pentafluoro-λ6-sulfanyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-5-oxo-1,2,4-triazin-3-yl]-3-hydroxy-benzonitrile; 3-(4-chloro-2-hydroxy-phenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazin-5-one; 6-[[(3R,5S)-1-ethyl-5-fluoro-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazin-5-one; and pharma- ceutically acceptable salts thereof.

[0075] Preferred examples of compounds of formula Ib described herein are 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one; (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one; 3-(4-chloro-2-hydroxy-phenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-5-one; and pharma- ceutically acceptable salts thereof.

[0076] The most preferred example of the compound of formula Ib described herein is 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one and its pharma- ceutically acceptable salts.

[0077] Other examples of formula Ib described herein include 6-((1-ethylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one or 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one, or any of their pharma- ceutically acceptable salts.

[0078] An embodiment of the present invention provides a compound according to formula I, wherein the compound of formula I is a compound of formula Ib. [ka]

[0079] Moreover, one embodiment of the present invention is R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, or nitrile; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; R 3 is H, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; Z is -O- or -NH-; R 4 is a heterocycle optionally substituted with 1 to 2 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -COH, or cycloalkyl optionally substituted with halo; or R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or R 4is arylalkyl or heteroarylalkyl, wherein the arylalkyl or heteroarylalkyl optionally bears up to three substituents independently selected from alkyl, halo, haloalkyl, and -OH; Compounds of Formula I, and pharma- ceutically acceptable salts, are provided:

[0080] One embodiment of the present invention comprises: R 1 is H, halo, alkyl, haloalkyl, or haloalkoxy; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; R 3 is H, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; Z is -O- or -NH-; R 4 is a heterocycle optionally substituted with 1 to 2 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -COH, or cycloalkyl optionally substituted with halo; or R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or R 4 is arylalkyl or heteroarylalkyl, wherein the arylalkyl or heteroarylalkyl optionally bears up to three substituents independently selected from alkyl, halo, haloalkyl, and -OH; Compounds of Formula I, and pharma- ceutically acceptable salts, are provided:

[0081] 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.

[0082] Embodiments of the present invention also provide compounds according to formula I as described herein and pharma- ceutically acceptable salts or esters thereof, particularly compounds according to formula I as described herein and pharma- ceutically acceptable salts thereof, more particularly compounds according to formula I as described herein.

[0083] One embodiment of the present invention is 1 is H, halo, alkyl, haloalkyl, or haloalkoxy.

[0084] One embodiment of the present invention is 1 is Cl, OCF3, CF3, or CH3.

[0085] One embodiment of the present invention is 1 is Cl or CF.

[0086] One embodiment of the present invention is 1 is CF3.

[0087] One embodiment of the present invention is 2 is H, halo, alkyl, haloalkyl, or cycloalkyl, wherein cycloalkyl is optionally substituted with halo.

[0088] One embodiment of the present invention is 2 is H, halo, alkyl or haloalkyl.

[0089] One embodiment of the present invention is 2 is H.

[0090] One embodiment of the present invention is 3 is H, alkyl, haloalkyl, or cycloalkyl, wherein cycloalkyl is optionally substituted with halo.

[0091] One embodiment of the present invention is 3 is H, alkyl or haloalkyl.

[0092] One embodiment of the present invention is 3 is alkyl.

[0093] One embodiment of the present invention is 4 is a heterocycle optionally substituted with alkyl.

[0094] One embodiment of the present invention is 4 is an alkyl substituted pyrrolidine, furan, piperidine, or pyran ring.

[0095] One embodiment of the present invention is 4 is an alkyl substituted pyrrolidine or piperidine ring.

[0096] One embodiment of the present invention is 4 is an alkyl substituted piperidine ring.

[0097] One embodiment of the present invention is 4 is tert-butylpiperidine.

[0098] One embodiment of the present invention is 4 is ethylpiperidine.

[0099] One embodiment of the present invention provides a compound according to formula I described herein, wherein Z is -NH-.

[0100] One embodiment of the present invention comprises: R 1 is Cl, OCF3, alkyl or haloalkyl; R 2 is H, halo, alkyl, haloalkyl, or cycloalkyl (optionally substituted with F); R 3 is H, alkyl, haloalkyl, or cycloalkyl (optionally substituted with F); Z is -O- or -NH-; R 4 is a heterocycle optionally substituted with 1 to 2 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -COH, or cycloalkyl optionally substituted with halo; or R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; Provided are compounds according to formula I described herein.

[0101] One embodiment of the present invention comprises: R 1 is Cl, CH3, OCF3, or CF3; R 2 is H, halo, alkyl or haloalkyl; R 3 is H, alkyl or haloalkyl; Z is -O- or -NH-; R 4is a heterocycle containing 1 heteroatom optionally substituted with 1 to 2 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -COH, or cycloalkyl optionally substituted with halo; or R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; Provided are compounds according to formula I described herein.

[0102] One embodiment of the present invention comprises: R 1 is Cl, CH3, OCF3, or CF3; R 2 is H, halo, alkyl or haloalkyl; R 3 is H, alkyl or haloalkyl; Z is -O- or -NH-; R 4 is a heterocycle containing 1 heteroatom optionally substituted with 1-2 substituents independently selected from halo, alkyl, or haloalkyl; Provided are compounds according to formula I described herein.

[0103] One embodiment of the present invention comprises: R 1 is Cl or CF3; R 2 is H, halo, alkyl or haloalkyl; R 3 is H, alkyl or haloalkyl; Z is -NH-; R 4 is a heterocycle containing 1 heteroatom optionally substituted with 1-2 substituents independently selected from halo, alkyl, or haloalkyl; Provided are compounds according to formula I described herein.

[0104] One embodiment of the present invention comprises: R 1is Cl or CF3; R 2 but H; R 3 is CH3; Z is -NH-; R 4 is an alkyl-substituted piperidine ring; Provided are compounds according to formula I described herein.

[0105] One embodiment of the present invention comprises: R 1 is CF3; R 2 but H; R 3 is CH3; Z is -NH-; R 4 is an alkyl-substituted piperidine ring; Provided are compounds according to formula I described herein.

[0106] A specific example of a compound of formula I described herein is 6-((1-ethylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one, or a pharma- ceutically acceptable salt thereof.

[0107] The processes for the preparation of compounds of formula I described herein are subject of the present invention. The synthesis of compounds of formula I can be achieved, for example, according to Scheme 1.

[0108] The present invention also relates to a compound according to the invention when prepared according to the process of the invention.

[0109] General synthesis scheme for triazinone compounds: Compounds of formula I can be prepared according to variations of the methods described above and the following Scheme 1. Starting materials are commercially available or can be prepared according to known methods.

[0110] Scheme 1 [ka]

[0111] Compounds of general formula I, such as Example 1, can be synthesized according to the synthetic route outlined in Scheme 1. Starting from commercially available aryl bromides II, such as 1-bromo-2-methoxy-4-(trifluoromethyl)benzene (CAS: 402-07-3), compounds of general formula III were obtained after reaction with methyl isothiocyanate in the presence of n-BuLi in dry THF. Subsequent alkylation using methyl iodide, methyl bromide or other suitable alkylating reagent in the presence of a base such as potassium hydroxide gave IV. Subsequent reaction with hydrazine hydrate gave intermediates of general formula V, which were then cyclized with ethyl thiooxamate and a base such as triethylamine to give the corresponding triazinone VI. Subsequent Sandmeyer reaction with tert-butyl nitrite in the presence of Cu(I)Cl gave VII. Diazotization can also be performed using sodium nitrite or an equivalent reagent to form a diazonium intermediate, followed by the addition of copper chloride. Subsequent nucleophilic aromatic substitution with an amine according to general formula 6a and a base, preferably N,N-diisopropylethylamine or triethylamine, in a solvent such as DMSO, DMF or an ether such as THF at elevated temperature gave VIII. In the final step, the aryl methyl ether group was cleaved with the well-known boron tribromide (BBr3) in dichloromethane to give compounds of general formula I, such as Example 1. Final deprotection can also be achieved by using benzenethiol, potassium carbonate or related bases in solvents such as NMP at elevated temperature.

[0112] Scheme 2 [ka]

[0113] Alternatively, compounds of formula I or Ib can be synthesized according to an alternative synthetic route as shown in scheme 2. For example, starting from 6-bromo-4-methyl-2H-1,2,4-triazine-3,5-dione (IX; CAS: 15870-75-4), PMB protection was carried out by reaction of 4-methoxybenzyl chloride in the presence of a base, such as an alkali carbonate or alkali phosphate, preferably potassium carbonate, in DMF. Alternatively, other alkylating agents such as bromide, mesylate, tosylate, in the presence of other bases such as cesium carbonate, DIPEA or triethylamine in solvents such as THF or DMSO, or any other standard procedure known to those skilled in the art can be carried out to obtain intermediates of general formula X. This is followed by a palladium catalyzed amination reaction such as Buchwald, preferably using hetaryl bromides bearing (3R)-1-ethylpiperidin-3-amine, (3R)-1-methylpiperidin-3-amine or any of the amines claimed, in the presence of a catalyst such as BINAP Pd G3 using, for example, cesium carbonate as base. DMSO was used as the solvent, but the reaction can also be carried out in DMF, THF or other solvents to give intermediates of general formula XI. Alternatively, XI can be obtained by nucleophilic aromatic substitution reactions known to those skilled in the art. PMB deprotection was then achieved by the addition of trifluoromethanesulfonic acid in DCM at room temperature. PMB deprotection can also be achieved using hydrogenation in the presence of a commercially available palladium on carbon catalyst such as Pd / C in a solvent such as methanol or ethanol. Chlorination by addition of POCl3 and heating the reaction gave intermediates of general formula XII. Finally, the left side was introduced by Suzuki-Miyaura cross coupling, well known to those skilled in the art, in the presence of a palladium catalyst as XPhos Pd G3 and a boronic acid or a boronic acid pinacol ester 7a, according to standard conditions well known to those skilled in the art. In the case of aryl methyl ethers, the final products were obtained by adding boron tribromide (BBr3) in dichloromethane to give compounds of general formula I or Ib, and in the case of SEM, the final compounds were obtained after reaction with TFA. In general, other phenol protecting group modifications known to those skilled in the art can be applied. In the following, specific examples of each exemplified compound are explained in more detail.

[0114] The present invention therefore relates to the compounds according to the invention when prepared according to the process of the invention.

[0115] Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing the compounds of the present invention and therapeutically inert carriers, diluents or excipients, and methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, the compounds of formula Ib can be formulated into galenic dosage forms by mixing at ambient temperature, at an appropriate pH, and at the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration employed. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compounds of formula Ib are formulated in acetate buffer at pH 5. In another embodiment, the compounds of formula Ib are sterile. The compounds can be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

[0116] 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 delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0117] 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, as well as epidural and intranasal, and, where desired for localized treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0118] 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, bulking agents and further active agents.

[0119] Typical formulation is 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, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide proper presentation of the drug (i.e., a compound of the invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0120] The compounds of formula Ib and their pharma- ceutically acceptable salts can be processed with pharma- ceutically 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.

[0121] The compounds of formula I and their pharma- ceutically acceptable salts can be processed with pharma- ceutically 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.

[0122] Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid substances, and liquid polyols.

[0123] Suitable adjuvants for the production of solutions and syrups are, by way of example, water, polyols, saccharose, invert sugar, glucose etc.

[0124] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils etc.

[0125] Suitable adjuvants for suppositories are, by way of example, natural or hardened oils, waxes, fats, semisolid or liquid polyols etc.

[0126] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrin, mannitol or many other carriers and excipients known in the art.

[0127] Furthermore, the 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. The pharmaceutical preparations of the present invention may further contain other therapeutically valuable substances.

[0128] The dosage can vary widely and will of course be adapted to the individual requirements in 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), preferably divided into 1 to 3 individual administrations, which may, if appropriate, consist of, for example, equal amounts. For topical administration, the formulation may contain 0.001% to 15% by weight of medicament, and the required dosage, which may be between 0.1 and 25 mg, may be administered either by a single administration per day or per week, by multiple administrations (2 to 4 times) per day, or by multiple administrations per week. However, it will be clear that the upper or lower limits given herein may be exceeded, where this is indicated.

[0129] One embodiment of the present invention is a compound according to formula Ib as described herein for use as a therapeutically active substance.

[0130] One embodiment of the present invention is a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition, which disease, disorder or condition is responsive to NLRP3 inhibition.

[0131] One embodiment of the present invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

[0132] One embodiment of the present invention is a compound according to formula I as described herein for use as a therapeutically active substance.

[0133] 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, which disease, disorder or condition is responsive to NLRP3 inhibition.

[0134] 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.

[0135] 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 activation of NLRP3.

[0136] There is evidence for a role for NLRP3-induced IL-1 and IL-18 in 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).

[0137] In one embodiment, the disease, disorder or condition is (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) diabetes-related symptoms; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3. is selected from.

[0138] In another embodiment, the disease, disorder or condition is: (i) Cancer; (ii) infectious diseases; (iii) central nervous system disorders; (iv) cardiovascular disease; (v) liver disease; (vi) eye disease; or (vii) Skin diseases is selected from.

[0139] In a further exemplary embodiment of the invention, the disease, disorder or condition is inflammation. Examples of inflammation that can be treated or prevented include: (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) conditions of the gastrointestinal tract 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 distant from the gut (e.g. migraine, rhinitis or eczema); (v) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust-induced asthma, in particular chronic or refractory asthma, e.g. late stage asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, purulent rhinitis (rhinitis pumlenta), dry rhinitis, 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, Behcet's disease, vasculitis, or Wegener's granulomatosis; (vii) autoimmune conditions such as systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes mellitus, 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 infectious disease 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, Legionella, 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 crystal 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, hepatoblastomatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (xiv) liver conditions such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcohol-induced hepatitis, nonalcoholic 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 Examples of such reactions include inflammatory responses associated with or resulting from inflammation.

[0140] One embodiment of the present invention comprises: (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) diabetes-related symptoms; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3. and / or a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from the group consisting of:

[0141] One embodiment of the present invention is the use of a compound according to formula Ib as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0142] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0143] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0144] One embodiment of the present invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0145] One embodiment of the present invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0146] One embodiment of the present invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0147] One embodiment of the present invention is the use of a compound according to formula Ib 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.

[0148] One embodiment of the present invention is the use of a compound according to formula Ib 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.

[0149] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0150] 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 Ib as described herein.

[0151] 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 Ib as described herein.

[0152] One embodiment of the present invention is a method of treating or preventing a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), comprising administering an effective amount of a compound according to formula Ib as described herein.

[0153] One embodiment of the present invention relates to a method of inhibiting NLRP3 comprising administering an effective amount of a compound according to formula Ib described herein.

[0154] Also, one embodiment of the present invention is a compound of formula Ib as described herein when prepared according to any one of the processes described.

[0155] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to Formula Ib described herein and a therapeutically inert carrier.

[0156] One embodiment of the present invention comprises: (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) diabetes-related symptoms; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3. and / or a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from the group consisting of:

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] One embodiment of the present invention is a method of treating or preventing 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 as described herein.

[0164] 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 as described herein.

[0165] 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.

[0166] 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.

[0167] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to Formula I, as described herein, and a therapeutically inert carrier.

[0168] Assay procedure NLRP3 and pyroptosis It is well established that activation of NLRP3 leads to cell pyroptosis, a feature that plays a key role in the manifestation 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 as well as the release of proinflammatory cytokines (e.g., IL-1β) from cells.

[0169] THP-1 cells: culture and preparation THP-1 cells (ATCC#TIB-202) were grown in RPMI containing L-glutamine (Gibco#11835) supplemented with 1 mM sodium pyruvate (Sigma#S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma#P4333) in 10% fetal bovine serum (FBS) (Sigma#F0804). Cells were passaged periodically until confluent (approximately 10 6The THP-1 cells were grown to 100,000 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 by 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 thus prepared were used for compound screening.

[0170] THP-1 cell pyroptosis assay For compound screening, the following method stepwise assay was followed.

[0171] 1. Seed THP-1 cells (25,000 cells / well) in 40 μl of RPMI medium (without FBS) containing 1.0 μg / ml LPS in 96-well black-walled, clear-bottom cell culture plates coated with poly-D-lysine (VWR#734-0317).

[0172] 2. Add 5 μl of compound (8 point half log dilutions with the top dose at 10 μM) or vehicle (DMSO 0.1% FAC) to appropriate wells.

[0173] 3. Incubate at 37℃, 5% CO2 for 3 hours.

[0174] 4. Add 5 μl of Nigericin (Sigma # N7143) (FAC 5 μM) to all wells.

[0175] 5. Incubate at 37℃, 5% CO2 for 1 hour.

[0176] 6. At the end of the incubation period, spin the plate at 300xg for 3 minutes and remove the supernatant.

[0177] 7. 50 μl of Resazurin (Sigma #R7017) (FAC 100 μM Resazurin in RPMI medium without FBS) is then added and the plate is incubated at 37° C. and 5% CO2 for a further 1-2 hours.

[0178] 8. Plates were read on an Envision reader at Ex 560nm and Em 590nm.

[0179] 9. IC 50 Fit the data to a nonlinear regression equation (4-parameter log inhibitor vs. response variable slope)

[0180] The results of the pyroptosis assay were analyzed using THP IC 50 These are summarized in Table 1 below.

[0181] Human whole blood IL-1β release assay

[0182] For systemic delivery, the ability of a compound to inhibit NLRP3 when present in the bloodstream is of great importance. Therefore, we investigated the NLRP3 inhibitory activity of a number of compounds in human whole blood according to the following protocol.

[0183] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel.

[0184] 1. Plate out 80 μl of whole blood containing 1 μg / ml LPS into a 96-well clear bottom cell culture plate (Corning #3585).

[0185] 2. Add 10 μl of compound (8 point half log dilutions with the top dose at 10 μM) or vehicle (DMSO 0.1% FAC) to appropriate wells.

[0186] 3. Incubate at 37℃, 5% CO2 for 3 hours.

[0187] 4. Add 10 μl of Nigericin (Sigma # N7143) (10 μM FAC) to all wells.

[0188] 5. Incubate at 37℃, 5% CO2 for 1 hour.

[0189] 6. At the end of the incubation period, spin the plates at 300 x g for 5 minutes to pellet the cells and remove 20 μl of supernatant and add to a 96-well v-bottom plate for IL-1β analysis (Note: these plates containing supernatants can be stored at -80°C for analysis at a later date).

[0190] 7. IL-1β was measured according to the manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000).

[0191] 8. IC 50 Fit the data to a nonlinear regression equation (4-parameter log inhibitor vs. response variable slope)

[0192] Human whole blood assay results were analyzed using HWB IC 50 These are summarized in Table 1 below.

[0193] hERG Screening Assay cell CHO-crelox hERG cell line (ATCC reference Nr. 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.

[0194] Experimental solution The extracellular solution contains (in mM): NaCl 150; KCl 4; CaCl2 1; MgCl2 1; HEPES 10; pH 7.2-7.4 with NaOH, osmolality 290-330 mOsm. The internal solution contains (in mM): KCl, 10; KF, 100; NaCl, 10; HEPES, 10; EGTA, 20; pH=7.0-7.4 with KOH, osmolality 260-300 mOsm.

[0195] Electrophysiology The effects of compounds on hERG K+ current parameters will be evaluated at two concentrations in at least quadruplicate cells.

[0196] 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.

[0197] Cells were held at a resting voltage of -80 mV and stimulated with the voltage pattern shown in Figure 1 to activate hERG channels and conduct outward IKhERG currents at a stimulation frequency of 0.1 Hz (6 bpm).

[0198] 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 block. Concentration-response data were fitted with the following relationship:

number

[0199] 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). [Table 1] TIFF2024517917000009.tif246169 TIFF2024517917000010.tif238169 TIFF2024517917000011.tif249169 TIFF2024517917000012.tif229169 TIFF2024517917000013.tif248169 TIFF2024517917000014.tif246169 TIFF2024517917000015.tif222169 TIFF2024517917000016.tif121169 [Table 2] TIFF2024517917000018.tif111169

[0200] The invention will now be illustrated by the following examples, which have no limiting character.

[0201] Where preparations are obtained as mixtures of enantiomers, the pure enantiomers may be obtained by methods described herein or known to those skilled in the art, such as chiral chromatography or crystallization.

[0202] Experimental Method Abbreviation: [Table 3]

[0203] Analysis method NMR spectra were run on a Bruker 400 MHz spectrometer using an ICON-NMR under TopSpin program control. Spectra were measured at 298 K and referenced to the solvent resonance unless otherwise stated.

[0204] LC-MS method: Method 1: Using SHIMADZU LCMS-2020, Agilent 1200 LC / G1956A MSD and Agilent 1200\G6110A, Agilent 1200 LC&Agilent 6110 MSD. Mobile phase: A: 0.038% TFA in water (v / v); B: 0.019% TFA in acetonitrile (v / v). Column: Kinetex EVO C 18 2.1 × 30 mm, 5 μm.

[0205] Method 2: Using SHIMADZU LCMS-2020, Agilent 1200 LC / G1956A MSD and Agilent 1200\G6110A, Agilent 1200 LC&Agilent 6110 MSD. Mobile phase: A: 0.025% NH3·H2O in water (v / v); B: acetonitrile. Column: Kinetex EVO C18 2.1X30 mm, 5um.

[0206] Purification Method (Example 1; Step I) Automated reverse-phase column chromatography was performed using a Gilson GX-281 system driven by a Gilson-322 pump module, a Gilson-156 UV photometer detection unit and a Gilson-281 fraction collector. Phenomenex Gemini: 150mm * 25mm * 5um pH(Water(10mM NH4HCO3)-ACN):7~8 Average particle size: 5μm

[0207] Prior to use the column was conditioned with 100% MeCN (2 min) followed by 1% MeCN (0.8 min). Flow rate = 28 mL / min.

[0208] Separation operation: [Table 4]

[0209] Detection wavelengths: 220 and 254 nm. Before each new run, the cartridge was cleaned using the conditioning method. EXAMPLES

[0210] Unless otherwise stated, all examples and intermediates were prepared under a nitrogen atmosphere.

[0211] Example 1: 6-((1-ethylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one [ka]

[0212] Step A: 2-Methoxy-N-methyl-4-(trifluoromethyl)benzothioamide [ka]

[0213] To a mixture of 1-bromo-2-methoxy-4-(trifluoromethyl)benzene (5.0 g, 19.6 mmol, 1 equiv.) in THF was added dropwise at -70°C under N2 and stirred for 10 min, then methyl isothiocyanate (2150 mg, 29.4 mmol, 1.5 equiv.) was added and stirred at 25°C for 1 h. TLC (PE / EtOAc=3:1) showed the reaction was complete. The mixture was quenched with water (10 ml) and the aqueous layer was extracted twice with EtOAc (100 mL). The combined organic layers were washed with water (50 mL) and dried over Na2SO4. The crude product was purified by column chromatography on silica gel (gradient from PE:EtOAc=100:1 to 5:1) to give the title compound (1 g, 20.5% yield) as a black oil. LCMS: m / z 249.9 (M+H) + (ES + ).

[0214] Step B: Methyl 2-methoxy-N-methyl-4-(trifluoromethyl)benzenecarboximidothioate [ka]

[0215] Then, to 2-methoxy-N-methyl-4-(trifluoromethyl)benzenecarbothioamide (3.3 g, 11.3 mmol, 1 equiv.) in MeCN (20 mL) was added KOH (694 mg, 12.4 mmol, 1.1 equiv.) and MeI (1.6 g, 11.3 mmol, 1 equiv.) and the reaction was stirred at 50° C. for 2 h. The mixture was poured into ice water (w / w=1 / 1) (10 mL) and stirred for 1 min. The aqueous phase was diluted with EtOAc (100 mL). * 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC (SiO2, PE / EtOAc=3:1) to give the title compound (1.7 g, 40% yield) as a black oil. LCMS: m / z 263.8 (M+H)+ (ES + ).

[0216] Step C: N-amino-2-methoxy-N'-methyl-4-(trifluoromethyl)benzamidine [ka]

[0217] A solution of methyl 2-methoxy-N-methyl-4-(trifluoromethyl)benzene-carboximidothioate (700 mg, 2.7 mmol, 1 equiv.) in EtOH (1 mL) was added dropwise to a mixture of hydrazine hydrate (1.4 g, 26.6 mmol, 10 equiv.) in EtOH (2 mL) at 70 °C under N2 and stirred at 70 °C for 2 h. The mixture was poured into ice water (w / w=1 / 1) (10 mL) and stirred for 5 min. The aqueous phase was diluted with EtOAc (50 mL). * The combined organic phase was extracted with brine (10 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo The crude product was purified by reverse-phase flash chromatography (0.1% TFA condition) to afford the title compound (340 mg, 45% yield) as a white solid. LCMS: m / z 248.1 (M+H) + (ES + ).

[0218] Step D: 6-amino-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one [ka]

[0219] A mixture of N-amino-2-methoxy-N'-methyl-4-(trifluoromethyl)benzamidine (290 mg, 1.2 mmol, 1 equiv), TEA (237 mg, 2.4 mmol, 2 equiv) and ethyl thioxamate (234 mg, 1.8 mmol, 1.5 equiv) in EtOH (5 mL) was stirred at 80°C for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by reverse-phase flash chromatography (0.1% TFA condition) to give the title compound (160 mg, 43% yield) as a pale yellow solid. LCMS: m / z 300.9 (M+H) + (ES + ).

[0220] Step E: 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one [ka]

[0221] A mixture of 6-amino-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one (100 mg, 0.33 mmol, 1 equiv.), tert-butyl nitrite (69 mg, 0.67 mmol, 2 equiv.), and CuCl (66 mg, 0.67 mmol, 2 equiv.) in ACN (3 mL) was stirred at 70° C. for 1 h under N2 atmosphere. The mixture was poured into ice water (w / w=1 / 1) (5 mL) and stirred for 5 min. The aqueous phase was diluted with ethyl acetate (20 mL). * The combined organic phase was extracted with brine (10 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (SiO2, PE / EtOAc=1 / 1) to give the title compound (40 mg, 38% yield) as a yellow solid. LCMS: m / z 320.0 (M+H) + (ES + ).

[0222] Step F: tert-Butyl 3-[[3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-5-oxo-1,2,4-triazin-6-yl]amino]piperidine-1-carboxylate [ka]

[0223] To a mixture of 6-chloro-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one (40 mg, 0.11 mmol, 1 equiv.) and tert-butyl 3-aminopiperidine-1-carboxylate (214 mg, 1.1 mmol, 10 equiv.) was added DIEA (276 mg, 2.14 mmol, 20 equiv.) in DMSO (1 mL) and the reaction was stirred at 60° C. for 16 h. The mixture was then concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% TFA condition) to give the title compound (40 mg, 73% yield) as a white solid. LCMS: m / z 484.1 (M+H) + (ES + ).

[0224] Step G: 3-[2-Methoxy-4-(trifluoromethyl)phenyl]-4-methyl-6-(3-piperidylamino)-1,2,4-triazin-5(4H)-one [ka]

[0225] A mixture of tert-butyl 3-[[3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-5-oxo-1,2,4-triazin-6-yl]amino]piperidine-1-carboxylate (40 mg, 0.08 mmol, 1 equiv.) and HCl / dioxane (1.0 mL, 4 mmol, 48 equiv.) was stirred at 25° C. for 1 h. The mixture was then concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% HCl condition) to give the title compound as a yellow solid (HCl salt, 30 mg, 72% yield). LCMS: m / z 384.0 (M+H) + (ES + ).

[0226] Step H: 6-[(1-ethyl-3-piperidyl)amino]-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; [ka]

[0227] A mixture of 3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-6-(3-piperidylamino)-1,2,4-triazin-5-one; hydrochloride salt (30 mg, 0.07 mmol, 1 equiv.), acetaldehyde (0.05 mL, 0.36 mmol, 5 equiv.), NaOAc (29 mg, 0.36 mmol, 5 equiv.) in 1,2-dichloroethane (1 mL) was stirred at 25° C. for 1 h, followed by addition of NaBH3CN (23 mg, 0.36 mmol, 5 equiv.) and stirring at 25° C. for 1 h.

[0228] The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase flash (0.1% TFA condition) to give the title compound as a yellow solid (TFA salt, 30 mg, 72% yield). LCMS: m / z 412.0 (M+H) + (ES + ).

[0229] Step I: 6-[(1-ethyl-3-piperidyl)amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5(4H)-one [ka]

[0230] A mixture of boron tribromide (143 mg, 0.57 mmol, 10 equiv.) and 6-[(1-ethyl-3-piperidyl)amino]-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid (30.0 mg, 0.06 mmol, 1 equiv.) in DCM (3 mL) was stirred at -70°C for 2 h. The pH was then adjusted to approximately pH 8 by addition of NH3H2O, then filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC (column Waters Xbridge 150 * 25mm * Purification by 5 um, water (10 mM NH4HCO3)-ACN, B%: 32%-62%, 10 min) afforded the title compound (10 mg, 0.03 mmol, 43% yield) as a white solid. LCMS: m / z 398.1 (M+H) + (ES + ).

[0231] Example 2: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one [ka]

[0232] Step A: 6-bromo-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione

[0233] 6-Bromo-4-methyl-2H-1,2,4-triazine-3,5-dione (13.8 g, 63.1 mmol, 1.0 equiv) and potassium carbonate (4.84 g, 31.5 mmol, 0.50 equiv) were suspended in dry DMF (125 mL) and 4-methoxybenzyl chloride (10.3 mL, 75.7 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc (50 mL), washed with 10 wt% aqueous LiCl (2×30 mL), dried using a phase separator, and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (330 g column, 0-50% EtOAc / isohexane) to give the title compound (15.9 g, 77% yield) as a white solid. 1 H NMR(500 MHz,DMSO-d6)δ7.33-7.25(m,2H),6.97-6.89(m,2H),5.00(s,2H),3.74(s,3H),3.20(s,3H).

[0234] Step B: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione

[0235] (3R)-1-Ethylpiperidin-3-amine (6.0 g, 46.9 mmol, 1.53 equiv.) and 6-bromo-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione (10 g, 30.7 mmol, 1.0 equiv.) and cesium carbonate (20 g, 61.3 mmol, 2.0 equiv.) were dissolved in DMSO (125 mL) and the mixture was degassed (N2) for 5 min. The reaction vessel was evacuated and backfilled with N2 (3x), then (rac)-BINAP Pd G3 (1 g, 1.01 mmol, 0.030 equiv.) was added and the reaction mixture was placed under N2 and then stirred at 95° C. for 24 h. The reaction mixture was partitioned between EtOAc (500 mL) and water (500 mL). The organic phase was isolated, washed with brine (3×300 mL), dried using a phase separator, and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (220 g column, 0-7% (0.7 N ammonia in MeOH) in DCM) to give the title compound (10.4 g, 86% yield) as an orange oil. LCMS m / z 374.2 [M+H] + ,ESI pos.

[0236] Step C: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-2H-1,2,4-triazine-3,5-dione; trifluoromethanesulfonate salt

[0237] 6-[[(3R)-1-ethyl-3-piperidyl]amino]-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione (10.4 g, 25.1 mmol, 1.0 equiv) was dissolved in DCM (75 mL). Trifluoromethanesulfonic acid (3.33 mL, 37.7 mmol, 1.5 equiv) was added to the reaction. The resulting solution was stirred at room temperature for 24 h. An additional portion of trifluoromethanesulfonic acid (3.33 mL, 37.7 mmol, 1.5 equiv) was added and the reaction mixture was stirred for an additional 3 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel (220 g column, 0-10% (0.7 N ammonia in MeOH / DCM) to afford the title compound (17.04 g, 84% yield) as a yellow oil. LCMS m / z 254.5 [M+H] + ,ESI pos.

[0238] Step D: 3-chloro-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one

[0239] 6-[[(3R)-1-Ethyl-3-piperidyl]amino]-4-methyl-2H-1,2,4-triazine-3,5-dione; trifluoromethanesulfonate (17.04 g, 21.1 mmol, 1 equiv.) was dissolved in phosphorus oxychloride (75.0 mL, 804.6 mmol, 38.1 equiv.) and the reaction was stirred at 120° C. for 72 h.

[0240] A 15 mL aliquot of the reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc (200 mL) and washed with 1:1 brine:saturated aqueous NaHCO3 (200 mL). The organic phase was isolated and the aqueous phase was back-extracted with EtOAc (200 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (1.03 g, 17% yield) as a brown oil. The remaining reaction mixture was subjected to the same work-up conditions and scaled proportionally to give the title compound (5.06 g, 79% yield) as a brown oil. LCMS m / z 274.4 ([37Cl]M+H) +,ESI pos.

[0241] Step A': 5-bromo-2,3-dihydrobenzofuran-4-ol

[0242] To a solution of 2,3-dihydrobenzofuran-4-ol (CAS#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 x 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 give the title compound (1.90 g, 60% yield) as a yellow solid. LCMS: m / z 212.8 [MH] - ,ESI neg.

[0243] Step B': 2-[(5-bromo-2,3-dihydrobenzofuran-4-yl)oxymethoxy]ethyl-trimethylsilane

[0244] To a solution of 5-bromo-2,3-dihydrobenzofuran-4-ol (Example 7, Step A) (1.00 g, 4.65 mmol, 1.0 equiv) in ACN (20 mL) was added K2CO3 (1.29 g, 9.3 mmol, 2.0 equiv). The mixture was stirred at 20° C. for 0.5 h, and 2-(trimethylsilyl)ethoxymethyl chloride (0.99 mL, 5.58 mmol, 1.2 equiv) was added dropwise to the mixture. The mixture was stirred at 20° C. for 2 h. TLC (PE:EtOAc=10:1) showed that the starting material was consumed and another major spot was formed. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL×3). The organic phase was washed with brine (150 mL), dried over anhydrous sodium hydroxide, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EtOAc=20:1 to 15:1) to give the title compound (1.30 g, yield 81%) as a yellow oil. 1 H NMR(400 MHz,DMSO-d6)δ=7.30(d,1H),6.49(d,1H),5.19(s,2H),4.54(t,2H),3.87 -3.74(m,2H),3.32-3.26(m,2H),0.94-0.86(m,2H),-0.01--0.05(m,9H).

[0245] Step C`: Trimethyl-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl]oxymethoxy]ethyl]silane

[0246] To a solution of 2-[(5-bromo-2,3-dihydrobenzofuran-4-yl)oxymethoxy]ethyl-trimethylsilane (1.20 g, 3.48 mmol, 1.0 equiv) in isopropyl acetate (20 mL) was added bis(pinacolato)diboron (1.06 g, 4.17 mmol, 1.2 equiv), anhydrous AcOK (0.75 g, 7.65 mmol, 2.2 equiv), Xphos (166 mg, 0.350 mmol, 0.100 equiv) and XPhos Pd G3 (295 mg, 0.350 mmol, 0.100 equiv). The mixture was degassed with N2 three times and stirred under N2 at 80 °C for 12 h. TLC (PE: EtOAc = 20: 1) showed that the starting material was consumed and one new spot was detected. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL×3). The organic phase was washed with brine (30 mL×2), dried over anhydrous sodium hydroxide, filtered, and the filtrate was concentrated under reduced pressure. The residue was first purified by column chromatography (SiO2, PE:EtOAc=80:1-50:1) followed by reversed phase flash (CombiFlash 0.1% NH3.H2O aqueous ACN) and followed by lyophilization to give the title compound (288.3 mg, 20% yield) as a colorless oil. LCMS: m / z 393.1[M+H] + ,ESI pos.

[0247] Step E: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one

[0248] 3-Chloro-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one (160 mg, 0.530 mmol, 1.0 equiv) (Example 2, Step D), trimethyl-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl]oxymethoxy]ethyl]silane (208 mg, 0.530 mmol, 1.0 equiv) (Example 2, Step C′) and saturated aqueous NaCO (0.75 mL) were suspended in 1,4-dioxane (4 mL) and the reaction mixture was sparged with N, then evacuated and backfilled with N (3x). XPhos Pd G3 (45 mg, 0.050 mmol, 0.10 equiv) was added and the reaction mixture was placed under N2 and then stirred at 80°C for 24 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with 1:1 water:brine (50 mL). The organic phase was filtered through Celite® and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (24 g column, 0-10% (0.7N NH3 in MeOH) / DCM) to give the SEM protected product. This was dissolved in DCM (6 mL) and TFA (3 mL) and stirred at room temperature for 3 h before concentrating in vacuo. The resulting residue was dissolved in MeOH (4 mL) and ethylenediamine (1 mL) was added. The mixture was stirred for 2 h and then concentrated in vacuo. The resulting residue was dissolved in 5 mL of DMSO, filtered and purified with Waters X-Select CSH C 18Purification was 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) on an ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL-1 eluting with 0.1% formic acid in water-MeCN gradient over 12.5 min using UV across all wavelengths with PDA, QDA and ELS detectors. The at-column dilution pump provided 2 mL min-1 of methanol throughout the method, which is included in the MeCN percentages below. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, ramp from 5% MeCN to 15% MeCN; 10.5-10.6 min, ramp from 15% MeCN to 100% MeCN; 10.6-12.5 min, hold at 100% MeCN. This gave the title compound (47 mg, 23% yield) as a light brown solid. LCMS m / z 372.2 [M+H] + ,ESI pos.

[0249] Example 3: 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-3-piperidyl]amino]-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0250] Step A: tert-Butyl-(R)-3-((3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate

[0251] To a solution of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (50.0 mg, 0.16 mmol, 1.0 equiv.) in NMP (0.5 mL) was added DIEA (2.03 g, 1.56 mmol, 10.0 equiv.) and tert-butyl (R)-3-aminopiperidine-1-carboxylate (1.57 g, 0.78 mmol, 5.0 equiv.), and the reaction mixture was then stirred in a microwave at 100° C. for 2 h. The reaction mixture was diluted with DMF (2 mL) and then purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). Finally, the eluent was lyophilized to give the title compound (50 mg, 65% yield) as a yellow solid. LC-MS (Method 1): m / z 484.0 [M+H] + ,ESI pos.

[0252] Step B: 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-3-piperidyl]amino]-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0253] To a solution of tert-butyl (R)-3-((3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate (Example 3, Step A) (40.0 mg, 0.08 mmol, 1.0 equiv.) in DCM (1 mL) was added BBr3 (0.2 mL) at -40°C, and the reaction mixture was stirred at 20°C for 1 h under nitrogen atmosphere. The reaction mixture was quenched with water (0.5 mL), the pH was adjusted to 8 using NH3·H2O, and then concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). The eluent was lyophilized to give the title compound (38.1 mg, 94% yield) as a yellow solid. LC-MS (Method 1): m / z 370.1 [M+H] + ,ESI pos.

[0254] Example 4: 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[(8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino]-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0255] Step A: tert-Butyl-(1R,2R,5R)-2-(((benzyloxy)carbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0256] To a solution of benzyl alcohol (1.91 g, 17.6 mmol, 5.0 equiv) in toluene (54 mL) was added TEA (7.12 g, 7.05 mmol, 2.0 equiv) and DPPA (1.07 g, 3.88 mmol, 1.1 equiv). The resulting reaction mixture was stirred at 80° C. for 4 h, after which commercially available 8-(1,1-dimethylethyl) 8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (CAS#1366053-52-2, 900 mg, 3.53 mmol, 1.0 equiv) was added and stirred at 70° C. for 12 h under nitrogen atmosphere. The above reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0-5:1) to give the desired title compound (900 mg, 71% yield) as a yellow oil. LC-MS (Method 1): m / z 359.2 [MH] - ,ESI neg.

[0257] Step B: Benzyl ((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)carbamate

[0258] To a solution of the above tert-butyl-(1R,2R,5R)-2-(((benzyloxy)carbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (Example 4, Step A) (800 mg, 2.22 mmol, 1.0 equiv.) in DCM (8 mL) was added TFA (16.0 mL, 208 mmol, 93.6 equiv.). The resulting reaction mixture was stirred at 20° C. for 1 h, and then it was concentrated under reduced pressure to give the title product (800 mg, 96% yield) as a yellow gum. LC-MS (Method 1): m / z 261.1 [M+H] + ,ESI pos.

[0259] Step C: Benzyl ((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)carbamate

[0260] To a solution of the above benzyl ((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)carbamate (Example 4, Step B) (800.0 mg, 2.14 mmol, 1.0 equiv) in MeOH (16 mL) was added TEA (0.6 mL, 4.27 mmol, 2.0 equiv), acetic acid (513.3 mg, 8.55 mmol, 4.0 equiv), 4 Å molecular sieves (400 mg) and formaldehyde (1734.50 mg, 37% w / w in water, 21.4 mmol, 10 equiv). The reaction mixture was stirred at 20° C. for 0.5 h, then sodium cyanoborohydride (402.9 mg, 6.41 mmol, 3.0 equiv) was added. The reaction mixture was stirred at 20° C. for 1 h, then quenched with water (0.2 mL), diluted with MeOH (5 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C 18 , 0.1% NH3·H2O / MeCN in water) and then lyophilization of the eluent afforded the title compound (400 mg, 63% yield) as a yellow solid. LC-MS (Method 1): m / z 275.1 [M+H] + ,ESI pos.)

[0261] Step D: (1R,2R,5R)-8-Methyl-8-azabicyclo[3.2.1]octan-2-amine

[0262] To a solution of the above benzyl (8-methyl-8-azabicyclo[3.2.1]octan-2-yl)carbamate (Example 4, Step C) (200 mg, 0.73 mmol, 1.0 equiv) in MeOH (2 mL) was added Pd / C (40.0 mg), then the reaction mixture was degassed, purged with hydrogen three times, and stirred under hydrogen atmosphere (760 mmHg) at 20° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (100 mg, 98% yield) as a yellow solid. LC-MS (Method 1): m / z 141.2 [M+H] + ,ESI pos.

[0263] Step E: 3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(8-methyl-8-azabicyclo[3.2.1]octan-2-yl]amino]-1,2,4-triazin-5-one

[0264] To a solution of the above 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (50.0 mg, 0.16 mmol, 1.0 equiv.) in NMP (0.1 mL) was added DIEA (100.0 mg, 0.77 mmol, 4.92 equiv.) and the above 8-methyl-8-azabicyclo[3.2.1]octan-2-amine (Example 4, Step C) (50.0 mg, 0.36 mmol, 2.28 equiv.). The mixture was stirred at 130° C. for 2 h under microwave conditions. The reaction was diluted with DMF (2 mL), filtered, and the filtrate was purified by reverse phase column chromatography (C 18 , 0.1% TFA in water-MeCN) and then the eluent was lyophilized to give the title compound (5 mg, 7% yield) as a yellow solid. LC-MS (Method 1): m / z 424.1 [M+H] + ,ESI pos.

[0265] Step F: 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(2R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]amino]-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0266] To a solution of 6-((8-azabicyclo[3.2.1]octan-2-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 4, Step E) (5.0 mg, 0.01 mmol, 1.0 equiv.) in DCM (1 mL) was added BBr3 (50.0 mg, 0.2 mmol, 16.94 equiv.) portionwise at -40°C, and the mixture was stirred at 20°C for 1 h. The mixture was quenched with water (0.5 mL), then the pH was adjusted to 8 with NH3·H2O, dissolved in MeOH (1 mL), and purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). The eluent was lyophilized to give the title compound (1.21 mg, 18% yield) as a yellow oil. LC-MS (Method 1): m / z 410.2 [M+H] + ,ESI pos.

[0267] Example 5: (R)-6-((1-(cyclopropylmethyl)piperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one; 2,2,2-trifluoroacetic acid [ka]

[0268] Step A: tert-Butyl (R)-(1-(cyclopropylmethyl)piperidin-3-yl)carbamate

[0269] To a mixture of commercially available tert-butyl (R)-piperidin-3-ylcarbamate (CAS#309956-78-3, 1.0 g, 4.99 mmol, 1.0 equiv.), (bromomethyl)cyclopropane (0.48 mL, 4.99 mmol, 1.0 equiv.) in MeCN (10 mL), K2CO3 (7.58 g, 5.49 mmol, 1.1 equiv.) was added at 25 °C and the reaction mixture was stirred under N2 for 2 h. LC-MS showed that the desired mass was detected. The mixture was poured into water (20 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). The eluent was lyophilized to give the title compound (300 mg, 24% yield) as an off-white solid. LC-MS (Method 2): m / z 255.6 [M+H] + ,ESI pos.

[0270] Step B: (R)-1-(cyclopropylmethyl)piperidin-3-amine

[0271] To a mixture of the above tert-butyl N-[(3R)-1-(cyclopropylmethyl)-3-piperidyl]carbamate (Example 5, Step A) (150 mg, 0.59 mmol, 1.0 equiv) in EtOAc (2 mL) was added another solution of HCl in EtOAc (2.0 mL, 8.0 mmol, 4 M, 13.6 equiv) at 25° C., and the reaction mixture was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure to give the crude product, which was then dissolved in water (5 mL) and adjusted to pH ∼8 with saturated Na2CO3 solution. The solution was lyophilized, then triturated with DCM (30 mL), filtered, and the filtrate was concentrated under reduced pressure to give the title compound (70.0 mg, 77% yield) as a yellow oil. 1H NMR(400MHz,CD3OD):δ 3.22-3.20(m,1H),3.08-2.95(m,1H),2.85-2.90(m,1H),2.33-2.31(m,2H),2.24-2.22(m,1H),2.02-1.98(m,1H),1.78-1.8 8(m,1H),1.75-1.73(m,1H),1.66-1.54(m,1H),1.27-1.24(m,1H),0.90-0.80(m,1H),0.57-0.50(m,2H),0.15-0.14(m,2H).

[0272] Step C: (R)-6-((1-(cyclopropylmethyl)piperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0273] To a mixture of the above 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (30.0 mg, 0.09 mmol, 1.0 equiv.) and (R)-1-(cyclopropylmethyl)piperidin-3-amine (Example 5, Step B) (70.0 mg, 0.45 mmol, 4.84 equiv.) in NMP (1 mL) was added DIEA (60.6 mg, 0.47 mmol, 5.0 equiv.). The mixture was stirred at 90° C. under nitrogen atmosphere for 2 h. LC-MS showed that the desired mass was detected. The mixture was concentrated in vacuo. The resulting residue was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) and the eluent was lyophilized to give the title compound (30.0 mg, 73% yield) as a yellow solid. LC-MS (Method 2): m / z 438.0 [M+H] + ,ESI pos.

[0274] Step D: (R)-6-((1-(cyclopropylmethyl)piperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one; 2,2,2-trifluoroacetic acid

[0275] To a mixture of the above (R)-6-((1-(cyclopropylmethyl)piperidin-3-yl)amino)-3-(2-methoxy-4(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 5, Step C) (30.0 mg, 0.07 mmol, 1.0 equiv.) in DCM (2 mL) was added boron tribromide (687.2 mg, 2.74 mmol, 40.0 equiv.) in portions, the reaction mixture was stirred at -60°C for 10 min, then at 25°C for 50 min, and LC-MS showed that the desired mass was detected. The mixture was cooled to 50°C and cooled to 50°C. . The pH was adjusted to about 7 with HO, then filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) and the eluent was lyophilized to give the title compound (5.67 mg, 13% yield) as a yellow solid. LC-MS (Method 2): m / z 423.9 [M+H] + ,ESI pos.

[0276] Example 6: (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one; 2,2,2-trifluoroacetic acid [ka]

[0277] Step A: (R)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0278] To a mixture of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (40.0 mg, 0.13 mmol, 1.0 equiv.) and ((R)-1-methylpiperidin-3-amine (71.4 mg, 0.63 mmol, 5 equiv.) in NMP (1 mL) was added DIEA (80.86 mg, 0.63 mmol, 5.0 equiv.). The reaction mixture was stirred at 90° C. for 2 h. The mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) and then the fractions were lyophilized to give the title compound (30.0 mg, 60% yield) as a white solid. LC-MS (Method 2): m / z 398.2 [M+H] + ,ESI pos.

[0279] Step B: (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one; 2,2,2-trifluoroacetic acid

[0280] A mixture of the above (R)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one (Example 6, Step A) (30.0 mg, 0.08 mmol, 1.0 equiv.) and boron tribromide (189.12 mg, 0.75 mmol, 10.0 equiv.) in DCM (1 mL) was stirred at -60°C for 10 min and then at 25°C for 50 min. The mixture was adjusted to pH 7 with NH3·H2O, then filtered and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) and then the eluent was lyophilized to give the title product (5.48 mg, 14% yield) as a yellow solid. LC-MS (Method 2): m / z 384.1 [M+H] + ,ESI pos.

[0281] Example 7: 6-(1,2,3,5,6,7,8,8a-Octahydroindolizin-8-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0282] Step A: 6,7-Dihydroindolizin-8(5H)-one oxime

[0283] To a solution of commercially available 6,7-dihydroindolizin-8(5H)-one (CAS no. 54906-44-4, 400.0 mg, 2.96 mmol, 1.0 equiv.) in ethanol (6 mL) and water (2 mL), hydroxylamine hydrochloride (617 mg, 8.88 mmol, 3.0 equiv.) and NaOAc·3H2O (1.21 g, 8.88 mmol, 3.0 equiv.) were added and then stirred at 100 °C for 4 h. The reaction solution was cooled to room temperature and a lot of solid was formed, then filtered and the solid was dried under reduced pressure to give the title compound (300 mg, 67% yield) as a yellow solid. LC-MS (Method 1): m / z 151.1 [M+H] + ,ESI pos.

[0284] Step B: Octahydroindolizine-8-amine

[0285] To a solution of the above 6,7-dihydroindolizin-8(5H)-one oxime (Example 7, Step A) (300 mg, 2.0 mmol, 1.0 equiv) in MeOH (10 mL) was added Pd / C (100.0 mg) and concentrated HCl (1.97 g, 2.0 mmol, 1.0 equiv). The reaction mixture was degassed and purged with hydrogen three times, then stirred under hydrogen atmosphere (760 mmHg) at 20° C. for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with MeOH (20 mL) and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, then the solution was lyophilized to give a yellow solid, which was triturated with a mixture of DCM (20 mL) and MeOH (2 mL) and finally filtered. The filtrate was concentrated under reduced pressure to give the title compound (200 mg, 71% yield) as a black oil. 1 H NMR(400 MHz,MeOH-d4)δ 3.79-3.51(m,3H),3.46-3.36(m,1H),3.26-3.01(m,2H),2.57-2.41(m,1H), 2.37-2.28(m,1H),2.25-2.09(m,3H),2.08-1.93(m,2H),1.90-1.70(m,1H).

[0286] Step C: 3-(2-Methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((octahydroindolizin-8-yl)amino)-1,2,4-triazin-5(4H)-one

[0287] To a solution of the above 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (100 mg, 0.31 mmol, 1.0 equiv.) and the above octahydroindolizine-8-amine (Example 7, Step B) (132 mg, 0.94 mmol, 3.0 equiv.) in NMP (0.5 mL) was added DIEA (406.7 mg, 3.13 mmol, 10.0 equiv.). The mixture was stirred at 100° C. under microwave conditions for 2 h. The reaction was diluted with DMF (2 mL), filtered, and the filtrate was purified by reverse phase flash (0.1% TFA in water-MeCN), and the eluent was then lyophilized to give the title compound (60 mg, 44.4% yield) as a yellow solid. LC-MS (method 1): m / z 424.1[M+H] + ,ESI pos.

[0288] Step D: 6-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0289] To a solution of the above 3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((octahydroindolizin-8-yl)amino)-1,2,4-triazin-5(4H)-one (Example 7, step C) (30.0 mg, 0.07 mmol, 1.0 equiv.) in DCM (1 mL) was added BBr3 (88.7 mg, 0.35 mmol, 5.0 equiv.) dropwise at -40°C and then stirred at 20°C for 1 h. The reaction mixture was quenched with water (0.5 mL). The pH was adjusted to 8 using NH3·H2O, dissolved in MeOH (1 mL) and then purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). The eluent was then lyophilized to give the title compound (8.74 mg, 22% yield) as a yellow oil. LC-MS (Method 1): m / z 410.0 [M+H] + ,ESI pos.

[0290] Example 8: 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-1-propyl-3-piperidyl]amino]-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0291] To a solution of (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one (Example 3, Step B) (15.0 mg, 0.03 mmol, 1.0 equiv.) in ethanol (1 mL), DIEA (8.01 mg, 0.06 mmol, 2.0 equiv.) was added, followed by dropwise addition of 1-bromopropane (38.2 mg, 0.31 mmol, 10.0 equiv.) at 0° C., and the mixture was stirred at 50° C. under nitrogen atmosphere for 4 hours. The reaction solution was concentrated under reduced pressure to give a yellow oil, which was purified by preparative HPLC (column Phenomenex Synergi Polar-RP 100 * 25mm * 4 μm; conditions: water (TFA)-MeCN) and then the eluent was lyophilized to give the title compound (3.96 mg, 23% yield) as a yellow oil. LC-MS (Method 1): m / z 411.9 [M+H] + ,ESI pos.

[0292] Example 9: 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[(1,5,5-trimethyl-3-piperidyl)amino]-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0293] Step A: tert-Butyl 5-((3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)-3,3-dimethylpiperidine-1-carboxylate

[0294] To a solution of the above 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (100 mg, 0.31 mmol, 1.0 equiv.) and commercially available tert-butyl 5-amino-3,3-dimethylpiperidine-1-carboxylate (CAS#1896921-12-2, 100 mg, 0.44 mmol, 1.4 equiv.) in 1,4-dioxane (2 mL), Cs2CO3 (255 mg, 0.78 mmol, 2.5 equiv.) and BinapPdG3 (62.1 mg, 0.06 mmol, 0.2 equiv.) were added. The mixture was stirred at 80° C. under N2 for 2 h. The above reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 2:1) to give the title compound (70 mg, yield 39%) as a yellow solid. LC-MS (Method 1): m / z 512.0 [M+H] + ,ESI pos.

[0295] Step B: 6-((5,5-dimethylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0296] To a solution of tert-butyl 5-((3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (Example 9, Step A) (60.0 mg, 0.12 mmol, 1.0 equiv.) in DCM (1 mL) was added TFA (6.0 mL, 77.9 mmol, 664 equiv.), and the reaction mixture was then stirred at 20° C. for 1 h. The reaction solution was concentrated under reduced pressure to give the title compound (60 mg, 97% yield) as a yellow oil. LC-MS (Method 1): m / z 411.9 [M+H] + ,ESI pos.

[0297] Step C: 3-(2-Methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1,5,5-trimethylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0298] To a solution of the above 6-((5,5-dimethylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 9, Step B) (60.0 mg, 0.11 mmol, 1.0 equiv.) in ethanol (2 mL), DIEA (73.7 mg, 0.57 mmol, 5.0 equiv.) and iodomethane (16.2 mg, 0.11 mmol, 1.0 equiv.) were added dropwise, and the reaction mixture was then stirred at 20° C. for 2 hours. The reaction mixture was purified by reverse phase column chromatography (C 18 , 0.1% NH3·H2O / MeCN in water) and then the eluent was lyophilized to give the title compound (25 mg, 51% yield) as a yellow solid. LC-MS (Method 1): m / z 426.0 [M+H] + ,ESI pos.

[0299] Step D: 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[(1,5,5-trimethyl-3-piperidyl)amino]-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0300] To a solution of the above 3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1,5,5-trimethylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one (Example 9, Step C) (20.0 mg, 0.05 mmol, 1.0 equiv) in DCM (1 mL) was added BBr3 (0.5 mL) at -40°C and then stirred at 20°C under N2 for 1 h. The reaction mixture was quenched with water (0.5 mL) at 0°C, diluted with MeOH (1 mL), and then the pH was adjusted to 7 with ammonium hydroxide and purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). The eluent was lyophilized to give the title compound (10.4 mg, 40% yield) as a yellow solid. LC-MS (Method 1): m / z 411.9 [M+H] + ,ESI pos.

[0301] Example 10: (R)-6-((1-cyclopropylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one [ka]

[0302] Step A: tert-Butyl (R)-(1-cyclopropylpiperidin-3-yl)carbamate

[0303] To a solution of commercially available tert-butyl (R)-piperidin-3-ylcarbamate (CAS#184637-48-7, 1.0 g, 4.99 mmol, 1.0 equiv.) in MeOH (40 mL) and acetic acid (5 mL) was added NaBH3CN (1.57 g, 24.9 mmol, 5.0 equiv.) and (1-ethoxycyclopropoxy)trimethylsilane (1.74 g, 9.99 mmol, 2.0 equiv.) at 0° C. The mixture was then stirred at 65° C. for 12 h. The reaction was cooled to 20° C., diluted with water (200 mL), and extracted with DCM (40 mL×3). The organic layer was washed with saturated aqueous Na2CO3 (60 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 2:1) to give the title compound (700 mg, yield 58%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 5.23-4.75(m,1H),3.80-3.60(m,1H),2.80-2.10(m,4H),1.75-1.25(m,13H),0.75-0.25(m,4H).

[0304] Step B: (1R)-1-Cyclopropylpiperidin-3-amine; 2,2,2-trifluoroacetic acid

[0305] To a solution of the above tert-butyl (R)-(1-cyclopropylpiperidin-3-yl)carbamate (Example 10, Step A) (600 mg, 2.5 mmol, 1.0 equiv.) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (2.0 mL). The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (919 mg, 100% yield) as a colorless oil, which was used directly in the next step without further purification. LC-MS (Method 2): m / z 141.2 9 [M+H] + ,ESI pos.

[0306] Step C: (R)-6-((1-cyclopropylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0307] To a solution of the above (R)-1-cyclopropylpiperidin-3-amine; 2,2,2-trifluoroacetic acid (Example 10, Step B) (273 mg, 0.74 mmol, 3.0 equiv.) in 1-butanol (2 mL) was added DIEA (319.4 mg, 2.47 mmol, 10.0 equiv.) and the above 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (79.0 mg, 0.25 mmol, 1.0 equiv.). The mixture was stirred at 110° C. for 3 hours. The reaction solution was filtered and the filtrate was purified by reverse phase column chromatography (C 18 , 0.1% in TFA / MeCN) and the eluent was lyophilized to give the title compound (90 mg, 68% yield) as a yellow gum. LC-MS (Method 2): m / z 424.1 [M+H] + ,ESI pos.

[0308] Step D: (R)-6-((1-cyclopropylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0309] To a solution of the above (R)-6-((1-cyclopropylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 10, step C) (90.0 mg, 0.17 mmol, 1.0 equiv.) in DCM (2 mL) was added BBr3 (210 mg, 0.84 mmol, 5.0 equiv.) at -60°C. The mixture was warmed to 20°C and stirred for 1 h. The reaction was quenched with water (1 mL), adjusted to about pH 8 with NH3·H2O, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xbridge 150 * 25mm *5 μm; Conditions: water (NH4HCO3) / MeCN). The eluent was lyophilized to give the title compound (15.7 mg, 22% yield) as a white solid. LC-MS (Method 2): m / z 410.2 9 [M+H] + ,ESI pos.

[0310] Example 11: 6-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one [ka]

[0311] Step A: 6-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0312] To a mixture of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (200.0 mg, 0.45 mmol, 1.0 equiv.) and commercially available (1S,3S)-3-amino-1-methylcyclobutan-1-ol hydrochloride (CAS number 1523606-23-6, 125 mg, 0.90 mmol, 2 equiv.) in NMP (3 mL) was added DIEA (175.3 mg, 1.36 mmol, 3.0 equiv.). The mixture was stirred at 95° C. for 2 h. LC-MS showed that the desired mass was detected. The mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography (C 18 The mixture was purified by HPLC using a 0.1% NH3·H2O / MeCN mixture in water and the eluent was lyophilized to give the title compound (70.0 mg, 37% yield) as a white solid. LC-MS (Method 2): m / z 385.1 [M+H] + ,ESI pos.

[0313] Step B: 6-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0314] To a mixture of the above 6-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 11, Step A) (70.0 mg, 0.18 mmol, 1.0 equiv.) in DCM (2 mL) was added boron tribromide (456.3 mg, 1.82 mmol, 10.0 equiv.). The reaction mixture was stirred at -60 °C for 10 min, followed by stirring at 25 °C for 50 min. LC-MS showed that the desired mass was detected. The mixture was adjusted to pH 7 with NH3·H2O, then filtered, and the filtrate was concentrated in vacuum. The crude product was purified by reverse phase column chromatography (C 18 The product was purified by HPLC using 0.1% NH3·H2O in water / MeCN (Method 2), and the eluent was lyophilized to give the title compound (3.94 mg, 6% yield) as a pale yellow solid. LC-MS (Method 2): m / z 371.0 [M+H] + ,ESI pos.

[0315] Example 12: 6-[(1-tert-butyl-3-piperidyl)amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0316] Step A: 6-[(1-tert-butyl-3-piperidyl)amino]-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one;

[0317] To a mixture of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (100.0 mg, 0.23 mmol, 1.0 equiv.) and 1-tert-butylpiperidin-3-amine; hydrochloride (131 mg, 0.68 mmol, 3.0 equiv.) in NMP (1 mL) was added DIEA (87.7 mg, 0.68 mmol, 3.0 equiv.). The reaction mixture was stirred at 95° C. under N2 for 2 h. LC-MS showed that the desired mass was detected. The mixture was concentrated in vacuo to give the crude product, which was purified by reverse phase column chromatography (C 18 The mixture was purified by HPLC using a 0.1% TFA / MeCN mixture in water and the eluent was lyophilized to give the title compound (45.0 mg, 44% yield) as a white solid. LC-MS (Method 2): m / z 440.1 [M+H] + ,ESI pos.

[0318] Step B: 6-[(1-tert-butyl-3-piperidyl)amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0319] To a mixture of 6-[(1-tert-butyl-3-piperidyl)amino]-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one (45.0 mg, 0.1 mmol, 1.0 equiv.) in DCM (2 mL) was added boron tribromide (128 mg, 0.51 mmol, 5.0 equiv.) and the reaction mixture was stirred at -60 °C for 10 min and then at 25 °C for 50 min under N2. LC-MS showed that the desired mass was detected. The mixture was adjusted to pH 7 with NH3·H2O, then filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase column chromatography (C 18 , 1% TFA / MeCN in water) and the eluent was lyophilized to give the title compound (24.6 mg, 43% yield) as a pale yellow solid. LC-MS (Method 2): m / z 426.2 [M+H] + ,ESI pos.

[0320] Example 13: 6-(2-Azabicyclo[2.2.1]heptan-6-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0321] Step A: tert-Butyl 6-((3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0322] To a mixture of the above 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (48.2 mg, 0.15 mmol, 0.2 equiv.) in NMP (0.5 mL) was added DIEA (195 mg, 1.51 mmol, 2.0 equiv.) and commercially available tert-butyl 6-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate (CAS#1005077-74-6, 160 mg, 0.75 mmol, 1.0 equiv.) in a microwave tube. The mixture was then stirred at 130° C. for 2 h under microwave atmosphere. The reaction mixture was quenched by the addition of water (5 mL). The residue was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) to give the title compound (30.0 mg, 8% yield) as a yellow oil. LC-MS (Method 2): m / z 496.2 [M+H] + ,ESI pos.

[0323] Step B: 6-(2-azabicyclo[2.2.1]heptan-6-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0324] To a mixture of the above tert-butyl 6-[[3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-5-oxo-1,2,4-triazin-6-yl]amino]-2-azabicyclo[2.2.1]heptane-2-carboxylate (Example 13, Step A) (30.0 mg, 0.06 mmol, 1.0 equiv.) in DCM (1 mL) was added BBr3 (1.51 mg, 0.61 mmol, 10.0 equiv.) under N2 at -60 °C and the mixture was stirred at -60 °C for 10 min and then at 25 °C for 1 h. The reaction mixture was quenched by the addition of ice water (2 mL) and the pH was adjusted to about 7 with NH3·H2O solution. The mixture was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) to give the title compound (10.7 mg, 43% yield) as a yellow solid. LC-MS (Method 2): m / z 382.1 [M+H] + ,ESI pos.

[0325] Example 14: 6-[[(3R,5S)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0326] Step A: tert-Butyl ((3R,5S)-1-ethyl-5-methylpiperidin-3-yl)carbamate

[0327] To a solution of commercially available tert-butyl ((3R,5S)-5-methylpiperidin-3-yl)carbamate (CAS#1187055-56-6, 250 mg, 1.17 mmol, 1.0 equiv.) in MeCN (2.5 mL) was added K2CO3 (323 mg, 2.33 mmol, 2.0 equiv.) and ethyl bromide (0.1 mL, 1.28 mmol, 1.1 equiv.). The reaction mixture was stirred at 25 °C under N2 for 12 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (DCM:MeOH=10:1, R f =0.2) to afford the title compound (85.0 mg, 31% yield) as a white solid. 1 H NMR(400 MHz,MeOD-d4)δ 3.81-3.55(m,1H),3.10-3.07(m,1H),2.88-2.84(m,1H),2.51-2.42(m,2H),1.91(d,1H),1.7 7-1.69(m,1H),1.61(t,1H),1.51(t,1H),1.43(s,9H),1.10(t,3H),0.92(d,3H),0.82(q,1H).

[0328] Step B: (3R,5S)-1-Ethyl-5-methylpiperidin-3-amine; 2,2,2-trifluoroacetic acid

[0329] To a mixture of tert-butyl ((3R,5S)-1-ethyl-5-methylpiperidin-3-yl)carbamate (Example 14, Step A) (265 mg, 1.09 mmol, 1.0 equiv) in DCM (5 mL) was added TFA (2.0 mL, 2.19 mmol, 2.0 equiv) at 0° C., and the mixture was then stirred at 25° C. for 1 h. The reaction mixture was then concentrated under reduced pressure to give the title compound (160 mg, 57% yield) as a yellow oil. LC-MS (Method 2): m / z 143.1 [M+H] + ,ESI pos.

[0330] Step C: 6-(((3R,5S)-1-ethyl-5-methylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0331] To a mixture of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (35.9 mg, 0.11 mmol, 0.2 equiv.) in NMP (0.5 mL) was added (3R,5S)-1-ethyl-5-methylpiperidin-3-amine; 2,2,2-trifluoroacetic acid (Example 14, Step B) (80.0 mg, 0.56 mmol, 1.0 equiv.) in a microwave tube, and the mixture was then stirred at 130° C. for 2 h under microwave conditions. The reaction mixture was quenched by the addition of water (5 mL). The residue was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). The eluate was dried by lyophilization to give the title compound (20.0 mg, 8% yield) as a yellow oil. LC-MS (Method 2): m / z 426.2 [M+H] + ,ESI pos.

[0332] Step D: 6-[[(3R,5S)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0333] To a mixture of 6-[[(3R,5S)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid (Example 14, step C) (20.0 mg, 0.04 mmol, 1.0 equiv.) in DCM (1 mL) was added BBr3 (92.9 mg, 0.37 mmol, 10.0 equiv.) dropwise at -60°C. The mixture was stirred at -60°C for 10 min, and then the mixture was stirred at 25°C under N2 for 1 h. The reaction mixture was quenched by the addition of ice water (2 mL) and the pH was adjusted to about 7 with NH3·H2O solution. The mixture was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) and then purified by preparative HPLC (column: 3_Phenomenex Luna C 18 75 * 30mm * Purification by elution with 3 μm elution water (TFA)-MeCN) afforded the title compound (1.83 mg, 7% yield) as a white solid. LC-MS (Method 2): m / z 412.1 [M+H] + ,ESI pos.

[0334] Example 15: 6-[[(3R,5R)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0335] Step A: tert-Butyl (3R,5R)-3-((3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)-5-methylpiperidine-1-carboxylate

[0336] To a mixture of tert-butyl (3R,5R)-3-amino-5-methyl-piperidine-1-carboxylate (50.3 mg, 0.23 mmol, 1.0 equiv.) in NMP (0.4 mL), the above 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (150.0 mg, 0.47 mmol, 2.0 equiv.) was added in a microwave tube, and the mixture was then stirred at 130° C. for 2 hours under a microwave reactor. After cooling to room temperature, the reaction mixture was quenched by the addition of water (5 mL). The residue was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) to give the title compound (30.0 mg, 13% yield) as a yellow solid. LC-MS (Method 2): m / z 498.2 [M+H] + ,ESI pos.

[0337] Step B: 3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R,5R)-5-methyl-3-piperidyl]amino]-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0338] To a mixture of tert-butyl (3R,5R)-3-[[3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-5-oxo-1,2,4-triazin-6-yl]amino]-5-methyl-piperidine-1-carboxylate (30.0 mg, 0.06 mmol, 1.0 equiv.) in DCM (1 mL) was added TFA (20.6 mg, 0.18 mmol, 3.0 equiv.) at 0° C., and the mixture was then stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (50.0 mg, >99% yield) as a yellow oil. LC-MS (Method 2): m / z 398.1 [M+H] + ,ESI pos.

[0339] Step C: 6-[[(3R,5R)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0340] To a mixture of 3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R,5R)-5-methyl-3-piperidyl]amino]-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid (50.0 mg, 0.1 mmol, 1.0 equiv.) in DMF (0.5 mL), DIEA (25.2 mg, 0.2 mmol, 2.0 equiv.) and iodoethane (0.01 mL, 0.11 mmol, 1.1 equiv.) were added. The mixture was then stirred at 25° C. for 2 h. The reaction mixture was quenched by the addition of water (10 mL), then extracted with EtOAc (50 mL×3), washed with brine (30 mL×2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) to give the title compound (10.0 mg, 19% yield) as a yellow solid. LC-MS (Method 2): m / z 426.2 [M+H] + ,ESI pos.

[0341] Step D: 6-[[(3R,5R)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0342] To a mixture of 6-[[(3R,5R)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid (10.0 mg, 0.02 mmol, 1.0 equiv.) in DCM (0.5 mL), BBr3 (46.4 mg, 0.19 mmol, 10.0 equiv.) was added at -60 °C under N2, the mixture was stirred at -60 °C for 10 min, then the mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was quenched with 2 mL of ice water and the pH was adjusted to about 7 with NH3·H2O solution. The mixture was purified by reverse phase column chromatography (C 18 , 0.1% TFA water / MeCN conditions) to give the title compound (1.76 mg, 12% yield) as a white solid. LC-MS (Method 2): m / z 412.1 [M+H] + ,ESI pos.

[0343] Example 16: 6-[[(5S)-5-Fluoro-1-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0344] Step A: tert-Butyl (3S,5R)-3-fluoro-5-((3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate

[0345] To a solution of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (100.0 mg, 0.31 mmol, 1.0 equiv.) in NMP (1.0 mL) was added DIEA (0.11 mL, 0.63 mmol, 2.0 equiv.) and tert-butyl (3R,5S)-3-amino-5-fluoropiperidine-1-carboxylate (CAS#1271810-13-9, 136.6 mg, 0.63 mmol, 2.0 equiv.). The mixture was stirred at 90° C. for 12 h. The mixture was cooled to 20° C. and purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). The eluent was lyophilized to give the title compound (100.0 mg, 64% yield) as a yellow solid. LC-MS (Method 2): m / z 502.0 [M+H] + ,ESI pos.

[0346] Step B: 6-[[(3R,5S)-5-fluoro-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one

[0347] To a solution of the above tert-butyl (3S,5R)-3-fluoro-5-((3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate (Example 16, Step A) (100.0 mg, 0.20 mmol, 1.0 equiv.) in DCM (2 mL) was added TFA (2.0 mL). The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo to give the title compound (2.04 mg, 4% yield) as a yellow oil. LC-MS (Method 2): m / z 401.9 [M+H] + ,ESI pos.

[0348] Step C: 6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0349] To a solution of the above 6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 16, Step B) (80.0 mg, 0.2 mmol, 1.0 equiv.) in ethanol (2 mL), DIEA (0.07 mL, 0.4 mmol, 2.0 equiv.) and iodomethane (28.3 mg, 0.2 mmol, 1.0 equiv.) were added. The mixture was stirred at 20° C. for 2 h. The mixture was then quenched with water (3 mL). The pH was adjusted to about 7 by the addition of 1 M aqueous HCl, and the mixture was then purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). The eluent was lyophilized to give the title compound (60.0 mg, 72% yield) as a yellow solid. LC-MS (Method 2): m / z 416.1 [M+H] + ,ESI pos.

[0350] Step D: 6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0351] To a mixture of 6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 16, step C) (50.0 mg, 0.12 mmol, 1.0 equiv) and K2CO3 (166.1 mg, 1.2 mmol, 10.0 equiv) in NMP (2 mL) was added benzenethiol (186 μL, 1.82 mmol, 15.1 equiv) under N2. The mixture was then stirred at 190 °C for 15 min under microwave conditions. The reaction mixture was cooled to 20 °C and purified by reverse phase column chromatography (C 18 The crude product was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100, 0.1% TFA / MeCN in water). The eluent was lyophilized to give the crude product, which was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100 * 25 mm * Purified by HPLC (HPLC: 4 μm; conditioned water (0.1% TFA)-MeCN). The eluent was lyophilized to give the title compound (1.7 mg, 3% yield) as a white solid. Note: Racemization appears to have occurred during deprotection at elevated temperature. 1 H NMR(400 MHz,MeOD-d4)δ 7.55(d,1H),7.31-7.28(m,1H),7.24(s,1H),5.40-5.30(m,1H),4.20-4.07(m,1H),4.00-3.79(m,2H) ,3.78-3.45(m,2H),3.64(s,3H),2.95(s,3H),2.48-2.40(m,1H),2.28-2.20(m,1H).LC-MS(Method 2):m / z 402.2[M+H] + ,ESI pos.

[0352] Example 17: 6-[[(3R)-6,6-dimethyl-3-piperidyl)amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0353] Step A: tert-Butyl (R)-(6,6-dimethylpiperidin-3-yl)carbamate

[0354] To a mixture of commercially available tert-butyl (R)-(6-oxopiperidin-3-yl)carbamate (CAS#1228566-94-6, 450.0 mg, 2.1 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (20 mL), ZrCl4 (2.94 g, 12.6 mmol, 6.0 equiv.) was added at -10°C and stirred at this temperature for 0.5 h, then methylmagnesium bromide (14.0 mL, 42.0 mmol, 20.0 equiv.) was added and the mixture was stirred at 20°C for 12 h. The above reaction mixture was quenched with cold water (100 mL), filtered and the filtrate was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 0:1) to give the title compound (130 mg, yield 27%) as a yellow oil. 1 H NMR(400 MHz,MeOD-d4)δ 3.42-3.32(m,1H),2.93-2.81(m,1H),2.63-2.50(m,1H),1.83-1.73(m,1H),1.62-1.52(m,2H),1.48-1.41(m,10H),1.14-1.09(m,6H).

[0355] Step B: (R)-6,6-Dimethylpiperidin-3-amine; 2,2,2-trifluoroacetic acid

[0356] To a solution of tert-butyl (R)-(6,6-dimethylpiperidin-3-yl)carbamate (130.0 mg, 0.57 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (1.0 mL) dropwise, and then the mixture was stirred for 2 h at 20° C. The above reaction solution was concentrated under reduced pressure to give a yellow solid, which was triturated with ethyl acetate (2 mL), filtered, and the cake was collected and dried under reduced pressure to give the title compound (100 mg, 73% yield) as a white solid. 1H NMR(400 MHz,MeOD-d4)δ 3.56-3.43(m,2H),3.27-3.16(m,1H),2.16-2.06(m,1H),1.96-1.74(m,3H),1.50-1.33(m,6H).

[0357] Step C: (R)-6-((6,6-dimethylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0358] To a solution of (R)-6,6-dimethylpiperidin-3-amine; 2,2,2-trifluoroacetic acid (43.29 mg, 0.18 mmol, 1.0 equiv.) in 1,4-dioxane (1 mL) was added Cs2CO3 (145.57 mg, 0.45 mmol, 2.5 equiv.), 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (60.0 mg, 0.18 mmol, 1.0 equiv.) and BrettPhos PdG3 (32.4 mg, 0.04 mmol, 0.2 equiv.) and stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction mixture was diluted with acetonitrile (2 mL), filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) and then the eluent was lyophilized to give the title compound (5.0 mg, 5% yield) as a white solid. LC-MS (Method 1): m / z 412.2 [M+H] + ,ESI pos.

[0359] Step D: 6-[[(3R)-6,6-dimethyl-3-piperidyl)amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0360] To a solution of (R)-6-((6,6-dimethylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 17, Step C) (10.0 mg, 0.02 mmol, 1.0 e.) in DCM (1 mL) was added BBr3 (0.1 mL) dropwise at -40°C, and the reaction mixture was then stirred at 20°C for 1 h. The above reaction mixture was quenched with water (0.5 mL) at 0°C, diluted with MeOH (1 mL), and then the pH was adjusted to about 7 with ammonium hydroxide, followed by reverse phase column chromatography (C 18 The eluent was lyophilized to give a yellow solid, which was purified by preparative HPLC (column 3_Phenomenex Luna C 18 75 * 30mm * Further purification by HPLC (3 μm; conditions: water (TFA)-CH3CN) and then lyophilization of the eluent afforded the title compound (1.21 mg, 18% yield) as a white solid. LC-MS (Method 1): m / z 398.0 [M+H] + ,ESI pos.

[0361] Example 18: 6-[(3-hydroxyphenyl)methylamino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0362] Step A: 6-((3-hydroxybenzyl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0363] To a mixture of the above 6-chloro-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one (Example 1, Step E) (30.0 mg, 0.09 mmol, 1.0 equiv.) and commercially available 3-(aminomethyl)phenol (CAS#73604-31-6, 57.9 mg, 0.47 mmol, 5.0 equiv.) in NMP (1 mL) was added DIEA (6.64 mg, 0.47 mmol, 5.0 equiv.) and the reaction mixture was stirred at 95° C. under N for 2 h. LC-MS showed that the desired mass was detected. The mixture was concentrated under reduced pressure to give the crude product, which was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) and then the eluent was lyophilized to give the title compound (20.0 mg, 52% yield) as a yellow solid. LC-MS (Method 2): m / z 406.9 [M+H] + ,ESI pos.

[0364] Step B: 6-[(3-hydroxyphenyl)methylamino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0365] A mixture of the above 6-((3-hydroxybenzyl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 18, Step A) (20.0 mg, 0.05 mmol, 1.0 equiv.) and boron tribromide (493.2 mg, 1.97 mmol, 40.0 equiv.) in DCM (1 mL) was stirred at -60 °C for 10 min and then at 25 °C for 50 min. LC-MS showed that the desired mass was detected. The mixture was adjusted to pH 7 by addition of NH3·H2O, then filtered and the filtrate was concentrated in vacuo to give the crude product, which was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) and then the eluent was lyophilized to give the title compound (2.95 mg, 12% yield) as a yellow solid. LC-MS (Method 2): m / z 393.2 [M+H]+ ,ESI pos.

[0366] Example 19: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0367] Step A: (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0368] To a mixture of the above 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 1, Step E) (180.0 mg, 0.41 mmol, 1.0 equiv.) and (R)-1-ethylpiperidin-3-amine (156.6 mg, 1.22 mmol, 3.0 equiv.) in NMP (3 mL) was added DIEA (157.8 mg, 1.22 mmol, 3.0 equiv.) and the reaction mixture was stirred at 95° C. for 2 h. LC-MS showed that the desired mass was detected. The mixture was concentrated in vacuo to give the crude product, which was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). The eluent was lyophilized to give the title compound (75.0 mg, 61% yield) as a white solid. LC-MS (Method 2): m / z 412.2 [M+H] + ,ESI pos.

[0369] Step B: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0370] A mixture of the above (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 19, Step A) (75.0 mg, 0.19 mmol, 1.0 equiv.) and boron tribromide (243.6 mg, 0.97 mmol, 5.0 equiv.) in DCM (2 mL) was stirred at -60°C for 10 min and then at 25°C for 50 min. LC-MS showed that the desired mass was detected. The mixture was adjusted to pH 7 with NH3·H2O, then filtered and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) and then the eluent was lyophilized to give the title compound (35 mg, 32% yield) as a white solid. LC-MS (Method 2): m / z 398.0 [M+H] + ,ESI pos.

[0371] Example 19 was also synthesized according to this method as the free base. 6-[[(3R)-1-Ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one

[0372] 3-Chloro-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one (Example 2, Step D) (750.0 mg, 2.76 mmol, 1.0 equiv), saturated aqueous sodium carbonate (2.50 mL, 0.59 mmol, 0.21 equiv) and 2-methoxy-4-(trifluoromethyl)-phenylboronic acid (CAS#312936-89-3, 667.7 mg, 3.04 mmol, 1.1 equiv) were suspended in 1,4-dioxane (16 mL) and the reaction mixture was sparged with N2, then evacuated and filled with N2 (3x). Xphos Pd G3 (233.89 mg, 0.28 mmol, 0.1 equiv) was added and the reaction mixture was placed under N2 and then stirred at 80°C for 24 hours. The reaction mixture was filtered, dry loaded onto silica gel, and purified by chromatography on silica gel (24 g column, 0-10% (0.7 N NH3 in MeOH) / DCM) to give an intermediate product, which was then dissolved in DCM (30 mL) and BBr3 (1M in DCM) (13.8 mL, 13.8 mmol, 5.0 equiv) was added slowly at 0 °C. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The resulting residue was dissolved in MeOH (40 mL) and solid NaHCO3 (5 g) was added. The mixture was stirred at room temperature for 30 min, then filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (24 g column, 0-10% (0.7 N NH3 in MeOH) / DCM) and then purified using a Waters XBridge BEH C column. 18Purification was 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) using an ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, with a flow rate of 40 mL min-1 and eluting with a 0.3% ammonia in water-MeCN gradient over 12.5. The at-column dilution pump provided 2 mL min-1 of MeCN throughout the method, which is included in the MeCN percentages below. 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 to give the title compound (196.0 mg, 18% yield) as a white solid. LC-MS m / z 398.4[M+H] + ,ESI pos.

[0373] Example 20: 4-Cyclopropyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0374] Step A: N-Cyclopropyl-2-methoxy-4-(trifluoromethyl)benzothioamide

[0375] To a solution of commercially available 1-bromo-2-methoxy-4-(trifluoromethyl)benzene (CAS#402-07-3, 5.00 g, 19.6 mmol, 1.0 equiv) in THF (50 mL) was added n-BuLi (11.8 mL, 29.4 mmol, 1.5 equiv) dropwise under nitrogen atmosphere at -60°C and stirred at this temperature for 0.5 h, then a solution of isothiocyanatocyclopropane (2.53 g, 25.5 mmol, 1.3 equiv) in THF (3 mL) was added and the reaction mixture was stirred at -60°C for 10 min, then warmed to 25°C and stirred under nitrogen atmosphere for another 50 min. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL), extracted with EtOAc (100 mL x 3), washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE-PE:EA=30 / 1-10 / 1) to give the title compound (1.60 g, 30% yield) as a yellow oil. LC-MS (Method 1): m / z 276.1 [M+H] + ,ESI pos.

[0376] Step B: Methyl N-cyclopropyl-2-methoxy-4-(trifluoromethyl)benzimidothioate

[0377] To a solution of N-cyclopropyl-2-methoxy-4-(trifluoromethyl)benzothioamide (Example 20, Step A) (1.60 g, 5.81 mmol, 1.0 equiv) in DMF (10 mL) was added DIEA (0.82 g, 6.33 mmol, 1.1 equiv) at 20° C. and stirred for 10 min, followed by the addition of MeI (1.0 g, 7.08 mmol, 1.22 equiv). The mixture was stirred at 20° C. for 3 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 3 / 1) to give the title compound (1.30 g, 76% yield) as a yellow oil. LC-MS (method 1): m / z 290.0[M+H] + ,ESI pos.

[0378] Step C: N"-Cyclopropyl-2-methoxy-4-(trifluoromethyl)benzimide hydrazide

[0379] To a solution of methyl N-cyclopropyl-2-methoxy-4-(trifluoromethyl)benzimidothioate (Example 20, Step B) (1.30 g, 4.49 mmol, 1.0 equiv.) in ethanol (15 mL) was added hydrazine hydrate (2.28 g, 45.5 mmol, 10.1 equiv.). The mixture was stirred at 70° C. under a nitrogen atmosphere for 24 hours. The mixture was concentrated under reduced pressure and then purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). The eluent was lyophilized to give the title compound (900.0 mg, 50% yield) as a yellow solid. LC-MS (Method 1): m / z 274.1 [M+H] + ,ESI pos.

[0380] Step D: 6-Amino-4-cyclopropyl-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one

[0381] A mixture of N"-cyclopropyl-2-methoxy-4-(trifluoromethyl)benzimide hydrazide (Example 20, Step C) (390.0 mg, 1.43 mmol, 1.0 equiv), TEA (288.9 mg, 2.85 mmol, 2.0 equiv) and ethyl 2-amino-2-thioxoacetate (285.1 mg, 2.14 mmol, 1.5 equiv) in ethanol (8 mL) was stirred at 85°C under a nitrogen atmosphere for 4 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure and then purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water). The eluent was lyophilized to give the title compound (220 mg, 44% yield) as a yellow solid. LC-MS (Method 1): m / z 327.0 [M+H] + ,ESI pos.

[0382] Step E: 6-chloro-4-cyclopropyl-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one

[0383] To a mixture of 6-amino-4-cyclopropyl-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one (Example 20, Step D) (200.0 mg, 0.61 mmol, 1.0 equiv), CuCl (182.1 mg, 1.84 mmol, 3.0 equiv), LiCl (51.97 mg, 1.23 mmol, 2.0 equiv), benzyl(triethyl)azanium; chloride (530.56 mg, 2.33 mmol, 3.8 equiv) in MeCN (5 mL) was added tert-butyl nitrite (316.1 mg, 3.06 mmol, 5.0 equiv) at 25° C., and the reaction mixture was stirred at 70° C. for 1 h under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo and then purified by reverse phase column chromatography (C 18 , 0.1% TFA / MeCN in water) and then lyophilized to give the title compound (70.0 mg, 30% yield) as a yellow solid. LC-MS (Method 1): m / z 345.9 [M+H] + ,ESI pos.

[0384] Step F: (R)-4-Cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one

[0385] To a mixture of 6-chloro-4-cyclopropyl-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one (Example 20, Step E) (70.0 mg, 0.2 mmol, 1.0 equiv.) and (R)-1-ethylpiperidin-3-amine (77.9 mg, 0.61 mmol, 3.0 equiv.) in NMP (1 mL) was added DIEA (78.5 mg, 0.61 mmol, 3.0 equiv.) and then stirred at 95° C. for 2 h under nitrogen atmosphere. The mixture was concentrated in vacuo and then purified by reverse phase column chromatography (C 18, 0.1% TFA / MeCN in water) and the eluent was lyophilized to give the title compound (40.0 mg, 45% yield) as a yellow solid. LC-MS (Method 1): m / z 437.9 [M+H] + ,ESI pos.

[0386] Step G: 4-Cyclopropyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0387] To a solution of (R)-4-cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one (Example 20, Step F) (40.0 mg, 0.09 mmol, 1.0 equiv.) in DCM (4 mL) was added BBr3 (229 mg, 0.91 mmol, 10.0 equiv.) at -40°C and then stirred at 20°C for 1 h. The reaction mixture was quenched with water (0.5 mL), then the pH was adjusted to 8 with ammonium hydroxide, then concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and then purified by preparative HPLC (column: 3_Phenomenex Luna C 18 75 * 30 mm * 3 μm; Conditions: water (TFA)-MeCN). Finally, the eluent was lyophilized to give the title compound (12.7 mg, 25% yield) as a yellow oil. LC-MS (Method 1): m / z 423.9 [M+H] + ,ESI pos.

[0388] Example 21: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-fluoro-2-hydroxy-phenyl)-4-methyl-1,2,4-triazin-5-one [ka]

[0389] 3-Chloro-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one (Example 2, Step D) (100 mg, 0.330 mmol, 1.0 eq) saturated aqueous Na2CO3 (0.5 mL), commercially available (4-fluoro-2-hydroxy)phenylboronic acid (CAS#850568-00-2, 56.8 mg, 0.36 mmol, 1.1 eq) was suspended in 1,4-dioxane (3.5 mL), the reaction mixture was sparged with N2, then evacuated and back-filled with N2 (3x), Xphos Pd G3 (28.1 mg, 0.03 mmol, 0.1 eq) was added, the reaction mixture was placed under N2, then stirred at 80° C. for 18 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in 2 mL of DMSO, filtered, and purified using a Waters XBridge BEH C 18 Purification was 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) on an ODB prep column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL-1 eluting with 0.1% ammonia in water-MeCN gradient over 17.5 min using UV across all wavelengths with PDA and QDA and ELS detectors. The at-column dilution pump provided 2 mL min-1 MeCN throughout the method, which is included in the MeCN percentages below. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-15.5 min, ramp from 5% MeCN to 35% MeCN; 15.5-15.6 min, ramp from 35% MeCN to 100% MeCN; 15.6-17.5 min, hold at 100% MeCN. This gave the title compound (12.02 mg, 10% yield) as a light brown solid. LC-MS m / z 348.3[M+H] + ,ESI pos.

[0390] Example 22: 4-Ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-1,2,4-triazin-5-one [ka]

[0391] Step A: 6-bromo-4-ethyl-2H-1,2,4-triazine-3,5-dione

[0392] Sodium hydride (60% in mineral oil) (7.86 g, 19.7 mmol, 1.1 equiv) was placed in DMF (10 mL) under nitrogen and a solution of commercially available 2-acetyl-6-bromo-1,2,4-triazine-3,5-dione (CAS#20028-51-7, 4.18 g, 17.9 mmol, 1.0 equiv) in DMF (30 mL) was added dropwise. The reaction mixture was stirred at room temperature for 45 min, then iodoethane (1.57 mL, 19.7 mmol, 1.1 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (200 mL), washed with 10 wt% aqueous LiCl (2×100 mL), dried using a phase separator, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (120 g column, 0-5% DCM / MeOH) to give a yellow oil. The yellow oil was dissolved in EtOH (30 mL) and p-toluenesulfonic acid monohydrate (169.9 mg, 0.89 mmol, 0.05 equiv) was added. The reaction mixture was stirred at reflux for 16 h, then concentrated in vacuo and the resulting residue was partitioned between water (200 mL) and EtOAc (200 mL). The organic phase was isolated and the aqueous (aq.) was extracted with EtOAc (2x200 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo to give the title compound (2.85 g, 60% yield) as a pale yellow solid. LC-MS m / z 217.8 ([37Cl]M+H) + ,ESI pos.

[0393] Step B: 6-bromo-4-ethyl-2-[(4-methoxyphenyl)methyl]-1,2,4-triazine-3,5-dione

[0394] 6-Bromo-4-ethyl-2H-1,2,4-triazine-3,5-dione (Example 22, Step A) (2.85 g, 12.95 mmol, 1.0 equiv) and dipotassium carbonate (8.95 g, 6.48 mmol, 0.5 equiv) were suspended in dry DMF (30 mL) and 4-methoxybenzyl chloride (2.11 mL, 15.5 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc (50 mL), washed with 10 wt% aqueous LiCl (2×30 mL), dried using a phase separator, and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (24 g column, 0-50% EtOAc / isohexane) to give the title compound (3.91 g, 80% yield) as a white solid. 1 H NMR(500 MHz,DMSO-d6)δ 7.30-7.25(m,2H),6.93-6.88(m,2H),5.00(s,2H),3.83(q,2H),3.74(s,3H),1.12(t,3H).

[0395] Step C: 4-Ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-2-[(4-methoxyphenyl)methyl]-1,2,4-triazine-3,5-dione

[0396] Cesium carbonate (4.85 mg, 14.9 mmol, 4.5 equiv) and 6-bromo-4-ethyl-2-[(4-methoxyphenyl)methyl]-1,2,4-triazine-3,5-dione (Example 22, Step B) (1.25 g, 3.31 mmol, 1.0 equiv) and (3R)-1-ethylpiperidin-3-amine (6.36 mg, 4.96 mmol, 1.5 equiv) were dissolved in DMSO (16 mL) and the mixture was degassed (N2) for 5 min. The reaction vessel was evacuated and backfilled with N2 (3x), then Pd-176 (CAS#879689-47-1, 133 mg, 0.17 mmol, 0.05 equiv) was added and the reaction mixture was placed under N2 and then stirred at 95°C for 24 h. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was isolated, washed with brine (2x30mL), dried using a phase separator, and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (24g column, 0-10% (0.7N ammonia in MeOH) in DCM) to give the title compound (996mg, 71% yield) as a light brown oil. LC-MS m / z 388.4 (M+H). + ,ESI pos.

[0397] Step D: 4-Ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-2H-1,2,4-triazine-3,5-dione; trifluoromethanesulfonic acid

[0398] 4-Ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-2-[(4-methoxyphenyl)methyl]-1,2,4-triazine-3,5-dione (996.0 mg, 2.34 mmol, 1.0 equiv.) was dissolved in DCM (9 mL) and trifluoromethanesulfonic acid (0.31 mL, 3.51 mmol, 1.5 equiv.) was added to the reaction. The resulting solution was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel (24 g column, 0-10% (0.7 N ammonia in MeOH / DCM) to give the title compound (950 mg, 88% yield) as a yellow oil. LC-MS m / z 268.4 [M+H] +,ESI pos.

[0399] Step E: 3-chloro-4-ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-1,2,4-triazin-5-one

[0400] 4-Ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-2H-1,2,4-triazine-3,5-dione; trifluoromethanesulfonic acid (950 mg, 2.28 mmol, 1.0 equiv) was dissolved in phosphorus oxychloride (6.29 mL, 67.5 mmol, 29.6 equiv). The reaction was stirred at 90°C for 16 h and then concentrated in vacuo. The resulting residue was cooled in an ice bath and slowly quenched with 0.7N NH3 in MeOH, then dry loaded onto silica and purified by chromatography on silica gel (40 g column, 0-10% (0.7N ammonia in MeOH) / DCM) to give the title compound (768 mg, 89% yield) as a yellow gum. LC-MS m / z 285.9 ([37Cl]M+H) + ,ESI pos.

[0401] Step F: This step was synthesized by a similar method to that outlined above (see Example 21): [Table 5]

[0402] Example 23: 3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; formic acid [ka]

[0403] Step A: 3-[4-(difluoromethoxy)-2-methoxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one

[0404] 3-Chloro-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one (Example 2, step D) (260.0 mg, 0.91 mmol, 1.0 equiv.), commercially available 2-[4-(difluoromethoxy)-2-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS#2121514-61-0, 430.0 mg, 1.07 mmol, 1.18 equiv.) in saturated aqueous NaCO (0.5 mL, 0.91 mmol, 1.0 equiv.) and 1,4-dioxane (5 mL) was sparged (bubbled with N for 10 min and sonicated). XPhos Pd G3 (52.0 mg, 0.06 mmol, 0.07 equiv) was added and the reaction mixture was heated at 90 °C for 18 h. The crude mixture was passed through a plug of Celite®, rinsed with EtOAc (50 mL) and the reaction mixture was concentrated in vacuo. The reaction was purified by column chromatography (silica, 24 g, 10-20% MeOH (with 0.7 M NH3) followed by reverse phase column chromatography (C 18 , 26 g, purified with 10-60% acetonitrile:water (10 mM ammonium bicarbonate) to give the title compound (99.0 mg, 26% yield) as a light brown solid. LC-MS m / z 410.4 [M+H] + ,ESI pos.

[0405] Step B: 3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; formic acid

[0406] A suspension of 3-[4-(difluoromethoxy)-2-methoxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one (50.0 mg, 0.12 mmol, 1.0 equiv) and potassium carbonate (50.0 mg, 0.36 mmol, 2.96 equiv) in NMP (1 mL) in a MW vial was sonicated for 2 min, then benzenethiol (0.02 mL, 0.2 mmol, 1.61 equiv) was added and the resulting mixture was irradiated to 150° C. for 30 min. The reaction was cooled to room temperature, diluted with NMP (2.4 mL), filtered, and purified using a Waters X-Select CSH C 18 Purification was 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) on an ODB prep column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL-1 eluting with 0.1% formic acid in water-MeCN gradient over 12.5 min using UV across all wavelengths with PDA, QDA and ELS detectors. The at-column dilution pump provided 2 mL min-1 MeOH throughout the method, which is included in the MeCN percentages below. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, ramp from 5% MeCN to 25% MeCN; 10.5-10.6 min, ramp from 25% MeCN to 100% MeCN; 10.6-12.5 min, hold at 100% MeCN. Clean fractions were evaporated in a Genevac to give the title compound (24.0 mg, 43% yield) as an off-white solid. LC-MS m / z 396.3 [M+H] + ,ESI pos.

[0407] Example 24: 3-[4-(1,1-difluoroethyl)-2-hydroxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one [ka]

[0408] Step A: 1-Bromo-4-(1,1-difluoroethyl)-2-methoxybenzene

[0409] Diethylaminosulfur trifluoride (6.0 mL, 45.4 mmol, 10.4 equiv) was added dropwise to a solution of 1-(4-bromo-3-methoxy-phenyl)ethenone (CAS number 50870-44-5, 1.0 g, 4.37 mmol, 1.0 equiv) in DCM (8 mL) in a Teflon flask at 0° C. and the reaction mixture was warmed and stirred for 16 hours. The reaction mixture was cooled to 0° C. and diethylaminosulfur trifluoride (3.0 mL, 22.7 mmol, 5.2 equiv) was added and the reaction was left stirring for 4 days. The reaction mixture was cooled to 0° C. and diethylaminosulfur trifluoride (3.0 mL, 22.7 mmol, 5.2 equiv) was added and the reaction was left stirring for 18 hours. The reaction mixture was cooled to 0°C and carefully added dropwise to a vigorously stirred plastic beaker containing ice-cold 2M NaOH (250 mL), the reaction mixture was transferred to a separatory funnel and rinsed with DCM (75 mL). The separated aqueous layer was further extracted with DCM (2 x 50 mL) and the combined organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (silica, 40 g, 0-30% EtOAc:isohexane) followed by reverse phase column chromatography (C 18 The residue was purified with 40 g, 10-80% acetonitrile (0.1% formic acid):water (0.1% formic acid) to give the title compound (363.0 mg, 33% yield) as a pale yellow oil. 1 H NMR(500 MHz,CDCl3)δ 7.58(d,1H),7.03(s,1H),6.96(d,1H),3.93(s,3H),1.91(t,3H).

[0410] Step B: 3-[4-(1,1-difluoroethyl)-2-methoxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one

[0411] 1-Bromo-4-(1,1-difluoroethyl)-2-methoxy-benzene (Example 24, Step A) (210.0 mg, 0.84 mmol, 1.0 equiv), bis(pinacolato)diboron (263.0 mg, 1.04 mmol, 1.24 equiv) and potassium acetate (338.0 mg, 3.44 mmol, 4.12 equiv) were sparged (nitrogen was bubbled through with sonication for 10 min) in isopropyl acetate (3 mL). XPhos Pd G3 (35.0 mg, 0.04 mmol, 0.05 equiv) and XPhos (9.0 mg, 0.02 mmol, 0.02 equiv) were added and the reaction mixture was stirred at 90° C. for 3 h. The reaction mixture was cooled to room temperature and the above 3-chloro-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one (Example 2, Step D) (227.0 mg, 0.84 mmol, 1.0 equiv.) dissolved in isopropyl acetate (2 mL) was added to the reaction, followed by potassium carbonate (288.0 mg, 2.08 mmol, 2.49 equiv.) and water (1 mL). The reaction mixture was degassed by bubbling nitrogen through it for 10 minutes while stirring, then XPhos Pd G3 (21.0 mg, 0.02 mmol, 0.03 equiv.) and XPhos (4.0 mg, 0.01 mmol, 0.01 equiv.) were added and the reaction mixture was stirred at 90° C. for 16 hours. The crude reaction mixture was filtered through a plug of Celite® and rinsed with EtOAc (approximately 50 mL). The filtrate was concentrated under reduced pressure, then dissolved in DCM (5 mL) and passed through a pipette filled with Na2SO4. The resulting clear yellow solution was concentrated to give the title compound (588.0 mg, 52% yield) as a pale yellow oil. LC-MS m / z 408.4 [M+H] + ,ESI pos.

[0412] Step C: 3-[4-(1,1-difluoroethyl)-2-hydroxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one

[0413] Benzenethiol (3.0 μL, 0.03 mmol, 1.0 equiv) and potassium carbonate (8.0 mg, 0.06 mmol, 1.97 equiv) were added to a microwave vial containing 3-[4-(1,1-difluoroethyl)-2-methoxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one (12.0 mg, 0.03 mmol, 1.0 equiv) (Example 5, Step A) in NMP (1 mL). The reaction was irradiated to 150° C. for 15 min and then concentrated in vacuo. The resulting residue was dissolved in DMSO (1.3 mL), filtered and purified 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) on a Waters XBridge BEH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL-1 eluting with 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 provided 2 mL min-1 of MeOH throughout the method, which is included in the MeCN percentages below. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, ramp from 5% MeCN to 35% MeCN; 10.5-10.6 min, ramp from 35% MeCN to 100% MeCN; 10.6-12.5 min, hold at 100% MeCN. Clean fractions were evaporated in a Genevac to give the title compound (4.0 mg, 33% yield) as a white solid. LC-MS m / z 394.0[M+H] + ,ESI pos.

[0414] Example 25: 3-(4-Acetyl-2-hydroxy-phenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one [ka]

[0415] A solution of 3-[4-(1,1-difluoroethyl)-2-methoxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one (588.0 mg, 0.58 mmol, 1.0 equiv) (Example 24, Step B) in DCM (5 mL) was treated dropwise with boron tribromide (1M in DCM) (3.5 mL, 3.50 mmol, 6.06 equiv) at 0° C. After 30 min, the mixture was allowed to warm and stirred at room temperature for 1 h. The reaction was re-cooled and the reaction mixture was quenched with 0.7 M NH3 in MeOH (approximately 15 mL) and left to stir for 30 min. The reaction mixture was concentrated, then dissolved in DMSO / water (1:1, 3.5 mL), filtered and purified using Waters X-Select CSH C 18Purification was 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) on an ODB prep column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL-1 eluting with 0.1% formic acid in water-MeCN gradient over 12.5 min using UV across all wavelengths with PDA, QDA and ELS detectors. The at-column dilution pump provided 2 mL min-1 MeOH throughout the method, which is included in the MeCN percentages below. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, ramp from 5% MeCN to 22.5% MeCN; 10.5-10.6 min, ramp from 22.5% MeCN to 100% MeCN; 10.6-12.5 min, hold at 100% MeCN. Clean fractions were evaporated in a Genevac to give the title compound (15.8 mg, 7% yield) as a pale yellow solid. LC-MS m / z 371.9[M+H] + ,ESI pos.

[0416] Example 26: 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-5-one [ka]

[0417] Step A: 6-[[(3R)-1-benzyl-3-piperidyl]amino]-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione

[0418] 6-Bromo-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione (Example 2, Step A) (1.50 g, 4.60 mmol, 1.0 equiv.) and cesium carbonate (2.997 g, 9.2 mmol, 2.0 equiv.) and (R)-3-amino-1-benzylpiperidine (1.00 g, 5.26 mmol, 1.14 equiv.) were dissolved in DMSO (20 mL) and the mixture was degassed (N2) for 5 min. The reaction vessel was evacuated and backfilled with N2 (3x) and then ( rac )-BINAP Pd G3 (228.2 mg, 0.23 mmol, 0.05 equiv) was added and the reaction mixture was placed under N2 and then stirred at 95 °C for 24 h. The reaction mixture was partitioned between EtOAc (250 mL) and water (250 mL). The organic phase was isolated, washed with brine (3x200 mL), dried using a phase separator, and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (40 g column, 0-7% (0.7 N ammonia in MeOH) in DCM) to give the title compound (1.98 g, 87% yield) as a yellow oil. LC-MS m / z 436.4 [M+H] + ,ESI pos.

[0419] Step B: 6-[[(3R)-1-1-benzyl-3-piperidyl]amino]-4-methyl-2H-1,2,4-triazine-3,5-dione

[0420] 6-[[(3R)-1-benzyl-3-piperidyl]amino]-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione (Example 26, Step A) (1.98 g, 4.0 mmol, 1.0 equiv) was dissolved in DCM (18 mL). Trifluoromethanesulfonic acid (0.71 mL, 8.0 mmol, 2.0 equiv) was added to the reaction. The resulting solution was stirred at room temperature for 18 hours, then additional trifluoromethanesulfonic acid (0.71 mL, 8.0 mmol, 2.0 equiv) was added and the reaction mixture was stirred for an additional hour. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (40 g column, 0-10% (0.7 N ammonia in MeOH / DCM) to give the title compound (1.56 g, 3.35 mmol, 67% yield) as a light brown solid. LC-MS m / z 316.3 [M+H] + ,ESI pos.

[0421] Step C: 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-chloro-4-methyl-1,2,4-triazin-5-one

[0422] 6-[[(3R)-1-1-benzyl-3-piperidyl]amino]-4-methyl-2H-1,2,4-triazine-3,5-dione (Example 26, Step B) (0.25 g, 0.79 mmol, 1.0 equiv) was dissolved in phosphorus oxychloride (4.86 mL, 52.1 mmol, 65.7 equiv). The reaction was stirred at 100° C. for 24 h and then at 120° C. for an additional 24 h. The reaction mixture was concentrated in vacuo and then diluted with EtOAc (100 mL). The mixture was stirred vigorously and saturated aqueous NaHCO3 was added slowly to pH>8. The organic phase was separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo to give the title compound (208 mg, 72% yield) as a light brown oil. LC-MS m / z 334.3[M+H] + ,ESI pos.

[0423] Step D: 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one

[0424] 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-chloro-4-methyl-1,2,4-triazin-5-one (Example 26, Step C) (209.0 mg, 0.58 mmol, 1.0 equiv), 2-methoxy-4-(trifluoromethyl)-phenylboronic acid (CAS#312936-89-3, 139.36 mg, 0.63 mmol, 1.1 equiv) and saturated aqueous Na2CO3 (0.5 mL) were suspended in 1,4-dioxane (4 mL) and the reaction mixture was sparged with N2, then evacuated and refilled with N2 (3x). Xphos Pd G3 (48.8 mg, 0.06 mmol, 0.1 equiv) was added and the reaction mixture was placed under N2 and then stirred at 80 °C for 24 h. The reaction mixture was partitioned between EtOAc (50 mL) and brine (50 mL). The organic phase was isolated, dried using a phase separator, and concentrated in vacuo to give the title compound (310.0 mg, 0.65 mmol, 81% yield) as a brown solid. LC-MS m / z 474.3 [M+H] + ,ESI pos.

[0425] Step E: 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-5-one

[0426] 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one (Example 26, step D) (186.1 mg, 0.38 mmol, 1.0 equiv) was dissolved in MeOH (8 mL) and 20 wt% palladium hydroxide on carbon (50% in H2O) (80.1 mg, 0.060 mmol, 0.150 equiv) was added followed by the addition of formaldehyde (37 wt% in H2O) (0.28 mL, 3.8 mmol, 10 equiv). The reaction mixture was stirred under 3 bar H2 for 72 h. Then, additional 20 wt% palladium hydroxide on carbon (50% in water) (91.9 mg, 0.07 mmol, 0.1 equiv) was added and the reaction mixture was stirred under 5 bar H2 for 24 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuum. The resulting residue was dissolved in DCM (10 mL) and boron tribromide (1M in DCM) (3.27 mL, 3.27 mmol, 5.0 equiv) was slowly added. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuum. The resulting residue was dissolved in MeOH (20 mL) and Na2CO3 (5 g) was added. The reaction mixture was stirred at room temperature for 45 min and then filtered and the filtrate was concentrated in vacuum. The resulting residue was dissolved in 7.5 mL of DMSO, filtered and purified using a Waters XBridge BEH C 18Purification was 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) on an ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL-1 eluting with 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 provided 2 mL min-1 MeOH throughout the method, which is included in the MeCN percentages below. 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 to give the title compound (23.9 mg, 9% yield) as a white solid. LC-MS m / z 384.3[M+H] + ,ESI pos.

[0427] The following examples "Ex." were synthesized by methods similar to those outlined above. [Table 6]

[0428] Example 29: (M or P)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one and Example 30: (P or M)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one

[0429] 3-Chloro-6-[[(3R-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one (Example 2, Step D) (350 mg, 1.29 mmol, 1.0 equiv), saturated aqueous sodium carbonate (1.5 mL, 5.50 mmol, 4.27 equiv) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (389.1 mg, 1.29 mmol, 1.0 equiv) were suspended in 1,4-dioxane (10 mL) and the reaction mixture was sparged with N2, then evacuated and backfilled with N2 (3x). Xphos Pd G3 (54.57 mg, 0.06 mmol, 0.05 equiv) was added and the reaction mixture was placed under N2 and then stirred at 80 °C for 18 h. The reaction mixture was diluted with MeOH and then dry loaded onto silica gel before purification by column chromatography on silica gel (12 g column, 0-10% (0.7N NH3 in MeOH) / DCM) and chiral SFC with Waters prep 15, UV detection by DAD at 210-400 nm, 40 °C, 120 bar. The column was IH 10x 250 mm, 5 μM, flow rate 15 mL / min, 10% MeOH (0.03% ammonia), 90% CO2. This afforded the two atropisomers:

[0430] Atrop 1: Example 29 (36.5 mg, 6% yield) was obtained as a yellow solid. LC-MS m / z 412.4 [M+H] + ,ESI pos. 1 H NMR (500 MHz, DMSO-d6) δ 7.07(s,1H), 7.17(s,1H), 6.83(d,1H), 4.07-3.97(m,1H), 3.11(s,3H), 2.79-2.70(m,1H), 2.57-2.50(m,1H), 2.41-2.32(m,2H), 2.26-2.11(m,5H), 1.76-1.62(m,2H), 1.61-1.44(m,2H), 1.00(t,3H). Note: No phenol OH was observed.

[0431] Atrop 2: Example 30 (49.5 mg, 9% yield) was obtained as a yellow solid. LC-MS m / z 412.4 [M+H] + ,ESI pos. 1 H NMR (500 MHz, DMSO-d6) δ 10.65 (bs, 1H), 7.18 (s, 1H), 7.13-6.78 (m, 2H), 4.12-3.99 (m, 1H), 3.11 (s, 3H), 2.96-2.79 (m, 1H), 2.72-2.54 (m, 1H), 2.45-1.96 (m, 6H), 1.84-1.41 (m, 4H), 1.12-0.95 (m, 3H). Note: 1×N-CH signal is obscured by the water peak and therefore not observed.

[0432] Note: Diastereomeric atropisomers around the Ar-Ar double bond (stereochemistry assigned arbitrarily).

[0433] Example 31: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(pentafluoro-λ6-sulfanyl)phenyl]-4-methyl-1,2,4-triazin-5-one [ka]

[0434] Step A: 2-iodo-5-(pentafluoro-λ6-sulfanyl)phenol

[0435] A solution of p-toluenesulfonic acid (0.09 g, 0.52 mmol, 0.13 equiv) and 3-(pentafluorothio)phenol (900.0 mg, 4.09 mmol, 1.0 equiv) in MeOH (18 mL) was stirred at room temperature for 15 min, then the flask was covered with tin foil and a solution of N-iodosuccinimide (3.0 g, 13.3 mmol, 3.26 equiv) in MeOH (18 mL) was added dropwise over 10 min. The reaction mixture was left stirring at room temperature for 18 h. The solvent was removed under reduced pressure, redissolved in EtOAc (20 mL) and washed with saturated sodium thiosulfate solution (50 mL). The organic layer was collected and concentrated to dryness. The residue was purified by chromatography (SiO2, 24 g cartridge, 0-30% DCM:isohexane) to give the title compound (1.45 g, 99% yield) as a colorless solid. LC-MS: m / z 345.0[MH] - ,ESI neg.

[0436] Step B: Pentafluoro-(4-iodo-3-methoxyphenyl)-λ6-sulfane

[0437] Iodomethane (0.3 mL, 4.82 mmol, 1.15 equiv) was added to a stirred mixture of 2-iodo-5-(pentafluoro-λ6-sulfanyl)phenol (1.49 g, 4.19 mmol, 1.0 equiv), potassium carbonate (1.50 g, 10.9 mmol, 2.59 equiv). The mixture was then heated to 56° C. for 3 h and then at room temperature for 3 days. The reaction mixture was filtered and then concentrated to dryness. The resulting residue was partitioned between water (20 mL) and EtOAc (40 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to dryness to give an orange oil. The crude product was purified by column chromatography (SiO2, 40 g cartridge, isocratic isohexane) to give the title compound (1.36 g, 87% yield) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ 7.87(dt,1H),7.16-7.06(m,2H),3.94(s,3H).

[0438] Step C: [2-Methoxy-4-(pentafluoro-λ6-sulfanyl)phenyl]boronic acid

[0439] Isopropylmagnesium chloride (2M in THF, 2.4 mL, 4.8 mmol, 1.44 equiv) was added to a stirred solution of pentafluoro-(4-iodo-3-methoxy-phenyl)-λ6-sulfane (1.2 g, 3.33 mmol, 1.0 equiv) in THF (36 mL) cooled to 0° C. The mixture was left stirring at 0° C. for 30 min. Trimethylborate (0.84 mL, 7.53 mmol, 2.26 equiv) was then added and the mixture was left stirring at room temperature for 3 h. The mixture was concentrated and then redissolved in DCM (20 mL) and washed with 10% aqueous KH2PO3 (3×10 mL) followed by brine (20 mL). The organic layer was dried (MgSO4), filtered and concentrated to dryness. The resulting yellow residue was redissolved in DCM (36 mL) and acetic acid (0.6 mL) was added. The mixture was stirred at room temperature for 30 min then water (0.36 mL) was added followed by THF (1.2 mL). The mixture was left stirring at room temperature for 18 h. The reaction mixture was washed with 10% w / v aqueous KH2PO4 (25 mL) and the organic layer was dried (MgSO4), filtered and concentrated. The resulting solid was triturated with isohexane (30 mL) to give the title compound (576.0 mg, 62% yield) as a white powder. LC-MS: m / z 277.0 [MH] - ,ESI neg.

[0440] Step D: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(pentafluoro-λ6-sulfanyl)phenyl]-4-methyl-1,2,4-triazin-5-one

[0441] This step was synthesized following a similar method to that outlined above (see Example 27). [Table 7]

[0442] Example 34: 3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-5-one [ka]

[0443] Step A: 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one

[0444] 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-chloro-4-methyl-1,2,4-triazin-5-one (Example 26, Step C) (250.0 mg, 0.71 mmol, 1.0 equiv), 2-methoxy-4-(trifluoromethoxy)-phenylboronic acid (184.7 mg, 0.78 mmol, 1.1 equiv) and saturated aqueous Na2CO3 (0.3 mL) were suspended in 1,4-dioxane (4 mL) and the reaction mixture was sparged with N2, then evacuated and backfilled with N2 (3x). Xphos Pd G3 (60.3 mg, 0.07 mmol, 0.1 equiv) was added and the reaction mixture was placed under N2 and then stirred at 80°C for 24 h. The reaction mixture was partitioned between EtOAc (50 mL) and brine (50 mL). The organic phase was isolated, dried using a phase separator, and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (24 g column, 0-10% (0.7N NH3 in MeOH) / DCM) to give the title compound (180.0 mg, 47% yield) as a pale yellow solid. LC-MS m / z 490.4 [M+H] + ,ESI pos.

[0445] Step B: 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one

[0446] 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one (Example 35, Step A) (186.1 mg, 0.38 mmol, 1.0 equiv) was dissolved in MeOH (8 mL) and 20 wt% palladium hydroxide on carbon (50% in H2O) (80.08 mg, 0.06 mmol, 0.15 equiv) was added followed by the addition of formaldehyde (37 wt% in H2O) (0.28 mL, 3.80 mmol, 10.0 equiv). The reaction mixture was stirred under 5 bar H2 for 24 h. Further 20 wt% palladium hydroxide on carbon (50% in H2O) (91.9 mg, 0.070 mmol, 0.100 equiv) was added and the reaction mixture was stirred under 5 bar H2 for 24 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuum. The resulting residue was dissolved in DCM (10 mL) and boron tribromide (1M in DCM) (1.9 mL, 1.90 mmol, 5.0 equiv) was added slowly. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuum. The resulting residue was dissolved in MeOH (20 mL) and Na2CO3 (5 g) was added. The reaction mixture was stirred at room temperature for 45 min and then filtered and the filtrate was concentrated in vacuum. The resulting residue was dissolved in 11 mL of DMSO, filtered and purified using a Waters XBridge BEH C 18 Purification was 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) using an ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, with a flow rate of 40 mL-1 and 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 at 2 mL min throughout the method. -1of MeOH in 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 to give the title compound (70.4 mg, 46% yield) as a white solid. LC-MS m / z 400.3[M+H] + ,ESI pos.

[0447] Example 35: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0448] Step A: N-(cyclopropylmethyl)-2-methoxy-4-(trifluoromethyl)benzamide

[0449] To a solution of commercially available 2-methoxy-4-(trifluoromethyl)benzoic acid (CAS#448-36-2, 2.00 g, 9.08 mmol, 1.0 equiv.) and commercially available cyclopropylmethanamine (CAS#2516-47-4, 0.95 mL, 10.9 mmol, 1.2 equiv.) in DCM (20 mL) was added DIPEA (2952.5 mg, 22.7 mmol, 2.5 equiv.), EDCI (2.09 g, 10.9 mmol, 1.2 equiv.) and HOBt (1.60 g, 11.8 mmol, 1.3 equiv.). The resulting reaction mixture was stirred at 40° C. for 2 h. After completion of the reaction, water (50 mL) was added and the solution was extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0-3:1) to give the title compound (2.10 g, 85% yield) as a yellow oil. LC-MS (Method 2): m / z 273.8 [M+H] + ,ESI pos.

[0450] Step B: N-(cyclopropylmethyl)-2-methoxy-4-(trifluoromethyl)benzothioamide

[0451] To a solution of the above N-(cyclopropylmethyl)-2-methoxy-4-(trifluoromethyl)benzamide (Example 35, Step A) (2.10 g, 7.69 mmol, 1.0 equiv.) in THF (40 mL) was added Lawesson's reagent (2.312 g, 4.61 mmol, 0.6 equiv.). The mixture was stirred at 70° C. for 2 h and cooled to room temperature after completion. The above reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography column (petroleum ether:ethyl acetate=1:0-10:1) to give the title compound (2.20 g, 93% yield) as a yellow oil. LC-MS (Method 2): m / z 290 [M+H] + ,ESI pos.

[0452] Step C: Methyl N-(cyclopropylmethyl)-2-methoxy-4-(trifluoromethyl)benzimidothioate

[0453] To a solution of the above N-(cyclopropylmethyl)-2-methoxy-4-(trifluoromethyl)benzothioamide (Example 35, Step B) (2.00 g, 6.91 mmol, 1.0 equiv) in DMF (40 mL) was added DIEA (2.68 g, 20.74 mmol, 3.0 equiv) at 20° C. and stirred for 10 min. Then, MeI (1.67 g, 11.8 mmol, 1.7 equiv) was added to the mixture. The mixture was stirred at 40° C. for 2 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium hydroxide, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (C 18 , 120 g, 0.1% TFA / MeCN in water) and then the desired fractions were combined and lyophilized to give the title compound (1.0 g, 48% yield) as a yellow oil. LC-MS (Method 2): m / z 303.9 [M+H] + ,ESI pos.

[0454] Step D: N"-(cyclopropylmethyl)-2-methoxy-4-(trifluoromethyl)benzimide hydrazide To a solution of methyl N-(cyclopropylmethyl)-2-methoxy-4-(trifluoromethyl)benzimidothioate (Example 35, Step C) (500.0 mg, 1.65 mmol, 1.0 equiv.) in ethanol (15 mL) was added hydrazine hydrate (835 mg, 16.7 mmol, 10.1 equiv.). The mixture was stirred at 70° C. for 6 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by column chromatography (C 18 , 20 g, 0.1% NH3·H2O in water / MeCN) and then the desired fractions were combined and lyophilized to give the title compound (200 mg, 41% yield) as a yellow solid. LC-MS (Method 2): m / z 288.1 [M+H] + ,ESI pos.

[0455] Step E: 6-amino-4-(cyclopropylmethyl)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one

[0456] A mixture of the above N"-(cyclopropylmethyl)-2-methoxy-4-(trifluoromethyl)benzimide hydrazide (Example 35, Step D) (150 mg, 0.52 mmol, 1.0 equiv), TEA (106 mg, 1.04 mmol, 2.0 equiv) and ethyl thioxamate (104 mg, 0.78 mmol, 1.5 equiv) in ethanol (3 mL) was stirred at 85°C for 1 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (C 18 , 20 g, 0.1% TFA / MeCN in water) and then the desired fractions were combined and lyophilized to give the title compound (70.0 mg, 37% yield) as a yellow solid. LC-MS (Method 2): m / z 341.1 [M+H] + ,ESI pos.

[0457] Step F: 6-chloro-4-(cyclopropylmethyl)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one

[0458] To a mixture of 6-amino-4-(cyclopropylmethyl)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one (Example 35, Step E) (70.0 mg, 0.21 mmol, 1.0 equiv.), CuCl (61.09 mg, 0.62 mmol, 3.0 equiv.), LiCl (17.4 mg, 0.41 mmol, 2.0 equiv.), benzyl(triethyl)azanium; chloride (178 mg, 0.78 mmol, 3.8 equiv.) in MeCN (2.5 mL) was added tert-butyl nitrite (106.1 mg, 1.03 mmol, 5.0 equiv.) at 25° C., then stirred at 70° C. for 1 h under N2 atmosphere. After completion of the reaction, the solution was cooled to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase flash (0.1% TFA / MeCN in water) followed by lyophilization to give the title compound (30.0 mg, 38% yield) as a yellow solid. LC-MS (Method 2): m / z 360.0 [M+H]+, ESI pos.

[0459] Step G: (R)-4-(cyclopropylmethyl)-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one

[0460] To a mixture of the above 6-chloro-4-(cyclopropylmethyl)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one (Example 35, Step E) (30.0 mg, 0.08 mmol, 1.0 equiv.) and (3R)-1-ethylpiperidin-3-amine (53.5 mg, 0.42 mmol, 5.0 equiv.) in NMP (0.5 mL) was added DIEA (32.3 mg, 0.25 mmol, 3.0 equiv.), then stirred at 90° C. for 2 h under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (C 18, 20 g, 0.1% TFA / MeCN in water) and then the desired fractions were combined and lyophilized to give the title compound (30.0 mg, 75% yield) as a yellow solid. LCMS (Method 2): m / z 452.2 [M+H]+, ESI pos.

[0461] Step H: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0462] To a solution of the above (R)-4-(cyclopropylmethyl)-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-5(4H)-one (Example 35, Step F) (10.0 mg, 0.02 mmol, 1.0 equiv.) in DCM (1 mL) was added BBr3 (55.4 mg, 0.22 mmol, 10.0 equiv.) at -40°C and then stirred at 20°C for 1 h. The reaction mixture was quenched with water (0.5 mL), then the pH was adjusted to about 8 with NH3.H2O, then concentrated under reduced pressure, and the residue was dissolved in methanol (2 mL) and then purified by preparative HPLC (column 3_Phenomenex Luna C 18 Purification by HPLC (75×30 mm×3 μm; Conditions water (TFA)-MeOH; Start B 23; End B 43; Gradient time (min) 7; 100% B; Retention time (min) 2; Flow rate (mL / min) 25) and then removal of the solvent by lyophilization afforded the title compound (0.82 mg, 7% yield) as a white solid. LCMS (Method 2): m / z 384.1 [M+H]+, ESI pos.

[0463] Example 36: 6-[[(3R,5S)-1-Methyl-5-fluoro-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid [ka]

[0464] Step A: 6-[[(3R,5S)-1-methyl-5-fluoro-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazin-5-one; 2,2,2-trifluoroacetic acid

[0465] To a mixture of 6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Example 16, Step B) (20.0 mg, 0.05 mmol, 1.0 equiv) and K2CO3 (66.4 mg, 0.48 mmol, 10.0 equiv) in NMP (1 mL) was added benzenethiol (49 μL, 0.48 mmol, 10.0 equiv) under N2, then stirred at 190 °C for 30 min under microwave conditions. The reaction mixture was cooled to 20 °C and purified by column chromatography (C 18 The product was purified by preparative HPLC (column: 3_Phenomenex Luna C 18 Purified a second time by 75×30 mm×3 μm, conditions: water (0.1% TFA)-MeCN, start B: 15; end B: 45, gradient time (min): 7; 100% B hold time (min): 2; flow rate (mL / min): 25). The desired fractions were combined and lyophilized to give the title compound (4.14 mg, 16% yield) as a yellow solid. LCMS (Method 2): m / z 387.9 [M+H]+, ESI pos.

[0466] Reference Example RE-A: 2-[6-[(1-ethyl-3-piperidyl)amino]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol

[0467] RE-A was synthesized similarly as described in WO20200234715.

[0468] Example A' The compound of formula Ib can be used in a manner known per se as active ingredient to produce tablets of the following composition: Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0469] Example B' The compound of formula Ib can be used in a manner known per se as active ingredient to produce capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0470] 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: Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0471] Example B The compounds of formula I can be used in a manner known per se as active ingredient to produce capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Formula Ib 【Chemistry 1】 (In the formula, R １ H, acetyl, SF ５ , halo, alkyl, haloalkyl, haloalkoxy, or nitrile; R ５ is H; Or, R １ and R ５ and the atoms to which they are attached form 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 3-6 membered cycloalkyl ring optionally substituted with 1-2 substituents independently selected from halo or alkyl; R ２ is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; R ３ is H, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo; Z is -O- or -NH-; R ４ is halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO ２ a heterocycle optionally substituted with 1 to 3 substituents independently selected from H, cycloalkylalkyl, or cycloalkyl optionally substituted with halo; or R ４ is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or R ４ is arylalkyl or heteroarylalkyl, the arylalkyl or heteroarylalkyl having 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or a pharma- ceutically acceptable salt thereof.

2. R ５ is H or R １ and R ５ and the atoms to which they are attached form a 4-6 membered heterocycle containing a single O heteroatom, or R １ and R ５ and the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring.

3. R ５ is H or R １ and R ５ and the atoms to which they are attached form a 5-membered heterocycle containing a single O atom.

4. R １ But Acetyl, SF ５ 3. The compound of claim 1 or 2, which is halo, haloalkyl, haloalkoxy or nitrile.

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

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

7. R ２ The compound according to claim 1 or 2, wherein is H.

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

9. R ３ The compound according to claim 1 or 2, wherein is alkyl.

10. R ４ is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, or cycloalkylalkyl; or R ４ is cycloalkyl optionally substituted with two substituents independently selected from alkyl, and -OH; or R ４ 3. The compound of claim 1 or 2, wherein is arylalkyl substituted with OH.

11. R ４ 3. The compound according to claim 1 or 2, wherein is ethylpiperidine.

12. The compound of claim 1 or 2, wherein Z is -NH-.

13. R １ But Acetyl, SF ５ , halo, haloalkyl, haloalkoxy or nitrile; R ５ is H; Or, R １ and R ５ and the atoms to which they are attached form a 4-6 membered heterocycle containing a single O heteroatom, or R １ and R ５ and the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R ２ is H or alkyl; R ３ is H, alkyl or cycloalkyl; Z is -NH-; R ４ is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, or cycloalkylalkyl; or R ４ is cycloalkyl optionally substituted with two substituents independently selected from alkyl, and -OH; or R ４ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: is arylalkyl substituted with OH.

14. R １ But Acetyl, SF ５ , halo, haloalkyl, haloalkoxy or nitrile; R ５ is H; Or, R １ and R ５ and the atoms to which they are attached form a 5-membered heterocycle containing a single O, R ２ is H or alkyl; R ３ is H, alkyl or cycloalkyl; Z is -NH-; R ４ is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, or cycloalkylalkyl; or R ４ is cycloalkyl optionally substituted with two substituents independently selected from alkyl, and -OH; or R ４ 14. The compound of claim 1 or 13, or a pharma- ceutically acceptable salt thereof, wherein: is arylalkyl substituted with OH.

15. The compound is 6-((1-ethylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-3-piperidyl]amino]-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[(8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino]-1,2,4-triazin-5-one; (R)-6-((1-(cyclopropylmethyl)piperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one; (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one; 6-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-1-propyl-3-piperidyl]amino]-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[(1,5,5-trimethyl-3-piperidyl)amino]-1,2,4-triazin-5-one; (R)-6-((1-cyclopropylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one; 6-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one; 6-[(1-tert-butyl-3-piperidyl)amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-(2-azabicyclo[2.2.1]heptan-6-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R,5S)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R,5R)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(5S)-5-fluoro-1-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R)-6,6-dimethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[(3-hydroxyphenyl)methylamino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 4-cyclopropyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-fluoro-2-hydroxy-phenyl)-4-methyl-1,2,4-triazin-5-one; 4-ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-1,2,4-triazin-5-one; 3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 3-[4-(1,1-difluoroethyl)-2-hydroxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 3-(4-acetyl-2-hydroxy-phenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; (M or P)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; (P or M)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(pentafluoro-λ6-sulfanyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-5-oxo-1,2,4-triazin-3-yl]-3-hydroxy-benzonitrile; 3-(4-chloro-2-hydroxy-phenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazin-5-one; 6-[[(3R,5S)-1-ethyl-5-fluoro-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazin-5-one 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, selected from:

16. The compound is 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one; (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 3-[4-(difluoromethoxy)-2-hydroxy-phenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one; 3-(4-chloro-2-hydroxy-phenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-5-one 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, selected from:

17. 3. The compound according to claim 1 or 2, wherein the compound is 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazin-5-one or a pharma- ceutically acceptable salt thereof.

18. Reaction of a compound of formula XI to a compound of formula XII 【Chemistry 2】 (In the formula, R ３ and R ４ is as defined in claim 1) 3. A method for preparing a compound according to claim 1 or 2, comprising:

19. 3. A compound according to claim 1 or 2 for use as a therapeutically active substance.

20. 3. A compound according to claim 1 or 2 for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

21. 3. A pharmaceutical composition comprising a compound according to claim 1 or 2 and a therapeutically inert carrier.

22. 22. The pharmaceutical composition of claim 21 for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

23. 3. A compound according to claim 1 or 2 for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

24. 22. A pharmaceutical composition according to claim 21 for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

25. 3. Use of a compound according to claim 1 or 2 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

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