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 the Invention The present invention relates to organic compounds useful for treatment and / or prevention in mammals, particularly compounds that modulate NLRP3 inhibition.

[0002] The present invention relates to formula Ib

Chemical Formula

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

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

[0005] NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental, and host-derived factors. When activated, NLRP3 binds to apoptosis-related speckled proteins containing a caspase activation and recruitment domain (ASC). The ASC then polymerizes to form a large aggregate known as ASC speck. The polymerized ASC then interacts with the cysteine ​​protease caspase-1 to form a complex called the inflammasome. This results in the activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (referred to as 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 speck can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 to induce apoptotic cell death.

[0006] Caspase-1 cleaves pro-IL-1β and pro-IL-18, converting them to their active forms, which are then secreted from cells. Activated caspase-1 also cleaves gasdelmin-D, inducing 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 groupbox 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and allowing IL-1α to be released. In human cells, caspase-1 can also regulate the processing and secretion of IL-37. Many other caspase-1 substrates, such as components of the cytoskeleton and glycolysis pathway, can contribute to caspase-1-dependent inflammation.

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

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

[0009] Because Macklewells syndrome (MWS), familial influenza autoinflammatory syndrome (FCAS), and neonatal-onset multiorgan inflammatory disease (NOMID), all hereditary CAPS disorders, are caused by gain-of-function mutations in NLRP3, NLRP3 is defined as a key component of the inflammatory process. NLRP3 is also involved in the pathogenesis of many complex diseases, particularly metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0010] The role of NLRP3 in central nervous system disorders such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS) is emerging. Lung diseases have also been shown to be affected by NLRP3. Furthermore, NLRP3 plays a role in the development of liver disease, kidney disease, and aging. Many of these associations are linked to NLRP3. - / - Although defined using mice, insights into the specific activation of NLRP3 in these diseases also exist. In type 2 diabetes (T2D), the deposition of islet amyloid polypeptides 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. Glybrid inhibits IL-1β production at micromolar concentrations in response to NLRP3 activation, but does not respond to NLRC4 or NLRP1 activation. Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), but these drugs have limited efficacy and are nonspecific.

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

[0013] There is a need to provide compounds with improved pharmacological and / or physiological and / or physicochemical properties, and / or compounds that serve as useful alternatives to known compounds. [Brief explanation of the drawing]

[0014] [Figure 1] This figure shows the voltage pattern in the hERG test. [Overview of the project]

[0015] This invention relates to formula Ib [ka] (In the formula, R 1 However, it is H, acetyl, SF5, halo, alkyl, haloalkyl, haloalkoxy, or nitrile; R 5 But is it H? Or, R 1 and R 5Furthermore, the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom optionally substituted with one or two substituents independently selected from halo or alkyl, or R 1 and R 5 Furthermore, the atoms to which they are bonded form a 3-6 membered cycloalkyl ring, optionally substituted with 1-2 substituents independently selected from halo or alkyl groups; R 2 However, the compound is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, and the cycloalkyl or cycloalkylalkyl is optionally substituted with a halo; R 3 However, the element is H, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, and the cycloalkyl or cycloalkylalkyl is optionally substituted with a halo; Z is either -O- or -NH-; R 4 However, it is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO2H, cycloalkylalkyl, or cycloalkyl optionally substituted with halo; or R 4 However, it is a cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or R 4 (However, the substituent is an 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 and pharmaceutically acceptable salts thereof.

[0016] The term "alkyl" refers to a monovalent linear or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. In some embodiments, unless otherwise stated, alkyl refers to a monovalent linear or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms (C 1-6 -alkyl) or 1 to 4 carbon atoms (C 1-4-Contains alkyl) C 1-6 -Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl. Certain alkyl groups include methyl, ethyl, propyl, and butyl. When an alkyl residue having a specific number of carbon atoms is named, all geometric isomers having that number of carbon atoms may be included. For example, "butyl" may include n-butyl, sec-butyl, isobutyl, and t-butyl, and "propyl" may include n-propyl and isopropyl.

[0017] The term "alkoxy" is derived from the fact that R' is C 1-6 - Represents an alkyl group, the group of formula -O-R'. C 1-6 - Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Specific examples are methoxy and ethoxy.

[0018] The term "acetyl" refers to a group of the formula -C(=O)-R' (where R' is an alkyl group). An example of acetyl is -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. The aryl may be unsubstituted or substituted as described herein.

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

[0021] The term "cycloalkyl" refers to monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbons. In some embodiments, unless otherwise stated, cycloalkyls contain 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, cycloalkyls are saturated monocyclic or polycyclic hydrocarbons. In other embodiments, cycloalkyls contain one or more double bonds (e.g., cycloalkyls fused to an aryl or heteroaryl ring, or non-aromatic monocyclic hydrocarbons containing one or two double bonds). Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, and spiro[3.3]heptanyl. Bicyclic means a ring system consisting of two saturated carbon rings sharing two carbon atoms. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, or cycloheptyl. Specific 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 groups include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, and hydroxycyclopropylmethyl. A specific example is cyclopropylmethyl.

[0023] The terms “halogen,” “halide,” and “halo” are used interchangeably herein and refer to fluoro, chloro, bromo, or iodine. Specific halogens are fluoro and chloro.

[0024] The term "haloalkyl" is C 1-6 - At least one hydrogen atom of the alkyl group is replaced by the same or a different halogen atom. 1-6- Represents an alkyl group. Specific examples include fluoromethyl, difluoromethyl, and trifluoromethyl.

[0025] The term "haloalkoxy" is C 1-6 - At least one hydrogen atom of the alkoxy group is replaced by the same or a different halogen atom C 1-6 - Represents an alkoxy group. Examples of haloalkoxys are difluoromethoxy, trifluoromethoxy, difluoroethoxy, and trifluoroethoxy. Specific examples are difluoromethoxy and trifluoromethoxy. A preferred example is trifluoromethoxy.

[0026] The term "heteroaryl" refers to a monovalent aromatic compound comprising, alone or in combination with other groups, one to four ring heteroatoms selected from N, O, or S, with the remaining ring atom being carbon. Preferably, monocyclic heteroaryls have one or two heteroatoms. Five-membered 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 hydrogen atoms of the alkyl group is substituted by a heteroaryl group. An example of a heteroarylalkyl group is pyridinyl alkyl.

[0028] The term "heterocyclic" refers to a monocyclic or bicyclic ring system of 3 to 10 ring atoms, or 3 to 8 ring atoms, that contains 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocyclic rings include oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, or piperazinyl. Examples of partially unsaturated heterocyclic rings include dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydropyridinyl, or dihydropyranyl. Specific examples of heterocyclic compounds include octahydroindolidinyl, azabicyclo[2.2.1]heptan-6-yl, azabicyclo[3.2.1]octan-2-yl, piperidinyl, or furanil. Preferred examples are furanil and piperidinyl.

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

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

[0031] The terms "nitrile" or "cyano" represent the -C≡N group.

[0032] The term "pharmaceutically acceptable salt" refers to salts that retain the biological efficacy and properties of a free base or free acid, and are not biologically or otherwise undesirable. Salts are formed using 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, and N-acetylcysteine. In addition, these salts can be prepared by adding inorganic bases or organic bases to free acids. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, and magnesium. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins. Compounds of formula Ib may also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of compounds of formula Ib are salts formed using formic acid, acetic acid, trifluoroacetic acid, and salts formed using hydrochloric acid that yield hydrochloride, dihydrochloride, or trihydrochloride.

[0033] The abbreviation uM stands for micromoles and is equivalent to the symbol μM.

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

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

[0036] Compounds of formula Ib may contain several chiral centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates.

[0037] According to the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can have either an "R" or "S" stereoconfiguration.

[0038] Furthermore, one embodiment of the present invention provides compounds according to formula I as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula Ib as described herein and pharmaceutically acceptable salts thereof, more specifically, compounds according to formula Ib as described herein.

[0039] One embodiment of the present invention is R 1 The present specification provides compounds of formula Ib, wherein the compound is acetyl, SF5, halo, haloalkyl, haloalkoxy, or nitrile.

[0040] One embodiment of the present invention is R 1 The present specification provides compounds of formula Ib, which are halo, haloalkyl, or haloalkoxy.

[0041] One embodiment of the present invention is R 1 However, this specification provides a compound according to formula Ib, which is a haloalkoxy.

[0042] One embodiment of the present invention is R 1 The present specification provides compounds according to formula Ib, wherein the compound is H, halo, alkyl, haloalkyl, or haloalkoxy.

[0043] One embodiment of the present invention is R 1 The present specification provides compounds according to formula Ib, wherein the compound is Cl, OCF3, CF3, or CH3.

[0044] One embodiment of the present invention is R 1 The present specification provides compounds of formula Ib, wherein the compound is Cl or CF3.

[0045] One embodiment of the present invention is R 1 However, this specification provides a compound according to formula Ib, which is CF3.

[0046] One embodiment of the present invention is R 2 The present specification provides compounds according to formula Ib, wherein the compound is H, halo, alkyl, haloalkyl, or cycloalkyl, and the cycloalkyl is optionally substituted with a halo.

[0047] One embodiment of the present invention is R 2 The present specification provides compounds according to formula Ib, wherein H is a halo, alkyl, or haloalkyl.

[0048] One embodiment of the present invention is R 2 The present specification provides compounds of formula Ib, wherein the compound is H or alkyl.

[0049] One embodiment of the present invention is R 2 This specification provides compounds according to formula Ib, wherein H is present.

[0050] One embodiment of the present invention is R 3 The present specification provides compounds according to formula Ib, wherein the compound is H, alkyl, haloalkyl, or cycloalkyl, and the cycloalkyl is optionally substituted with a halo.

[0051] One embodiment of the present invention is R 3 The present specification provides compounds of formula Ib, wherein H is alkyl or haloalkyl.

[0052] One embodiment of the present invention is R 3 This specification provides compounds according to formula Ib, wherein the alkyl group is present.

[0053] One embodiment of the present invention is R4 However, it is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, or cycloalkylalkyl; or R 4 However, it is a cycloalkyl group optionally substituted with two substituents independently selected from alkyl and -OH; or R 4 This specification provides compounds according to formula Ib, which are arylalkyl groups substituted with OH.

[0054] One embodiment of the present invention is R 4 However, this specification provides compounds according to formula Ib, which are heterocycles optionally substituted with alkyl groups.

[0055] One embodiment of the present invention is R 4 This specification provides compounds according to formula Ib, wherein the ring is an alkyl-substituted pyrrolidine, furan, piperidine, or pyran ring.

[0056] One embodiment of the present invention is R 4 This specification provides compounds of formula Ib described herein, wherein is an alkyl-substituted pyrrolidine or piperidine ring.

[0057] One embodiment of the present invention is R 4 This specification provides compounds according to formula Ib, wherein is an alkyl-substituted piperidine ring.

[0058] One embodiment of the present invention is R 4 This specification provides compounds according to formula Ib, wherein is tert-butylpiperidine.

[0059] One embodiment of the present invention is R 4 This specification provides compounds according to formula Ib, wherein the compound 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 is R5 Is H or R 1 and R 5 Furthermore, the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom, or R 1 and R 5 Furthermore, the present invention provides compounds according to formula Ib, wherein the atoms to which they are bonded form a 3- to 6-membered cycloalkyl ring.

[0062] One embodiment of the present invention is R 5 Is H or R 1 and R 5 The present invention provides compounds according to formula Ib, wherein the atoms to which they are bonded form a five-membered heterocycle containing a single oxygen atom.

[0063] One embodiment of the present invention is R 5 This specification provides compounds according to formula Ib, wherein H is present.

[0064] One embodiment of the present invention is R 1 and R 5 Furthermore, the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom optionally substituted with one or two substituents independently selected from halo or alkyl, or R 1 and R 5 The present invention provides compounds according to formula Ib, wherein the atoms to which they are bonded form a 3- to 6-membered cycloalkyl ring, which is optionally substituted with one or two substituents independently selected from halo or alkyl groups.

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

[0066] One embodiment of the present invention is R1 and R 5 The present invention provides compounds according to formula Ib, wherein the atoms to which they are bonded form a five-membered heterocycle containing a single oxygen heteroatom.

[0067] One embodiment of the present invention is R 1 However, these are acetyl, SF5, halo, haloalkyl, haloalkoxy, or nitrile; R 5 But is it H? Or, R 1 and R 5 Furthermore, the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom, or R 1 and R 5 Furthermore, the atoms to which they are bonded form a 3-6 membered cycloalkyl ring, R 2 However, it is H or alkyl; R 3 However, it is H, alkyl, or cycloalkyl; Z is -NH-; R 4 However, it is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, or cycloalkylalkyl; or R 4 However, it is a cycloalkyl group optionally substituted with two substituents independently selected from alkyl and -OH; or R 4 However, it is an arylalkyl group substituted with an OH group; This specification provides compounds according to formula Ib and pharmaceutically acceptable salts thereof.

[0068] One embodiment of the present invention is R 1 However, these are acetyl, SF5, halo, haloalkyl, haloalkoxy, or nitrile; R 5 But is it H? Or, R 1 and R 5and the atoms to which they are attached form a 5-membered heterocyclic ring containing a single O, R 2 is H or alkyl; R 3 is H, alkyl or cycloalkyl; Z is -NH-; R 4 is a heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl or cycloalkylalkyl; or R 4 is cycloalkyl optionally substituted with 2 substituents independently selected from alkyl and -OH; or R 4 is arylalkyl substituted with OH; There are provided compounds of formula Ib as described herein, and pharmaceutically acceptable salts thereof.

[0069] One embodiment of the present invention is R 1 is halo, haloalkyl or haloalkoxy; R 5 is H; or or, R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocyclic ring containing a single O, R 2 is H; or R 3 is alkyl; Z is -NH-; R 4 is a piperidyl ring optionally substituted with alkyl; There are provided compounds of formula Ib as described herein, and pharmaceutically acceptable salts thereof.

[0070] One embodiment of the present invention is R 1 is haloalkoxy; R 5 is H; or R 2 is H; R 3 However, it is alkyl; Z is -NH-; R 4 However, it is a piperidyl ring optionally substituted with an alkyl group; This specification provides compounds according to formula Ib and pharmaceutically acceptable salts thereof.

[0071] One embodiment of the present invention is R 1 However, it is H, halo, alkyl, haloalkyl, haloalkoxy, or nitrile; R 5 But is it H? Or, R 1 and R 5 Furthermore, the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom optionally substituted with one or two substituents independently selected from halo or alkyl, or R 1 and R 5 Furthermore, the atoms to which they are bonded form a 3- to 6-membered cycloalkyl ring having one or two substituents independently selected from halo or alkyl; R 2 However, the compound is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, and the cycloalkyl or cycloalkylalkyl is optionally substituted with a halo; R 3 However, the element is H, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, and the cycloalkyl or cycloalkylalkyl is optionally substituted with a halo; Z is either -O- or -NH-; R 4 However, it is a heterocycle optionally substituted with one or two substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO2H, or cycloalkyl optionally substituted with halo; or R 4 However, it is a cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or R 4 However, the substituent is an arylalkyl or heteroarylalkyl, and the arylalkyl or heteroarylalkyl may have up to three substituents independently selected from alkyl, halo, haloalkyl, and -OH; This specification provides compounds according to formula Ib and pharmaceutically acceptable salts thereof.

[0072] One embodiment of the present invention is R 1 and R 5 Furthermore, the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom optionally substituted with one or two substituents independently selected from halo or alkyl, or R 1 and R 5 Furthermore, the atoms to which they are bonded form a 3- to 6-membered cycloalkyl group, which is optionally substituted with one or two substituents independently selected from halo or alkyl groups; R 2 However, H is; R 3 However, it is methyl; Z is -NH-; R 4 However, it is an alkyl-substituted piperidine ring; This specification provides compounds according to formula Ib and pharmaceutically acceptable salts thereof.

[0073] One embodiment of the present invention is R 1 and R 5 Furthermore, the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom, or R 1 and R 5 Furthermore, the atoms to which they are bonded form a 4-6 membered cycloalkyl ring: R 2 However, H is; R 3 However, it is methyl; Z is -NH-; R 4However, it is an alkyl-substituted piperidine ring; This specification provides compounds according to formula Ib and pharmaceutically acceptable salts thereof.

[0074] Specific examples of compounds of formula Ib described herein are: 6-((1-ethylpiperidine-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-3-piperidyl]amino]-1,2,4-triazine-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-triazine-5-one; (R)-6-((1-(cyclopropylmethyl)piperidine-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one; (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-one; 6-(1,2,3,5,6,7,8,8a-octahydroindolidine-8-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-1-propyl-3-piperidyl]amino]-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[(1,5,5-trimethyl-3-piperidyl)amino]-1,2,4-triazine-5-one; (R)-6-((1-cyclopropylpiperidine-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one; 6-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one; 6-[(1-tert-butyl-3-piperidyl)amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-(2-azabicyclo[2.2.1]heptan-6-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R,5S)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R,5R)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(5S)-5-fluoro-1-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R)-6,6-dimethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[(3-hydroxyphenyl)methylamino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 4-Cyclopropyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-fluoro-2-hydroxyphenyl)-4-methyl-1,2,4-triazine-5-one; 4-Ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-1,2,4-triazine-5-one; 3-[4-(difluoromethoxy)-2-hydroxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 3-[4-(1,1-difluoroethyl)-2-hydroxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 3-(4-acetyl-2-hydroxyphenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-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-triazine-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-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(pentafluoro-λ6-sulfanyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-5-oxo-1,2,4-triazine-3-yl]-3-hydroxy-benzonitrile; 3-(4-chloro-2-hydroxyphenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazine-5-one; 6-[[(3R,5S)-1-ethyl-5-fluoro-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazine-5-one; Selected from the and pharmaceutically 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-triazine-5-one; (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 3-[4-(difluoromethoxy)-2-hydroxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazine-5-one; 3-(4-chloro-2-hydroxyphenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazine-5-one; Selected from the and pharmaceutically acceptable salts thereof.

[0076] The most preferred examples of the compounds of formula Ib described herein are 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazine-5-one and its pharmaceutically acceptable salts.

[0077] Other examples of formula Ib described herein include 6-((1-ethylpiperidine-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one or 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazine-5-one, or any pharmaceutically acceptable salt thereof.

[0078] Embodiments of the present invention provide compounds according to formula I, wherein the compound of formula I is the compound of formula Ib. [ka]

[0079] Furthermore, one embodiment of the present invention is R 1 However, it is H, halo, alkyl, haloalkyl, haloalkoxy, or nitrile; R 2 However, the compound is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, and the cycloalkyl or cycloalkylalkyl is optionally substituted with a halo; R 3 However, the element is H, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, and the cycloalkyl or cycloalkylalkyl is optionally substituted with a halo; Z is either -O- or -NH-; R 4 However, it is a heterocycle optionally substituted with one or two substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO2H, or cycloalkyl optionally substituted with halo; or R 4 However, it is a cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or R 4However, the substituent is an arylalkyl or heteroarylalkyl, and the arylalkyl or heteroarylalkyl may have up to three substituents independently selected from alkyl, halo, haloalkyl, and -OH; The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof.

[0080] One embodiment of the present invention is R 1 However, it is H, halo, alkyl, haloalkyl, or haloalkoxy; R 2 However, the compound is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, and the cycloalkyl or cycloalkylalkyl is optionally substituted with a halo; R 3 However, the element is H, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, and the cycloalkyl or cycloalkylalkyl is optionally substituted with a halo; Z is either -O- or -NH-; R 4 However, it is a heterocycle optionally substituted with one or two substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO2H, or cycloalkyl optionally substituted with halo; or R 4 However, it is a cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or R 4 However, the substituent is an arylalkyl or heteroarylalkyl, and the arylalkyl or heteroarylalkyl may have up to three substituents independently selected from alkyl, halo, haloalkyl, and -OH; The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof.

[0081] Compounds of formula I may contain several chiral centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomer racemates, or mixtures of diastereoisomer racemates.

[0082] Furthermore, embodiments of the present invention provide compounds according to formula I as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula I as described herein and pharmaceutically acceptable salts thereof, more specifically, compounds according to formula I as described herein.

[0083] One embodiment of the present invention is R 1 The present specification provides compounds according to formula I, wherein H is a halo, alkyl, haloalkyl, or haloalkoxy.

[0084] One embodiment of the present invention is R 1 The present specification provides compounds according to formula I, wherein the compound is Cl, OCF3, CF3, or CH3.

[0085] One embodiment of the present invention is R 1 The present specification provides compounds according to formula I, wherein the compound is Cl or CF3.

[0086] One embodiment of the present invention is R 1 However, this specification provides a compound according to formula I, which is CF3.

[0087] One embodiment of the present invention is R 2 The present specification provides compounds according to formula I, wherein the compound is H, halo, alkyl, haloalkyl, or cycloalkyl, and the cycloalkyl is optionally substituted with a halo.

[0088] One embodiment of the present invention is R 2 The present specification provides compounds according to formula I, wherein H is halo, alkyl, or haloalkyl.

[0089] One embodiment of the present invention is R 2 This specification provides compounds according to formula I, wherein H is present.

[0090] One embodiment of the present invention is R 3 The present specification provides compounds according to formula I, wherein H is alkyl, haloalkyl, or cycloalkyl, and the cycloalkyl is optionally substituted with a halo.

[0091] One embodiment of the present invention is R 3 The present specification provides compounds according to formula I, wherein H is alkyl or haloalkyl.

[0092] One embodiment of the present invention is R 3 This specification provides compounds according to formula I, wherein the alkyl group is present.

[0093] One embodiment of the present invention is R 4 However, this specification provides compounds according to formula I, which are heterocycles optionally substituted with alkyl groups.

[0094] One embodiment of the present invention is R 4 The present specification provides compounds according to formula I, wherein is an alkyl-substituted pyrrolidine, furan, piperidine, or pyran ring.

[0095] One embodiment of the present invention is R 4 This specification provides compounds according to formula I, wherein is an alkyl-substituted pyrrolidine or piperidine ring.

[0096] One embodiment of the present invention is R 4 This specification provides compounds according to formula I, wherein is an alkyl-substituted piperidine ring.

[0097] One embodiment of the present invention is R 4 This specification provides compounds according to formula I, wherein is tert-butylpiperidine.

[0098] One embodiment of the present invention is R 4 This specification provides compounds according to formula I, wherein ethylpiperidine is present.

[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 is R 1 However, it is Cl, OCF3, alkyl, or haloalkyl; R 2 However, it is H, halo, alkyl, haloalkyl or cycloalkyl (optionally substituted with F); R 3 However, it is H, alkyl, haloalkyl, or cycloalkyl (optionally substituted with F); Z is either -O- or -NH-; R 4 However, it is a heterocycle optionally substituted with one or two substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO2H, or cycloalkyl optionally substituted with halo; or R 4 However, it is a cycloalkyl group that is optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH groups. This specification provides compounds according to formula I described herein.

[0101] One embodiment of the present invention is R 1 However, it is Cl, CH3, OCF3, or CF3; R 2 However, it is H, halo, alkyl, or haloalkyl; R 3 However, it is H, alkyl, or haloalkyl; Z is either -O- or -NH-; R 4However, it is a heterocycle containing one heteroatom optionally substituted with one or two substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO2H, or cycloalkyl optionally substituted with halo; or R 4 However, it is a cycloalkyl group that is optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH groups. This specification provides compounds according to formula I described herein.

[0102] One embodiment of the present invention is R 1 However, it is Cl, CH3, OCF3, or CF3; R 2 However, it is H, halo, alkyl, or haloalkyl; R 3 However, it is H, alkyl, or haloalkyl; Z is either -O- or -NH-; R 4 However, it is a heterocycle containing one heteroatom that is optionally substituted with one or two substituents independently selected from halo, alkyl, or haloalkyl. This specification provides compounds according to formula I described herein.

[0103] One embodiment of the present invention is R 1 However, it is either Cl or CF3; R 2 However, it is H, halo, alkyl, or haloalkyl; R 3 However, it is H, alkyl, or haloalkyl; Z is -NH-; R 4 However, it is a heterocycle containing one heteroatom that is optionally substituted with one or two substituents independently selected from halo, alkyl, or haloalkyl. This specification provides compounds according to formula I described herein.

[0104] One embodiment of the present invention is R 1is Cl or CF3; R 2 is H; R 3 is CH3; Z is -NH-; R 4 is a piperidine ring substituted with alkyl, Provide a compound according to formula I described herein.

[0105] One embodiment of the present invention is, R 1 is CF3; R 2 is H; R 3 is CH3; Z is -NH-; R 4 is a piperidine ring substituted with alkyl, Provide a compound according to formula I described herein.

[0106] Specific examples of the compounds of formula I described herein are 6-((1-ethylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one, or a pharmaceutically acceptable salt thereof.

[0107] The method for the preparation of the compounds of formula I described herein is an object of the present invention. The synthesis of the compounds of formula I can be achieved, for example, according to Scheme 1.

[0108] The present invention also relates to the compounds according to the present invention when prepared according to the method of the present invention.

[0109] General synthetic scheme of triazinone compounds: The compounds of formula I can be prepared according to the variations of the above method and according to Scheme 1 below. The 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 with a commercially available aryl bromide II, such as 1-bromo-2-methoxy-4-(trifluoromethyl)benzene (CAS: 402-07-3), the compound of general formula III was obtained by reacting it with methyl isothiocyanate in the presence of n-BuLi in dry THF. Subsequently, alkylation was performed using methyl iodide, methyl bromide, or other suitable alkylating reagent in the presence of a base such as potassium hydroxide to obtain compound IV. The subsequent reaction with hydrazine hydrate yielded the intermediate of general formula V, which was then cyclized with ethyl thiooxamate and a base, such as triethylamine, to obtain the corresponding triazinon VI. Subsequently, using tert-butyl nitrite, the Sandmeyer reaction in the presence of Cu(I)Cl yielded VII. Diazotization can also be carried out using sodium nitrite or an equivalent reagent that forms a diazonium intermediate, followed by the addition of copper chloride. Next, VIII was obtained by nucleophilic aromatic substitution using an amine and a base according to general formula 6a, preferably N,N-diisopropylethylamine or triethylamine, in a solvent, DMSO, DMF, or ether, such as THF, at high temperature. In the final step, the arylmethyl ether group was cleaved with well-known boron tribromide (BBr3) in dichloromethane to obtain a compound of general formula I, for example, Example 1. Final deprotection can also be achieved by using benzenethiol, potassium carbonate, or a related base in the solvent as NMP at high temperature.

[0112] Scheme 2 [ka]

[0113] Alternatively, compounds of formula I or Ib can also be synthesized according to the alternative synthetic routes shown in Scheme 2. For example, starting with 6-bromo-4-methyl-2H-1,2,4-triazine-3,5-dione (IX; CAS: 15870-75-4), PMB protection was performed by reacting 4-methoxybenzyl chloride in DMF in the presence of a base, such as an alkaline carbonate or alkaline phosphate, preferably potassium carbonate. Alternatively, intermediates of general formula X can be obtained by carrying out other alkylating reagents such as bromides, mesylates, or tosylates in a solvent such as THF or DMSO in the presence of other bases such as cesium carbonate, DIPEA, or triethylamine, or by carrying out any other standard procedure known to those skilled in the art. Next, a palladium-catalyzed amination reaction such as Buchwald's was carried out in the presence of a catalyst such as BINAP Pd G3, preferably using hetalil bromide having (3R)-1-ethylpiperidine-3-amine, (3R)-1-methylpiperidine-3-amine, or any amine as described in the claims, with cesium carbonate used as a base. DMSO was used as the solvent, but the reaction can also be carried out in DMF, THF, or other solvents to obtain the intermediate of general formula XI. Alternatively, XI can be obtained by a nucleophilic aromatic substitution reaction known to those skilled in the art. Subsequently, PMB deprotection was achieved by adding trifluoromethanesulfonic acid in DCM at room temperature. PMB deprotection can also be achieved by hydrogenation in a solvent such as methanol or ethanol, in the presence of a commercially available palladium-carbon catalyst such as Pd / C. Chlorination by adding POCl3 and heating the reaction yielded the intermediate of general formula XII. Finally, the left-hand side was introduced by Suzuki-Miyaura cross-coupling, as is well known to those skilled in the art, in the presence of a palladium catalyst as XPhos Pd G3 and a boronic acid or pinacol ester 7a boronic acid, according to standard conditions well known to those skilled in the art. In the case of aryl methyl ethers, the final product was obtained by adding boron tribromide (BBr3) in dichloromethane to obtain compounds of general formula I or Ib, and in the case of SEM, the final compound was obtained after reaction with TFA. In general, other phenol protecting group modifications known to those skilled in the art can be applied. Specific examples of each of the exemplified compounds will be described in more detail below.

[0114] Therefore, the present invention relates to the compounds according to the present invention when produced according to the method of the present invention.

[0115] Another embodiment of the present invention provides pharmaceutical compositions or pharmaceuticals containing the compounds of the present invention and therapeutic inert carriers, diluents or excipients, as well as methods for using the compounds of the present invention to prepare such compositions and pharmaceuticals. In one example, the compound of formula Ib can be formulated into a galenic dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to the recipient at the dose and concentration used, at ambient temperature, appropriate pH, and of a desired degree of purity. The pH of the formulation depends primarily on the specific application and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula Ib is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula Ib is sterile. The compounds can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0116] The composition is formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical symptoms, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the healthcare professional.

[0117] The compounds of the present invention may be administered by any preferred means, including orally, topically (including buccal and sublingual), rectally, vaginally, percutaneously, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, subarachnoidally, and epidurally and intranasally, and, if desired in topical treatment, intralesional administration. Parenteral administration may include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0118] The compounds of the present invention can 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 components commonly used in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents, and further activators.

[0119] Typical formulations are prepared by mixing the compound of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, 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, flow enhancers, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide accurate presentation of a drug (i.e., the compound or pharmaceutical composition thereof of the present invention) or to assist in the manufacture of a pharmaceutical (i.e., a pharmaceutical).

[0120] The compounds of formula Ib and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

[0121] The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

[0122] Adjuvants suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols, etc.

[0123] Adjuvants suitable for the manufacture of solutions and syrups are, by way of example, water, polyols, sucrose, invert sugar, glucose, etc.

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

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

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

[0127] Furthermore, the pharmaceutical formulation may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for altering osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical formulation of the present invention may further contain other therapeutically valuable substances.

[0128] Dosage can vary widely and, of course, to suit the individual requirements of each specific case. Generally, for oral administration, a daily dose of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g., about 300 mg per person), is preferably divided into 1 to 3 individual doses, which, if appropriate, may consist of equal amounts, for example. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be between 0.1 and 25 mg, can be administered by a single dose per day or per week, by multiple doses per day (2 to 4 times), or by multiple doses per week. However, where indicated, it will be clear that the upper or lower limits given herein may be exceeded.

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

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

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

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

[0133] One embodiment of the present invention is a compound according to Formula I described herein for use in the treatment or prevention of a disease, disorder, or symptom, wherein the disease, disorder, or symptom is responsive to NLRP3 inhibition.

[0134] One embodiment of the present invention is a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or symptom, wherein the disorder or symptom 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 NLRP3 activation.

[0136] There is evidence regarding the roles of NLRP3-induced IL-1 and IL-18 in inflammatory responses associated with or resulting from numerous 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 symptom 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) Symptoms related to diabetes; and (xviii) Any disease in which an individual is determined to have germline or somatic nonsilent mutations in NLRP3 Selected from.

[0138] In another embodiment, the disease, disorder, or symptom is: (i) cancer; (ii) Infectious diseases; (iii) Central nervous system disorders; (iv) cardiovascular disease; (v) liver disease; (vi) Eye diseases; or (vii) Skin diseases Selected from.

[0139] In a further typical embodiment of the present invention, the disease, disorder, or symptom is inflammation. Examples of inflammation that can be treated or prevented include: (i) Skin conditions such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (ii) Joint 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 symptoms such as polymyositis or myasthenia gravis; (iv) Gastrointestinal symptoms 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 outside the gut (e.g., migraine, rhinitis, or eczema); (v) Respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (eosinophilic, bronchial, allergic, endogenous, exogenous, or dust-induced asthma, especially chronic or refractory asthma, e.g., late-stage asthma and airway hyperresponsiveness), bronchitis, rhinitis (acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, suppurative rhinitis (rhinitis pumlenta), xerotic rhinitis, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis, e.g., hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, ash-induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (vi) Vascular conditions such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (vii) Autoimmune conditions such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type 1 diabetes, idiopathic thrombocytopenic purpura, or Graves' disease; (viii) Eye symptoms such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (ix) Neurological symptoms such as multiple sclerosis or encephalomyelitis; (x) Infections or infection-related conditions, such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infections, acute or chronic parasitic infections, acute or chronic viral infections, acute or chronic fungal infections, meningitis, hepatitis (A, B, or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, hemorrhagic dengue fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis (including co-infection with Mycobacterium tuberculosis and HIV), Mycobacterium avium intracellulare, Pneumocystis jirovecii pneumonia, orchitis / epididymitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (xi) Renal symptoms such as mesangial proliferative glomerulonephritis, renal syndrome, nephritis, glomerulonephritis, obesity-associated glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritis syndrome, renal fibrosis including chronic crystalline nephropathy, or renal hypertension; (xii) Lymphatic symptoms such as Castleman disease; (xiii) Conditions of the immune system or related thereto, such as hyper-IgE syndrome, hepatoblastomatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (xiv) Liver conditions such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, hepatic fibrosis, or liver failure; (xv) Cancers including the cancers listed above; (xvi) burns, wounds, injuries, bleeding, 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 include inflammatory responses related to or resulting from such responses.

[0140] One embodiment of the present invention 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) Symptoms related to diabetes; and (xviii) Any disease in which an individual is determined to have germline or somatic nonsilent mutations in NLRP3 A compound according to formula Ib described herein for the treatment or prevention of a disease, disorder, or symptom selected from the above.

[0141] One embodiment of the present invention is the use of a compound according to formula Ib described herein in the treatment or prevention of a disease, disorder, or symptom 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 described herein for use in the treatment or prevention of a disease, disorder, or symptom selected from asthma or COPD.

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

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

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

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

[0147] One embodiment of the present invention is the use of a compound according to formula Ib described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder, or symptom 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 described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder, or symptom selected from asthma or COPD.

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

[0150] One embodiment of the present invention is a method for treating or preventing a disease, disorder, or symptom selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to formula Ib described herein.

[0151] One embodiment of the present invention is a method for treating or preventing a disease, disorder, or symptom selected from asthma or COPD, comprising administering an effective amount of a compound according to formula Ib described herein.

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

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

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

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

[0156] One embodiment of the present invention 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) Symptoms related to diabetes; and (xviii) Any disease in which an individual is determined to have germline or somatic nonsilent mutations in NLRP3 A compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or symptom selected from the above.

[0157] One embodiment of the present invention is the use of a compound according to Formula I described herein in the treatment or prevention of a disease, disorder, or symptom 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 described herein for use in the treatment or prevention of a disease, disorder, or symptom selected from asthma or COPD.

[0159] One embodiment of the present invention is a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or symptom selected from Alzheimer's disease and Parkinson's disease.

[0160] One embodiment of the present invention is a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or symptom selected from asthma or COPD.

[0161] One embodiment of the present invention is the use of a compound according to Formula I described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder, or symptom 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 described herein for the preparation of a pharmaceutical for the treatment or prevention of a disease, disorder, or symptom selected from asthma or COPD.

[0163] One embodiment of the present invention is a method for treating or preventing a disease, disorder, or symptom selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to Formula I described herein.

[0164] One embodiment of the present invention is a method for treating or preventing a disease, disorder, or symptom selected from asthma or COPD, comprising administering an effective amount of a compound according to Formula I described herein.

[0165] One embodiment of the present invention relates to a method for inhibiting NLRP3, comprising administering an effective amount of a compound according to Formula I described herein.

[0166] Furthermore, one embodiment of the present invention is a compound of formula I described herein, when manufactured 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 described herein and a therapeutically inactive carrier.

[0168] Assay procedure NLRP3 and pyroptosis It is well established that NLRP3 activation leads to cellular pyroptosis, and that this characteristic plays a crucial role in the manifestation of clinical diseases (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, inhibitors of NLRP3 are expected to block pyroptosis and the release of pro-inflammatory cytokines (e.g., IL-1β) from cells.

[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). The cells were periodically passaged until confluence (approximately 10) 6Cells were grown to a concentration of 625,000 cells / ml. On the day of the experiment, 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 dilution was performed to obtain a concentration of 625,000 cells / ml. LPS (Sigma#L4524) was added to this diluted cell solution to obtain a final assay concentration (FAC) of 1 μg / ml. 40 μl of the final preparation was dispensed into each well of a 96-well plate. The plates prepared in this manner were used for compound screening.

[0170] THP-1 cell pyroptosis assay For compound screening, we followed the stepwise assay method described below.

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

[0172] 2. Add 5 μl of the compound (8-point semi-logarithmic dilution using the highest dose of 10 μM) or the vehicle (DMSO 0.1% FAC) to the appropriate wells.

[0173] 3. Incubate at 37°C and 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°C and 5% CO2 for 1 hour.

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

[0177] 7. Next, add 50 μl of resazurin (Sigma#R7017) (100 μM FAC resazurin in RPMI medium without FBS) and incubate the plate at 37°C and 5% CO2 for a further 1-2 hours.

[0178] 8. The plate was read using an Envision reader at Ex 560nm and Em 590nm.

[0179] 9. IC 50 Fitting the data to a nonlinear regression equation (log-inhibitor versus response variable gradient, 4 parameters)

[0180] The results of the pyroptosis assay were obtained from THP IC. 50 This is 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 crucial. Therefore, the NLRP3 inhibitory activity of numerous compounds in human whole blood was investigated according to the following protocol.

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

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

[0185] 2. Add 10 μl of the compound (8-point semi-logarithmic dilution using the highest dose of 10 μM) or the vehicle (DMSO 0.1% FAC) to the appropriate wells.

[0186] 3. Incubate at 37°C and 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°C and 5% CO2 for 1 hour.

[0189] 6. At the end of the incubation period, rotate the plate at 300×g for 5 minutes to pellet the cells, remove 20 μl of supernatant, and add it to a 96-well v-bottom plate for IL-1β analysis (Note: These plates containing the supernatant can be stored at -80°C for analysis on 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 Fitting the data to a nonlinear regression equation (log-inhibitor versus response variable gradient, 4 parameters)

[0192] Results of human whole blood assays, HWB IC 50 This is summarized in Table 1 below.

[0193] hERG Screening Assay cell A CHO clerox hERG cell line (ATCC reference Nr. PTA-6812, female Chinese hamster cells) was created and validated using Roche. Immediately usable frozen CHO-hERG cells were cryopreserved at Evotec (Germany) and used directly in experiments.

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

[0195] Electrophysiology The effect of the compound on the hERG K+ current parameter will be evaluated at two concentrations in at least four cells.

[0196] The hERG test is performed using the SynchroPatch® 384 automated patch clamp system (Nanion Technologies GmbH, Germany). The K+ current is measured at 35-37°C in a whole cell composition using patch voltage clamp technology.

[0197] The cells were held at a quiescent voltage of -80 mV and stimulated with the voltage pattern shown in Figure 1, activating the hERG channel at a stimulation frequency of 0.1 Hz (6 bpm) and conducting an outward IKhERG current.

[0198] Data Analysis The amplitude of the IKhERG was recorded at each drug concentration and fractional blocks were defined by comparing it to the vehicle control value (set as 100%). The concentration-response data were fitted according to the following relationship:

number

[0199] The concentration-response curves were fitted using nonlinear regression analysis with 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] TIFF0007869248000008.tif246169 TIFF0007869248000009.tif238169 TIFF0007869248000010.tif249169 TIFF0007869248000011.tif229169 TIFF0007869248000012.tif248169 TIFF0007869248000013.tif246169 TIFF0007869248000014.tif222169 TIFF0007869248000015.tif121169 [Table 2] TIFF0007869248000017.tif111169

[0200] The present invention will now be described by the following embodiments, which do not have limiting features.

[0201] If the preparation is obtained as a mixture of enantiomers, the pure enantiomer can be obtained by the methods described herein or by methods 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 performed using ICON-NMR on a Bruker 400 MHz spectrometer under TopSpin program control. Spectra were measured at 298 K and referenced to solvent resonance unless otherwise specified.

[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 (v / v) in water; B: 0.019% TFA (v / v) in acetonitrile. Column: Kinetex EVO C 18 2.1 x 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 (v / v) in water; 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] The column was conditioned with 100% MeCN (2 minutes) before use, then with 1% MeCN (0.8 minutes). 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 a conditioning method. [Examples]

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

[0211] Example 1: 6-((1-ethylpiperidine-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-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 equivalent), n-BuLi (10.2 mL, 25.5 mmol, 1.3 equivalents) in THF was added dropwise under N2 at -70°C and stirred for 10 minutes. Then, methyl isothiocyanate (2150 mg, 29.4 mmol, 1.5 equivalents) was added and stirred at 25°C for 1 hour. TLC (PE / siRNA = 3:1) indicated that the reaction was complete. The mixture was quenched with water (10 ml), and the aqueous layer was extracted twice with siRNA (100 mL). The combined organic layers were washed with an aqueous solution of 50 mL of water and dried over Na2SO4. The crude product was purified by column chromatography on silica gel (gradient PE:siRNA = 100:1 to 5:1) to obtain the marked compound (1 g, yield 20.5%) as a black oily substance. LCMS: m / z 249.9 (M+H) + (ES + ).

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

[0215] Subsequently, 2-methoxy-N-methyl-4-(trifluoromethyl)benzenecarbothioamide (3.3 g, 11.3 mmol, 1 equivalent) in MeCN (20 mL) was mixed with KOH (694 mg, 12.4 mmol, 1.1 equivalent) and MeI (1.6 g, 11.3 mmol, 1 equivalent), and the reaction mixture was stirred at 50°C for 2 hours. The mixture was poured into ice water (w / w=1 / 1) (10 mL) and stirred for 1 minute. The aqueous phase was mixed with SiO2 (100 mL) * 3) Extraction was performed. 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 preparative TLC (SiO2, PE / siRNA = 3:1) to obtain the labeled compound (1.7 g, yield 40%) as a black oil. LCMS: m / z 263.8 (M+H)+ (ES + ).

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

[0217] To a mixture of hydrazine hydrate (1.4 g, 26.6 mmol, 10 equivalents) in EtOH (2 mL), a solution of methyl 2-methoxy-N-methyl-4-(trifluoromethyl)benzene-carboximidothioate (700 mg, 2.7 mmol, 1 equivalent) in EtOH (1 mL) was added dropwise under N2 at 70°C and stirred at 70°C for 2 hours. The mixture was poured into ice water (w / w=1 / 1) (10 mL) and stirred for 5 minutes. The aqueous phase was converted to SiO2 (50 mL) * 2) Extracted. Combined organic phases were mixed with brine (10 mL). * The product was washed (as described in 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography (under 0.1% TFA conditions) to obtain the labeled compound (340 mg, 45% yield) as a white solid. LCMS: m / z 248.1 (M+H) + (ES + ).

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

[0219] A mixture of N-amino-2-methoxy-N'-methyl-4-(trifluoromethyl)benzamidine (290 mg, 1.2 mmol, 1 equivalent), TEA (237 mg, 2.4 mmol, 2 equivalents), and ethylthiooxamate (234 mg, 1.8 mmol, 1.5 equivalents) was stirred at 80°C for 2 hours in EtOH (5 mL). The mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by reverse-phase flash chromatography (0.1% TFA conditions) to obtain the labeled compound (160 mg, yield 43%) 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-triazine-5(4H)-one [ka]

[0221] A mixture of 6-amino-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one (100 mg, 0.33 mmol, 1 equivalent), tert-butyl nitrite (69 mg, 0.67 mmol, 2 equivalents), and CuCl (66 mg, 0.67 mmol, 2 equivalents) in ACN (3 mL) was stirred at 70°C for 1 hour under an N2 atmosphere. The mixture was poured into ice water (w / w=1 / 1) (5 mL) and stirred for 5 minutes. The aqueous phase was converted to ethyl acetate (20 mL) * 3) Extracted. Combined organic phases were mixed with brine (10 mL). * The sample was washed (2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE / siRNA=1 / 1) to obtain the labeled compound (40 mg, yield 38%) as a yellow solid. LCMS: m / z 320.0 (M+H) + (ES + ).

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

[0223] A mixture of 6-chloro-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one (40 mg, 0.11 mmol, 1 equivalent) and tert-butyl 3-aminopiperidine-1-carboxylate (214 mg, 1.1 mmol, 10 equivalents) was mixed with DIEA (276 mg, 2.14 mmol, 20 equivalents) in DMSO (1 mL), and the reaction was stirred at 60°C for 16 hours. The mixture was then concentrated under vacuum. The crude product was purified by reverse-phase HPLC (0.1% TFA conditions) to obtain the marked compound (40 mg, yield 73%) as a white solid. LCMS: m / z 484.1 (M+H) + (ES + ).

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

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

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

[0227] A mixture of 3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-6-(3-piperidylamino)-1,2,4-triazine-5-one hydrochloride (30 mg, 0.07 mmol, 1 equivalent), acetaldehyde (0.05 mL, 0.36 mmol, 5 equivalents), and NaOAc (29 mg, 0.36 mmol, 5 equivalents) in 1,2-dichloroethane (1 mL) was stirred at 25°C for 1 hour, then NaBH3CN (23 mg, 0.36 mmol, 5 equivalents) was added and the mixture was stirred at 25°C for 1 hour.

[0228] The mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by reverse-phase flash (under 0.1% TFA conditions) to obtain the labeled 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-triazine-5(4H)-one [ka]

[0230] A mixture of boron tribromide (143 mg, 0.57 mmol, 10 equivalents) and 6-[(1-ethyl-3-piperidyl)amino]-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 2,2,2-trifluoroacetic acid (30.0 mg, 0.06 mmol, 1 equivalent) in DCM (3 mL) was stirred at -70°C for 2 hours. The pH was then adjusted to approximately pH 8 by adding NH3H2O, followed by filtration, and the filtrate was concentrated under vacuum. The crude product was separated by preparative HPLC (Waters Xbridge 150 column). * 25mm * The compound was purified with 5 μm of water (10 mM NH4HCO3)-ACN, B%: 32%-62%, 10 min, to obtain the labeled compound (10 mg, 0.03 mmol, yield 43%) 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-triazine-5-one [ka]

[0232] Process 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 equivalent) and potassium carbonate (4.84 g, 31.5 mmol, 0.50 equivalent) were suspended in dry DMF (125 mL), and 4-methoxybenzyl chloride (10.3 mL, 75.7 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with HCl (50 mL), washed with 10 wt% LiCl aqueous solution (2 × 30 mL), dried using a phase separator, and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel (330 g column, 0-50% HCl / isohexane) to obtain the labeled compound (15.9 g, yield 77%) 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] Process B: 6-[[(3R)-1-ethyl-3-piperidyl]amino]-2-[(4-methoxyphenyl)methyl]-4-methyl-1,2,4-triazine-3,5-dione

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

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

[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 equivalent) was dissolved in DCM (75 mL). Trifluoromethanesulfonic acid (3.33 mL, 37.7 mmol, 1.5 equivalents) was added to the reaction mixture. The resulting solution was stirred at room temperature for 24 hours. A further amount of trifluoromethanesulfonic acid (3.33 mL, 37.7 mmol, 1.5 equivalents) was added, and the reaction mixture was stirred for a further 3 hours. The reaction mixture was concentrated under vacuum, and the resulting residue was purified by chromatography on silica gel (220g column, 0-10% (MeOH / DCM with 0.7N ammonia)) to obtain the labeled compound (17.04g, yield 84%) as a yellow oily substance. LCMS m / z 254.5[M+H] + ,ESI pos.

[0238] Process D: 3-Chloro-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-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 equivalent) was dissolved in phosphorus oxychloride (75.0 mL, 804.6 mmol, 38.1 equivalents). The reaction mixture was stirred at 120°C for 72 hours.

[0240] A 15 mL aliquot of the reaction mixture was concentrated under vacuum, and the resulting residue was diluted with SiO2 (200 mL) and washed with a 1:1 brine:saturated NaHCO3 aqueous solution (200 mL). The organic phase was isolated, and the aqueous phase was back-extracted with SiO2 (200 mL). The combined organic extracts were dried (MgSO4) and concentrated under vacuum to obtain the labeled compound (1.03 g, yield 17%) as a brown oil. The remaining reaction mixture was subjected to the same workup conditions and scaled proportionally to obtain the labeled compound (5.06 g, yield 79%) as a brown oil. LCMS m / z 274.4 ([37Cl]M+H) +,ESI pos.

[0241] Process 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 equivalent) in methanol (40 mL), pyridinetribromide (4.70 g, 14.7 mmol, 1 equivalent) was added at -40°C. The resulting mixture was stirred at -40°C for 0.5 hours, then warmed to 20°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was dissolved in siRNA (100 mL). The organic layer was washed with 1N hydrochloric acid (100 mL x 2), followed by brine (100 mL), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:siRNA = 15:1~10:1) to obtain the marked compound (1.90 g, yield 60%) 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 equivalent) in ACN (20 mL), K2CO3 (1.29 g, 9.3 mmol, 2.0 equivalents) was added. The mixture was stirred at 20°C for 0.5 hours, and 2-(trimethylsilyl)ethoxymethyl chloride (0.99 mL, 5.58 mmol, 1.2 equivalents) was added dropwise to the mixture. The mixture was stirred at 20°C for 2 hours. TLC (PE:siRNA = 10:1) showed that the starting material had been consumed and another major spot had formed. The mixture was quenched with water (100 mL) and extracted with siRNA (100 mL x 3). The organic phase was washed with brine (150 mL), dried over anhydrous sodium phosphate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:dimethyl = 20:1-15:1) to obtain the labeled compound (1.30 g, 81% yield) as a yellow oily substance. 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]oxymethoxyethyl]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 equivalent) in isopropyl acetate (20 mL), bis(pinacolato)diborone (1.06 g, 4.17 mmol, 1.2 equivalents), anhydrous AcOK (0.75 g, 7.65 mmol, 2.2 equivalents), Xphos (166 mg, 0.350 mmol, 0.100 equivalents), and XPhos Pd G3 (295 mg, 0.350 mmol, 0.100 equivalents) were added. The mixture was degassed three times with N2 and stirred at 80°C under N2 for 12 hours. TLC (PE:siRNA=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 RINKAN (30 mL x 3). The organic phase was washed with brine (30 mL x 2), dried over anhydrous sodium phosphate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified first by column chromatography (SiO2, PE:RINKAN = 80:1-50:1), followed by reverse-phase flush (CombiFlash 0.1% NH3.H2O aqueous ACN), and lyophilized. The marked compound (288.3 mg, yield 20%) was obtained 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-triazine-5-one

[0248] 3-Chloro-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one (160 mg, 0.530 mmol, 1.0 equivalent) (Example 2, Step D), trimethyl-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl]oxymethoxyethyl]silane (208 mg, 0.530 mmol, 1.0 equivalent) (Example 2, Step C') and saturated Na2CO3 aqueous solution (0.75 mL) were suspended in 1,4-dioxane (4 mL), N2 was spurged into the reaction mixture, then the system was evacuated and refilled with N2 (3x). XPhos Pd G3 (45 mg, 0.050 mmol, 0.10 equivalents) was added, and the reaction mixture was placed under N2 and then stirred at 80°C for 24 hours. The reaction mixture was diluted with ELISA (50 mL) and washed with 1:1 water:brine (50 mL). The organic phase was filtered through Celite® and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel (24 g column, 0-10% (0.7 N NH3 in MeOH) / DCM) to obtain a SEM-protected product. This was dissolved in DCM (6 mL) and TFA (3 mL), stirred at room temperature for 3 hours, and then concentrated under vacuum. The resulting residue was dissolved in MeOH (4 mL) and ethylenediamine (1 mL) was added. The mixture was stirred for 2 hours and then concentrated under vacuum. The resulting residue was dissolved in 5 mL of DMSO, filtered, and then purified to Waters X-Select CSH C 18Purification was performed by reverse-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics 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, flow rate 40 mL-1, eluting with 0.1% formic acid in a water-MeCN gradient over 12.5 minutes using UV across all wavelengths with PDA, QDA, and ELS detectors. The at-column dilution pump provided methanol at a rate of 2 mL-1 throughout the process, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, gradient from 5% MeCN to 15% MeCN; 10.5-10.6 min, gradient from 15% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. This yielded the marked compound (47 mg, yield 23%) 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-triazine-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-triazine-6-yl)amino)piperidine-1-carboxylate

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

[0252] Process B: 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-3-piperidyl]amino]-1,2,4-triazine-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-triazine-6-yl)amino)piperidine-1-carboxylate (Example 3, Step A) (40.0 mg, 0.08 mmol, 1.0 equivalent) in DCM (1 mL), BBr3 (0.2 mL) was added at -40°C, and the reaction mixture was stirred under a nitrogen atmosphere at 20°C for 1 hour. 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 then subjected to reverse-phase column chromatography (C 18 The compound was purified using 0.1% TFA / MeCN in water. The eluent was freeze-dried to obtain the marked 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-triazine-5-one; 2,2,2-trifluoroacetic acid [ka]

[0255] Process 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 equivalents) in toluene (54 mL), TEA (7.12 g, 7.05 mmol, 2.0 equivalents) and DPPA (1.07 g, 3.88 mmol, 1.1 equivalents) were added. The resulting reaction mixture was stirred at 80°C for 4 hours, then 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 equivalent) was added, and the mixture was stirred at 70°C for 12 hours under a nitrogen atmosphere. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases 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 (silica gel, petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain the desired labeled compound (900 mg, 71% yield) as a yellow oily substance. LC-MS (Method 1): m / z 359.2 [MH] - ,ESI neg.

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

[0258] To a solution of the aforementioned 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 equivalent) in DCM (8 mL), TFA (16.0 mL, 208 mmol, 93.6 equivalents) was added. The resulting reaction mixture was stirred at 20°C for 1 hour, and then concentrated under reduced pressure to obtain the labeled product (800 mg, yield 96%) as yellow rubber. LC-MS (Method 1): m / z 261.1 [M+H] + ,ESI pos.

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

[0260] To a solution of the above-mentioned 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 equivalent) in MeOH (16 mL), TEA (0.6 mL, 4.27 mmol, 2.0 equivalent), acetic acid (513.3 mg, 8.55 mmol, 4.0 equivalent), 4 Å molecular sieve (400 mg), and formaldehyde (1734.50 mg, 37% w / w in water, 21.4 mmol, 10 equivalents) were added. The reaction mixture was stirred at 20°C for 0.5 hours, and then sodium cyanoborohydride (402.9 mg, 6.41 mmol, 3.0 equivalent) was added. The reaction mixture was stirred at 20°C for 1 hour, then quenched with water (0.2 mL), diluted with MeOH (5 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to reverse-phase column chromatography (C). 18 The compound was purified using 0.1% NH3·H2O / MeCN in water, and the eluent was then freeze-dried to obtain the marked compound (400 mg, 63% yield) as a yellow solid. LC-MS (Method 1): m / z 275.1 [M+H] + (ESI pos.)

[0261] Process D: (1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octane-2-amine

[0262] To a solution of the above-mentioned benzyl(8-methyl-8-azabicyclo[3.2.1]octan-2-yl) carbamate (Example 4, Step C) (200 mg, 0.73 mmol, 1.0 equivalent) in MeOH (2 mL), Pd / C (40.0 mg) was added. The reaction mixture was then degassed, purged three times with hydrogen, and stirred under a hydrogen atmosphere (760 mmHg) at 20°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the marked compound (100 mg, yield 98%) 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-triazine-5-one

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

[0265] Process 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-triazine-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-triazine-5(4H)-one (Example 4, Step E) (5.0 mg, 0.01 mmol, 1.0 equivalent) in DCM (1 mL), BBr3 (50.0 mg, 0.2 mmol, 16.94 equivalents) was gradually added at -40°C, and the mixture was then stirred at 20°C for 1 hour. 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 then subjected to reverse-phase column chromatography (C). 18 The compound was purified using 0.1% TFA / MeCN in water. The eluent was freeze-dried to obtain the marked compound (1.21 mg, yield 18%) as a yellow oil. LC-MS (Method 1): m / z 410.2 [M+H] + ,ESI pos.

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

[0268] Process A: tert-butyl(R)-(1-(cyclopropylmethyl)piperidine-3-yl)carbamate

[0269] A mixture of commercially available tert-butyl(R)-piperidine-3-ylcarbamate (CAS#309956-78-3, 1.0 g, 4.99 mmol, 1.0 equivalent) and (bromomethyl)cyclopropane (0.48 mL, 4.99 mmol, 1.0 equivalent) in MeCN (10 mL) was mixed with K2CO3 (7.58 g, 5.49 mmol, 1.1 equivalent) at 25°C, and the reaction mixture was stirred under N2 for 2 hours. 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 layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was analyzed by reverse-phase column chromatography (C 18 The compound was purified in water under 0.1% TFA / MeCN conditions. The eluent was freeze-dried to obtain the marked 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)piperidine-3-amine

[0271] To a mixture of the aforementioned tert-butyl N-[(3R)-1-(cyclopropylmethyl)-3-piperidyl]carbamate (Example 5, Step A) (150 mg, 0.59 mmol, 1.0 equivalent) in HCl (2 mL), another solution of HCl in HCl (2.0 mL, 8.0 mmol, 4 M, 13.6 equivalents) was added at 25°C, and the reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product, which was then dissolved in water (5 mL) and adjusted to approximately 8 pH with saturated Na2CO3 solution. The solution was freeze-dried, then polished with DCM (30 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain the marked compound (70.0 mg, yield 77%) as a yellow oily substance. 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] Process C:(R)-6-((1-(cyclopropylmethyl)piperidine-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one

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

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

[0275] To a mixture of the aforementioned (R)-6-((1-(cyclopropylmethyl)piperidine-3-yl)amino)-3-(2-methoxy-4(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 5, Step C) (30.0 mg, 0.07 mmol, 1.0 equivalent) in DCM (2 mL), boron tribromide (687.2 mg, 2.74 mmol, 40.0 equivalents) was gradually added, the reaction mixture was stirred at -60°C for 10 minutes, then at 25°C for 50 minutes, and LC-MS showed that the desired mass was detected. The mixture was then converted to NH3 . The pH was adjusted to approximately 7 with H2O, then filtered, and the filtrate was concentrated under vacuum. The crude product was subjected to reverse-phase column chromatography (C). 18 The compound was purified under 0.1% TFA / MeCN conditions in water, and the eluent was freeze-dried to obtain the marked compound (5.67 mg, yield 13%) 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-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-one; 2,2,2-trifluoroacetic acid [ka]

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

[0278] 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 1, Step E) (40.0 mg, 0.13 mmol, 1.0 equivalent) and ((R)-1-methylpiperidine-3-amine (71.4 mg, 0.63 mmol, 5 equivalents) were mixed in NMP (1 mL) to which DIEA (80.86 mg, 0.63 mmol, 5.0 equivalents) was added. The reaction mixture was stirred at 90°C for 2 hours. The mixture was concentrated under vacuum. The residue was subjected to reverse-phase column chromatography (C 18 The compound was purified under 0.1% TFA / MeCN conditions in water, and the fraction was then freeze-dried to obtain the marked compound (30.0 mg, 60% yield) as a white solid. LC-MS (Method 2): m / z 398.2 [M+H] + ,ESI pos.

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

[0280] The mixture of (R)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-one (Example 6, Step A) (30.0 mg, 0.08 mmol, 1.0 equivalent) and boron tribromide (189.12 mg, 0.75 mmol, 10.0 equivalent) in DCM (1 mL) was stirred at -60°C for 10 minutes, and then stirred at 25°C for 50 minutes. The mixture was adjusted to pH approximately 7 with NH3·H2O, then filtered, and the filtrate was concentrated under vacuum. The crude product was subjected to reverse-phase column chromatography (C 18 The product was purified under 0.1% TFA / MeCN conditions in water, and the eluent was then freeze-dried to obtain the marked product (5.48 mg, yield 14%) 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-Octahydroindolidine-8-ylamino)-3-[2-Hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 2,2,2-trifluoroacetic acid [ka]

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

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

[0284] Step B: Octahydroindolidine-8-amine

[0285] To a solution of the above-mentioned 6,7-dihydroindridine-8(5H)-oneoxime (Example 7, Step A) (300 mg, 2.0 mmol, 1.0 equivalent) in MeOH (10 mL), Pd / C (100.0 mg) and concentrated HCl (1.97 g, 2.0 mmol, 1.0 equivalent) were added. The reaction mixture was degassed, purged three times with hydrogen, and then stirred at 20°C for 12 hours under a hydrogen atmosphere (760 mmHg). The above reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with MeOH (20 mL), the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and then the solution was freeze-dried to obtain a yellow solid, which was polished with a mixture of DCM (20 mL) and MeOH (2 mL), and finally filtered. The filtrate was concentrated under reduced pressure to obtain the marked compound (200 mg, yield 71%) 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-((octahydroindolidine-8-yl)amino)-1,2,4-triazine-5(4H)-one

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

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

[0289] To a solution of 3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((octahydroindolidine-8-yl)amino)-1,2,4-triazine-5(4H)-one (Example 7, Step C) (30.0 mg, 0.07 mmol, 1.0 equivalent) in DCM (1 mL), BBr3 (88.7 mg, 0.35 mmol, 5.0 equivalent) was added dropwise at -40°C, and the mixture was then stirred at 20°C for 1 hour. 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 subjected to reverse-phase column chromatography (C). 18 The compound was purified using 0.1% TFA / MeCN in water. The eluent was then freeze-dried to obtain the marked compound (8.74 mg, 22% yield) as a yellow oily substance. 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-triazine-5-one; 2,2,2-trifluoroacetic acid [ka]

[0291] To a 1 mL solution of (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-(piperidine-3-ylamino)-1,2,4-triazine-5(4H)-one (Example 3, Step B) (15.0 mg, 0.03 mmol, 1.0 equivalent) in ethanol, 8.01 mg, 0.06 mmol, 2.0 equivalents of DIEA were added, followed by the dropwise addition of 1-bromopropane (38.2 mg, 0.31 mmol, 10.0 equivalents) at 0°C. The mixture was stirred at 50°C for 4 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to obtain a yellow oily substance, which was then subjected to preparative HPLC (column: Phenomenex Synergi Polar-RP 100). * 25mm * The compound was purified using a 4 μm solution (TFA-MeCN) under the following conditions: the eluent was freeze-dried to obtain the marked compound (3.96 mg, 23% yield) as a yellow oily substance. 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-triazine-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-triazine-6-yl)amino)-3,3-dimethylpiperidine-1-carboxylate

[0294] To a solution of the aforementioned 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 1, Step E) (100 mg, 0.31 mmol, 1.0 equivalent) and commercially available tert-butyl 5-amino-3,3-dimethylpiperidine-1-carboxylate (CAS#1896921-12-2, 100 mg, 0.44 mmol, 1.4 equivalent) in 1,4-dioxane (2 mL), Cs2CO3 (255 mg, 0.78 mmol, 2.5 equivalents) and BinapPdG3 (62.1 mg, 0.06 mmol, 0.2 equivalents) were added. The mixture was stirred under N2 at 80°C for 2 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were 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 = 1:0-2:1) to obtain the marked 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-dimethylpiperidine-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-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-triazine-6-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (Example 9, Step A) (60.0 mg, 0.12 mmol, 1.0 equivalent) in DCM (1 mL), TFA (6.0 mL, 77.9 mmol, 664 equivalents) was added, and the reaction mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the marked compound (60 mg, 97% yield) as a yellow oily substance. 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-trimethylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-one

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

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

[0300] To a solution of the aforementioned 3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1,5,5-trimethylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-one (Example 9, Step C) (20.0 mg, 0.05 mmol, 1.0 equivalent) in DCM (1 mL), BBr3 (0.5 mL) was added at -40°C, and the mixture was then stirred at 20°C for 1 hour under N2. 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 reverse-phase column chromatography (C) was performed. 18 The compound was purified using 0.1% TFA / MeCN in water. The eluent was freeze-dried to obtain the marked 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-cyclopropylpiperidine-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one [ka]

[0302] Step A: tert-butyl(R)-(1-cyclopropylpiperidine-3-yl)carbamate

[0303] A solution of commercially available tert-butyl(R)-piperidine-3-ylcarbamate (CAS#184637-48-7, 1.0 g, 4.99 mmol, 1.0 equivalent) in MeOH (40 mL) and acetic acid (5 mL) was mixed with NaBH3CN (1.57 g, 24.9 mmol, 5.0 equivalents) and (1-ethoxycyclopropoxy)trimethylsilane (1.74 g, 9.99 mmol, 2.0 equivalents) at 0°C. The mixture was then stirred at 65°C for 12 hours. The reaction product was cooled to 20°C, diluted with water (200 mL), and extracted with DCM (40 mL x 3). The organic layer was washed with saturated Na2CO3 aqueous solution (60 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:Â10:1~2:1) to obtain the labeled 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-cyclopropylpiperidine-3-amine; 2,2,2-trifluoroacetic acid

[0305] To a solution of the above-mentioned tert-butyl(R)-(1-cyclopropylpiperidine-3-yl)carbamate (Example 10, Step A) (600 mg, 2.5 mmol, 1.0 equivalent) in DCM (5 mL), 2,2,2-trifluoroacetic acid (2.0 mL) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the marked 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-cyclopropylpiperidine-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one

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

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

[0309] To a solution of (R)-6-((1-cyclopropylpiperidine-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 10, Step C) (90.0 mg, 0.17 mmol, 1.0 equivalent) in DCM (2 mL), BBr3 (210 mg, 0.84 mmol, 5.0 equivalents) was added at -60°C. The mixture was heated to 20°C and stirred for 1 hour. The reaction product was quenched with water (1 mL), adjusted to approximately pH 8 with NH3·H2O, and concentrated under reduced pressure. The residue was separated by preparative HPLC (column: waters Xbridge 150). * 25mm *5 μm; Condition: Purified with water (NH4HCO3) / MeCN). The eluent was freeze-dried to obtain the marked compound (15.7 mg, yield 22%) 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-triazine-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-triazine-5(4H)-one

[0312] 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 1, Step E) (200.0 mg, 0.45 mmol, 1.0 equivalent) and commercially available (1S,3S)-3-amino-1-methylcyclobutan-1-ol hydrochloride (CAS No. 1523606-23-6, 125 mg, 0.90 mmol, 2 equivalents) were mixed in NMP (3 mL) to which DIEA (175.3 mg, 1.36 mmol, 3.0 equivalents) was added. The mixture was stirred at 95°C for 2 hours. LC-MS showed that the desired mass was detected. The mixture was concentrated under vacuum. The residue was subjected to reverse-phase column chromatography (C 18 The compound was purified under conditions of 0.1% NH3·H2O / MeCN in water, and the eluent was freeze-dried to obtain the marked compound (70.0 mg, yield 37%) 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-triazine-5(4H)-one

[0314] To a mixture of the above-mentioned 6-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 11, Step A) (70.0 mg, 0.18 mmol, 1.0 equivalent) in DCM (2 mL), boron tribromide (456.3 mg, 1.82 mmol, 10.0 equivalent) was added. The reaction mixture was stirred at -60°C for 10 minutes, then stirred at 25°C for 50 minutes. LC-MS showed that the desired mass was detected. The mixture was adjusted to pH approximately 7 with NH3·H2O, then filtered, and the filtrate was concentrated under vacuum. The crude product was subjected to reverse-phase column chromatography (C 18 The compound was purified in water under 0.1% NH3·H2O / MeCN conditions, and the eluent was freeze-dried to obtain the marked compound (3.94 mg, yield 6%) 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-triazine-5-one; 2,2,2-trifluoroacetic acid [ka]

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

[0317] 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 1, Step E) (100.0 mg, 0.23 mmol, 1.0 equivalent) and 1-tert-butylpiperidine-3-amine hydrochloride (131 mg, 0.68 mmol, 3.0 equivalents) were mixed in NMP (1 mL) and DIEA (87.7 mg, 0.68 mmol, 3.0 equivalents) were added. The reaction mixture was stirred under N2 at 95°C for 2 hours. LC-MS showed that the desired mass was detected. The mixture was concentrated under vacuum to obtain the crude product, which was then subjected to reverse-phase column chromatography (C 18 The compound was purified under 0.1 TFA / MeCN conditions in water, and the eluent was freeze-dried to obtain the marked compound (45.0 mg, yield 44%) as a white solid. LC-MS (Method 2): m / z 440.1 [M+H] + ,ESI pos.

[0318] Process B: 6-[(1-tert-butyl-3-piperidyl)amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-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-triazine-5-one (45.0 mg, 0.1 mmol, 1.0 equivalent) in DCM (2 mL), boron tribromide (128 mg, 0.51 mmol, 5.0 equivalent) was added. The reaction mixture was stirred at -60°C for 10 minutes, then stirred under N2 at 25°C for 50 minutes. LC-MS showed that the desired mass was detected. The mixture was adjusted to pH approximately 7 with NH3·H2O, then filtered, and the filtrate was concentrated under vacuum. The residue was analyzed by reverse-phase column chromatography (C 18 The compound was purified under 1% TFA / MeCN conditions in water, and the eluent was freeze-dried to obtain the marked 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-triazine-5-one; 2,2,2-trifluoroacetic acid [ka]

[0321] Step A: tert-butyl6-((3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazine-6-yl)amino)-2-azabicyclo[2.2.1]heptane-2-carboxylate

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

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

[0324] To a mixture of the above-mentioned tert-butyl 6-[[3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-5-oxo-1,2,4-triazine-6-yl]amino]-2-azabicyclo[2.2.1]heptan-2-carboxylate (Example 13, Step A) (30.0 mg, 0.06 mmol, 1.0 equivalent) in DCM (1 mL), BBr3 (1.51 mg, 0.61 mmol, 10.0 equivalent) was added under N2 at -60°C, and the mixture was stirred at -60°C for 10 minutes, then stirred at 25°C for 1 hour. The reaction mixture was quenched by adding ice water (2 mL) and the pH was adjusted to approximately 7 with NH3·H2O solution. The mixture was then subjected to reverse-phase column chromatography (C 18 Purification by 0.1% TFA / MeCN in water yielded the marked 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-triazine-5-one; 2,2,2-trifluoroacetic acid [ka]

[0326] Process A: tert-butyl((3R,5S)-1-ethyl-5-methylpiperidine-3-yl)carbamate

[0327] A solution of commercially available tert-butyl((3R,5S)-5-methylpiperidine-3-yl)carbamate (CAS#1187055-56-6, 250 mg, 1.17 mmol, 1.0 equivalent) in MeCN (2.5 mL) was mixed with K2CO3 (323 mg, 2.33 mmol, 2.0 equivalents) and ethyl bromide (0.1 mL, 1.28 mmol, 1.1 equivalents). The reaction mixture was stirred under N2 at 25°C for 12 hours. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel (DCM:MeOH=10:1, R). f The compound was purified using a method (=0.2) to obtain the marked compound (85.0 mg, yield 31%) 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] Process B: (3R,5S)-1-ethyl-5-methylpiperidine-3-amine; 2,2,2-trifluoroacetic acid

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

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

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

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

[0333] 6-[[(3R,5S)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one;2,2,2-trifluoroacetic acid (Example 14, Step C) (20.0 mg, 0.04 mmol, 1.0 equivalent) was mixed in DCM (1 mL), to which BBr3 (92.9 mg, 0.37 mmol, 10.0 equivalent) was added dropwise at -60°C. The mixture was stirred at -60°C for 10 minutes, and then stirred under N2 at 25°C for 1 hour. The reaction mixture was quenched by adding ice water (2 mL) and the pH was adjusted to approximately 7 with NH3·H2O solution. The mixture was analyzed by reverse-phase column chromatography (C). 18 The solution was purified by 0.1% TFA / MeCN in water, and then subjected to preparative HPLC (column: 3_Phenomenex Luna C). 18 75 * 30mm * Upon purification using 3 μm, conditional water (TFA)-MeCN, the labeled compound (1.83 mg, 7% yield) was obtained 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-triazine-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-triazine-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 equivalent) in NMP (0.4 mL), the aforementioned 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 1, Step E) (150.0 mg, 0.47 mmol, 2.0 equivalents) was added in a microwave tube, and the mixture was then stirred under microwave conditions at 130°C for 2 hours. After cooling to room temperature, the reaction mixture was quenched by adding water (5 mL). The residue was analyzed by reverse-phase column chromatography (C 18 Purification by 0.1% TFA / MeCN in water yielded the marked compound (30.0 mg, 13% yield) as a yellow solid. LC-MS (Method 2): m / z 498.2 [M+H] + ,ESI pos.

[0337] Process B: 3-[2-Methoxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R,5R)-5-methyl-3-piperidyl]amino]-1,2,4-triazine-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-triazine-6-yl]amino]-5-methyl-piperidine-1-carboxylate (30.0 mg, 0.06 mmol, 1.0 equivalent) in DCM (1 mL), TFA (20.6 mg, 0.18 mmol, 3.0 equivalents) was added at 0°C, and the mixture was then stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the marked compound (50.0 mg, >99% yield) as a yellow oil. LC-MS (Method 2): m / z 398.1 [M+H] + ,ESI pos.

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

[0340] A mixture of 3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R,5R)-5-methyl-3-piperidyl]amino]-1,2,4-triazine-5-one and 2,2,2-trifluoroacetic acid (50.0 mg, 0.1 mmol, 1.0 equivalent) in DMF (0.5 mL) was mixed with DIEA (25.2 mg, 0.2 mmol, 2.0 equivalents) and iodoethane (0.01 mL, 0.11 mmol, 1.1 equivalents). The mixture was then stirred at 25°C for 2 hours. The reaction mixture was quenched by adding water (10 mL), then extracted with RINKAN (50 mL x 3), washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was analyzed by reverse-phase column chromatography (C 18 Upon purification by 0.1% TFA / MeCN in water, the marked compound (10.0 mg, yield 19%) was obtained as a yellow solid. LC-MS (Method 2): m / z 426.2 [M+H] + ,ESI pos.

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

[0342] A mixture of 6-[[(3R,5R)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one and 2,2,2-trifluoroacetic acid (10.0 mg, 0.02 mmol, 1.0 equivalent) in DCM (0.5 mL) was mixed with BBr3 (46.4 mg, 0.19 mmol, 10.0 equivalent) under N2 at -60°C. The mixture was stirred at -60°C for 10 minutes, then the mixture was warmed to 25°C and stirred for 1 hour. The reaction mixture was quenched with 2 mL of ice water and the pH was adjusted to approximately 7 with NH3·H2O solution. The mixture was then subjected to reverse-phase column chromatography (C 18 Upon purification by 0.1% TFA water / MeCN conditions, the marked compound (1.76 mg, yield 12%) was obtained 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-triazine-5-one; 2,2,2-trifluoroacetic acid [ka]

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

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

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

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

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

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

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

[0351] 6-(((3R,5S)-5-fluoro-1-methylpiperidine-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 16, Step C) (50.0 mg, 0.12 mmol, 1.0 equivalent) and K2CO3 (166.1 mg, 1.2 mmol, 10.0 equivalents) were mixed in NMP (2 mL), to which benzenethiol (186 μL, 1.82 mmol, 15.1 equivalents) was added under N2 conditions. The mixture was then stirred under microwave conditions at 190 °C for 15 minutes. The reaction mixture was cooled to 20 °C and reversed-phase column chromatography (C) was performed. 18 The eluent was purified by 0.1% TFA / MeCN in water. The eluent was freeze-dried to obtain the crude product, which was then subjected to preparative HPLC (column: Phenomenex Synergi Polar-RP 100). * 25 mm * The 4 μm sample was purified using conditional water (0.1% TFA)-MeCN). The eluent was freeze-dried to obtain the marked compound (1.7 mg, yield 3%) as a white solid. Note: Racemization is thought to have occurred during deprotection at high 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-triazine-5-one; 2,2,2-trifluoroacetic acid [ka]

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

[0354] A mixture of commercially available tert-butyl(R)-(6-oxopiperidine-3-yl)carbamate (CAS#1228566-94-6, 450.0 mg, 2.1 mmol, 1.0 equivalent) in 2-methyltetrahydrofuran (20 mL) was mixed with ZrCl4 (2.94 g, 12.6 mmol, 6.0 equivalents) at -10°C and stirred at this temperature for 0.5 hours. Then, methylmagnesium bromide (14.0 mL, 42.0 mmol, 20.0 equivalents) was added, and the mixture was stirred at 20°C for 12 hours. The 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 chromatography (petroleum ether:ethyl acetate = 5:1 to 0:1) to obtain the marked compound (130 mg, yield 27%) as a yellow oily substance. 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] Process B: (R)-6,6-dimethylpiperidine-3-amine; 2,2,2-trifluoroacetic acid

[0356] To a solution of tert-butyl(R)-(6,6-dimethylpiperidine-3-yl)carbamate (130.0 mg, 0.57 mmol, 1.0 equivalent) in DCM (1 mL), TFA (1.0 mL) was added dropwise, and the mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a yellow solid, which was polished with ethyl acetate (2 mL), filtered, and the cake was recovered. When dried under reduced pressure, the marked compound (100 mg, yield 73%) was obtained 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] Process C: (R)-6-((6,6-dimethylpiperidine-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one

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

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

[0360] (R)-6-((6,6-dimethylpiperidine-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 17, Step C) (10.0 mg, 0.02 mmol, 1.0 e.) was dissolved in DCM (1 mL), to which BBr3 (0.1 mL) was added dropwise at -40°C, and the reaction mixture was stirred at 20°C for 1 hour. 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 approximately 7 with ammonium hydroxide, and then reversed-phase column chromatography (C) was performed. 18 The eluent was purified by 0.1% TFA-ACN in water. The eluent was freeze-dried to obtain a yellow solid, which was then separated by preparative HPLC (column 3_Phenomenex Luna C). 18 75 * 30mm * The compound was further purified using a 3 μm solution (condition: water (TFA)-CH3CN), and the eluent was then freeze-dried to obtain the marked compound (1.21 mg, yield 18%) 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-triazine-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-triazine-5(4H)-one

[0363] To a mixture of the above-mentioned 6-chloro-3-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one (Example 1, Step E) (30.0 mg, 0.09 mmol, 1.0 equivalent) and commercially available 3-(aminomethyl)phenol (CAS#73604-31-6, 57.9 mg, 0.47 mmol, 5.0 equivalents) in NMP (1 mL), DIEA (6.64 mg, 0.47 mmol, 5.0 equivalents) was added, and the reaction mixture was stirred under N2 at 95°C for 2 hours. LC-MS showed that the desired mass was detected. The mixture was concentrated under reduced pressure to obtain the crude product, which was then subjected to reverse-phase column chromatography (C 18 The compound was purified in water under 0.1% TFA / MeCN conditions, and the eluent was then freeze-dried to obtain the marked compound (20.0 mg, yield 52%) as a yellow solid. LC-MS (Method 2): m / z 406.9 [M+H] + ,ESI pos.

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

[0365] The mixture of 6-((3-hydroxybenzyl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 18, Step A) (20.0 mg, 0.05 mmol, 1.0 equivalent) and boron tribromide (493.2 mg, 1.97 mmol, 40.0 equivalents) in DCM (1 mL) was stirred at -60°C for 10 minutes, and then stirred at 25°C for 50 minutes. LC-MS showed that the desired mass was detected. The mixture was adjusted to pH approximately 7 by adding NH3·H2O, then filtered, and the filtrate was concentrated under vacuum to obtain the crude product, which was then subjected to reverse-phase column chromatography (C 18 The compound was purified in water under 0.1% TFA / MeCN conditions, and the eluent was then freeze-dried to obtain the marked compound (2.95 mg, yield 12%) 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-triazine-5-one; 2,2,2-trifluoroacetic acid [ka]

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

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

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

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

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

[0372] 3-Chloro-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one (Example 2, Step D) (750.0 mg, 2.76 mmol, 1.0 equivalent), saturated sodium carbonate aqueous solution (2.50 mL, 0.59 mmol, 0.21 equivalents), and 2-methoxy-4-(trifluoromethyl)-phenylboronic acid (CAS#312936-89-3, 667.7 mg, 3.04 mmol, 1.1 equivalents) were suspended in 1,4-dioxane (16 mL), the reaction mixture was spurged with N2, then evacuated and packed with N2 (3x). Xphos Pd G3 (233.89 mg, 0.28 mmol, 0.1 equivalents) was added, 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 (24g column, 0-10% (0.7N NH3 in MeOH) / DCM) to obtain an intermediate product. This intermediate product was then dissolved in DCM (30mL), and BBr3 (1M in DCM) (13.8mL, 13.8 mmol, 5.0 equivalents) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under vacuum. The resulting residue was dissolved in MeOH (40mL) and solid NaHCO3 (5g) was added. The mixture was stirred at room temperature for 30 minutes, then filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by chromatography on silica gel (24g column, 0-10% (0.7N NH3 in MeOH) / DCM), and then Waters XBridge BEH C 18Purification was performed by reverse-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, flow rate 40 mL / min⁻¹, eluting over 12.5°C with 0.3% ammonia in a water-MeCN gradient. The at-column dilution pump provided 2 mL / min⁻¹ of MeCN throughout the method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, gradient from 5% MeCN to 30% MeCN; 10.5-10.6 min, gradient from 30% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. Evaporation of the clean fraction using Genevac yielded the marked compound (196.0 mg, yield 18%) 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-triazine-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 equivalent) in THF (50 mL), n-BuLi (11.8 mL, 29.4 mmol, 1.5 equivalents) was added dropwise at -60°C under a nitrogen atmosphere, and the mixture was stirred at this temperature for 0.5 hours. Then, a solution of isothiocyanatocyclopropane (2.53 g, 25.5 mmol, 1.3 equivalents) in THF (3 mL) was added, and the reaction mixture was stirred at -60°C for 10 minutes. Then, the mixture was heated to 25°C and stirred for a further 50 minutes under a nitrogen atmosphere. The reaction mixture was quenched with saturated NH4Cl (30 mL) aqueous solution, extracted with  (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 obtain the marked compound (1.60 g, 30% yield) as a yellow oily substance. 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 equivalent) in DMF (10 mL), DIEA (0.82 g, 6.33 mmol, 1.1 equivalent) was added at 20°C, and the mixture was stirred for 10 minutes, followed by the addition of MeI (1.0 g, 7.08 mmol, 1.22 equivalents). The mixture was stirred at 20°C for 3 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 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 obtain the marked compound (1.30 g, yield 76%) as a yellow oil. LC-MS (method 1): m / z 290.0[M+H] + ,ESI pos.

[0378] Process C: N"-Cyclopropyl-2-methoxy-4-(trifluoromethyl)benzimidohydrazide

[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 equivalent) in ethanol (15 mL), hydrazine hydrate (2.28 g, 45.5 mmol, 10.1 equivalents) was added. The mixture was stirred at 70°C for 24 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and then analyzed by reverse-phase column chromatography (C). 18 The compound was purified under 0.1% TFA / MeCN conditions in water. The eluent was freeze-dried to obtain the marked compound (900.0 mg, 50% yield) as a yellow solid. LC-MS (Method 1): m / z 274.1 [M+H] + ,ESI pos.

[0380] Process D: 6-amino-4-cyclopropyl-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine-5(4H)-one

[0381] A mixture of N”-cyclopropyl-2-methoxy-4-(trifluoromethyl)benzimidehydrazide (Example 20, Step C) (390.0 mg, 1.43 mmol, 1.0 equivalent), TEA (288.9 mg, 2.85 mmol, 2.0 equivalent), and ethyl 2-amino-2-thioxoacetate (285.1 mg, 2.14 mmol, 1.5 equivalent) in ethanol (8 mL) was stirred at 85°C for 4 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then analyzed by reverse-phase column chromatography (C). 18 The compound was purified using 0.1% TFA / MeCN in water. The eluent was freeze-dried to obtain the marked 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-triazine-5(4H)-one

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

[0384] Process F:(R)-4-cyclopropyl-6-((1-ethylpiperidine-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine-5(4H)-one

[0385] 6-Chloro-4-cyclopropyl-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine-5(4H)-one (Example 20, Step E) (70.0 mg, 0.2 mmol, 1.0 equivalent) and (R)-1-ethylpiperidine-3-amine (77.9 mg, 0.61 mmol, 3.0 equivalents) were mixed in NMP (1 mL), to which DIEA (78.5 mg, 0.61 mmol, 3.0 equivalents) was added, and the mixture was stirred at 95°C for 2 hours under a nitrogen atmosphere. The mixture was concentrated under vacuum and then analyzed by reverse-phase column chromatography (C 18The compound was purified using 0.1% TFA / MeCN in water, and the eluent was freeze-dried to obtain the marked compound (40.0 mg, yield 45%) as a yellow solid. LC-MS (Method 1): m / z 437.9 [M+H] + ,ESI pos.

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

[0387] (R)-4-cyclopropyl-6-((1-ethylpiperidine-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine-5(4H)-one (Example 20, Step F) (40.0 mg, 0.09 mmol, 1.0 equivalent) was dissolved in DCM (4 mL), to which BBr3 (229 mg, 0.91 mmol, 10.0 equivalent) was added at -40°C, and the mixture was then stirred at 20°C for 1 hour. The reaction mixture was quenched with water (0.5 mL), then the pH was adjusted to 8 with ammonium hydroxide, and then concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and then subjected to preparative HPLC (column: 3_Phenomenex Luna C 18 75 * 30 mm * 3 μm; Purified using water (TFA)-MeCN). Finally, the eluent was freeze-dried to obtain the marked 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-hydroxyphenyl)-4-methyl-1,2,4-triazine-5-one [ka]

[0389] 3-Chloro-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one (Example 2, Step D) (100 mg, 0.330 mmol, 1.0 eq) was suspended in a saturated Na2CO3 aqueous solution (0.5 mL) and commercially available (4-fluoro-2-hydroxy)phenylboronic acid (CAS#850568-00-2, 56.8 mg, 0.36 mmol, 1.1 equivalents) in 1,4-dioxane (3.5 mL). The reaction mixture was spurged with N2, then evacuated and back-packed with N2 (3x). Xphos Pd G3 (28.1 mg, 0.03 mmol, 0.1 equivalents) was added, and the reaction mixture was placed under N2 and stirred at 80°C for 18 hours. The reaction mixture was concentrated under vacuum. The resulting residue was dissolved in 2 mL of DMSO, filtered, and then subjected to Waters XBridge BEH C 18 Purification was performed by reverse-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics 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, flow rate 40 mL-1, eluting with 0.1% ammonia in a water-MeCN gradient over 17.5 minutes using UV across all wavelengths with PDA, QDA, and ELS detectors. The at-column dilution pump provided 2 mL-1 of MeCN throughout the process, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-15.5 min, gradient from 5% MeCN to 35% MeCN; 15.5-15.6 min, gradient from 35% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. This yielded the marked compound (12.02 mg, yield 10%) 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-triazine-5-one [ka]

[0391] Process 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 equivalents) 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 equivalent) in DMF (30 mL) was added dropwise. The reaction mixture was stirred at room temperature for 45 minutes, then iodoethane (1.57 mL, 19.7 mmol, 1.1 equivalents) was added dropwise, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with siRNA (200 mL), washed with 10 wt% LiCl aqueous solution (2 × 100 mL), dried using a phase separator, and concentrated under vacuum. The resulting residue was purified by silica gel flash chromatography (120 g column, 0-5% DCM / MeOH) to obtain a yellow oily substance. The yellow oily substance was dissolved in EtOH (30 mL), and p-toluenesulfonic acid monohydrate (169.9 mg, 0.89 mmol, 0.05 equivalents) was added. The reaction mixture was stirred under reflux for 16 hours, then concentrated under vacuum, and the resulting residue was partitioned into water (200 mL) and ethyl acetate (200 mL). The organic phase was isolated, and aqueous solution (aq.) was extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried using a phase separator and concentrated under vacuum to obtain the marked 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 equivalent) and dipotassium carbonate (8.95 g, 6.48 mmol, 0.5 equivalent) were suspended in dry DMF (30 mL), and 4-methoxybenzyl chloride (2.11 mL, 15.5 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with siRNA (50 mL), washed with 10 wt% LiCl aqueous solution (2 × 30 mL), dried using a phase separator, and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel (24 g column, 0-50% siRNA / isohexane) to obtain the labeled compound (3.91 g, yield 80%) 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] Process 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 equivalents), 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 equivalent), and (3R)-1-ethylpiperidine-3-amine (6.36 mg, 4.96 mmol, 1.5 equivalents) were dissolved in DMSO (16 mL), and the mixture was degassed for 5 minutes (N2). The reaction vessel was evacuated, refilled with N2 (3x), and then Pd-176 (CAS#879689-47-1, 133 mg, 0.17 mmol, 0.05 equivalents) was added. The reaction mixture was placed under N2 and then stirred at 95°C for 24 hours. The reaction mixture was partitioned into ELISA (50 mL) and water (50 mL). The organic phase was isolated, washed with brine (2 x 30 mL), dried using a phase separator, and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel (24 g column, 0-10% DCM (0.7 N ammonia in MeOH)) to obtain the marked compound (996 mg, 71% yield) as a light brown oily substance. LC-MS m / z 388.4 (M+H) + ,ESI pos.

[0397] Process 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 equivalent) was dissolved in DCM (9 mL), and trifluoromethanesulfonic acid (0.31 mL, 3.51 mmol, 1.5 equivalents) was added to the reaction mixture. The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was concentrated under vacuum, and the resulting residue was purified by chromatography on silica gel (24 g column, 0-10% (MeOH / 0.7 N ammonia in DCM)) to obtain the marked compound (950 mg, yield 88%) 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-triazine-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 equivalent) was dissolved in phosphorus oxychloride (6.29 mL, 67.5 mmol, 29.6 equivalents). The reaction mixture was stirred at 90°C for 16 hours and then concentrated under vacuum. The resulting residue was cooled in an ice bath, slowly quenched with 0.7N NH3 in MeOH, and then loaded onto silica in a dry state. Purification by chromatography on silica gel (40 g column, 0-10% (0.7N ammonia in MeOH) / DCM) yielded the marked compound (768 mg, yield 89%) as yellow rubber. LC-MS m / z 285.9 ([37Cl]M+H) + ,ESI pos.

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

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

[0403] Process A: 3-[4-(difluoromethoxy)-2-methoxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one

[0404] 3-chloro-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one (Example 2, Step D) (260.0 mg, 0.91 mmol, 1.0 equivalent) and 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 equivalents) were sparged in saturated Na2CO3 aqueous solution (0.5 mL, 0.91 mmol, 1.0 equivalent) and 1,4-dioxane (5 mL) (bubbled with N2 for 10 minutes and sonicated). XPhos Pd G3 (52.0 mg, 0.06 mmol, 0.07 equivalents) was added, and the reaction mixture was heated at 90°C for 18 hours. The crude mixture was passed through a celite® plug, rinsed with RINKAN (50 mL), and the reaction mixture was concentrated under vacuum. The reaction product was subjected to column chromatography (silica, 24 g, 10-20% MeOH (containing 0.7 M NH3)), followed by reverse-phase column chromatography (C 18 When purified with 26 g of acetonitrile in water (10 mM ammonium bicarbonate), the marked compound (99.0 mg, yield 26%) was obtained as a light brown solid. LC-MS m / z 410.4[M+H] + ,ESI pos.

[0405] Process B: 3-[4-(difluoromethoxy)-2-hydroxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; formic acid

[0406] A suspension of 3-[4-(difluoromethoxy)-2-methoxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one (50.0 mg, 0.12 mmol, 1.0 equivalent) and potassium carbonate (50.0 mg, 0.36 mmol, 2.96 equivalents) in NMP (1 mL) was sonicated for 2 minutes, then benzenethiol (0.02 mL, 0.2 mmol, 1.61 equivalents) was added, and the resulting mixture was irradiated at 150°C for 30 minutes. The reaction mixture was cooled to room temperature, diluted with NMP (2.4 mL), filtered, and filtered to Waters X-Select CSH C 18 Purification was performed by reverse-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, flow rate 40 mL-1, eluting with 0.1% formic acid in a water-MeCN gradient over 12.5 minutes using UV across all wavelengths with PDA, QDA, and ELS detectors. The at-column dilution pump provided 2 mL-1 of MeOH throughout the process, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, gradient from 5% MeCN to 25% MeCN; 10.5-10.6 min, gradient from 25% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. Evaporation of the clean fraction using Genevac yielded the marked 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-hydroxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one [ka]

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

[0409] Diethylamino sulfur trifluoride (6.0 mL, 45.4 mmol, 10.4 equivalents) was added dropwise to a Teflon® flask at 0°C in a solution of 1-(4-bromo-3-methoxyphenyl)ethenone (CAS No. 50870-44-5, 1.0 g, 4.37 mmol, 1.0 equivalent) in DCM (8 mL). The reaction mixture was heated and stirred for 16 hours. The reaction mixture was cooled to 0°C, diethylamino sulfur trifluoride (3.0 mL, 22.7 mmol, 5.2 equivalents) was added, and the reaction mixture was stirred for 4 days. The reaction mixture was cooled to 0°C, diethylamino sulfur trifluoride (3.0 mL, 22.7 mmol, 5.2 equivalents) was added, and the reaction mixture was stirred 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 × 50 mL), the combined organic layers were dried, (Na₂SO₄) and concentrated under reduced pressure. The crude reaction mixture was subjected to column chromatography (silica, 40 g, 0-30% alkyl:isohexane), followed by reverse-phase column chromatography (C₂). 18 When purified with 40g of acetonitrile (0.1% formic acid) and water (0.1% formic acid), the marked compound (363.0mg, yield 33%) was obtained as a pale yellow oily substance. 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-methoxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one

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

[0412] Process C: 3-[4-(1,1-difluoroethyl)-2-hydroxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one

[0413] Benzenthiol (3.0 μL, 0.03 mmol, 1.0 equivalent) and potassium carbonate (8.0 mg, 0.06 mmol, 1.97 equivalents) 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-triazine-5-one (12.0 mg, 0.03 mmol, 1.0 equivalent) (Example 5, Step A) in NMP (1 mL). The reaction mixture was irradiated at 150°C for 15 minutes and then concentrated in vacuum. The obtained residue was dissolved in DMSO (1.3 mL), filtered, and purified by reverse-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 a Waters XBridge BEH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL-1, with UV across all wavelengths using PDA, QDA, and ELS detectors, eluting with 0.3% ammonia in a water-MeCN gradient over 12.5 minutes. The at-column dilution pump provided 2 mL-1 of MeOH throughout the process, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, gradient from 5% MeCN to 35% MeCN; 10.5-10.6 min, gradient from 35% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. Evaporation of the clean fraction using Genevac yielded the marked compound (4.0 mg, yield 33%) as a white solid. LC-MS m / z 394.0[M+H] + ,ESI pos.

[0414] Example 25: 3-(4-acetyl-2-hydroxyphenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-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-triazine-5-one (588.0 mg, 0.58 mmol, 1.0 equivalent) (Example 24, Step B) in DCM (5 mL) was treated dropwise with boron tribromide (1 M in DCM) (3.5 mL, 3.50 mmol, 6.06 equivalents) at 0°C. After 30 minutes, the mixture was warmed and stirred at room temperature for 1 hour. The reaction mixture was recooled, and the reaction mixture was quenched with 0.7 M NH3 in MeOH (approximately 15 mL) and stirred for 30 minutes. The reaction mixture was concentrated, then dissolved in DMSO / water (1:1, 3.5 mL), filtered, and served with Waters X-Select CSH C 18Purification was performed by reverse-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics 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, flow rate 40 mL-1, eluting with 0.1% formic acid in a water-MeCN gradient over 12.5 minutes using UV across all wavelengths with PDA, QDA, and ELS detectors. The at-column dilution pump provided 2 mL-1 of MeOH throughout the process, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, gradient from 5% MeCN to 22.5% MeCN; 10.5-10.6 min, gradient from 22.5% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. Evaporation of the clean fraction using Genevac yielded the marked compound (15.8 mg, yield 7%) 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-triazine-5-one [ka]

[0417] Process 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 equivalent), cesium carbonate (2.997 g, 9.2 mmol, 2.0 equivalents), and (R)-3-amino-1-benzylpiperidine (1.00 g, 5.26 mmol, 1.14 equivalents) were dissolved in DMSO (20 mL), and the mixture was degassed for 5 minutes (N2). The reaction vessel was evacuated, refilled with N2 (3x), and then, rac )-BINAP Pd G3 (228.2 mg, 0.23 mmol, 0.05 equivalents) was added, and the reaction mixture was placed under N2 and stirred at 95°C for 24 hours. The reaction mixture was partitioned into ELISA (250 mL) and water (250 mL). The organic phase was isolated, washed with brine (3 x 200 mL), dried using a phase separator, and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel (40 g column, 0-7% in DCM (0.7 N ammonia in MeOH)) to obtain the marked compound (1.98 g, yield 87%) as a yellow oil. LC-MS m / z 436.4 [M+H] + ,ESI pos.

[0419] Process 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 equivalent) was dissolved in DCM (18 mL). Trifluoromethanesulfonic acid (0.71 mL, 8.0 mmol, 2.0 equivalents) was added to the reaction mixture. The resulting solution was stirred at room temperature for 18 hours, and then further trifluoromethanesulfonic acid (0.71 mL, 8.0 mmol, 2.0 equivalents) was added, and the reaction mixture was stirred for a further 1 hour. The reaction mixture was concentrated under vacuum and purified by chromatography on silica gel (40g column, 0-10% (0.7N ammonia in MeOH / DCM)) to obtain the labeled compound (1.56g, 3.35 mmol, 67% yield) as a light brown solid. LC-MS m / z 316.3[M+H] + ,ESI pos.

[0421] Process C: 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-chloro-4-methyl-1,2,4-triazine-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 equivalent) was dissolved in phosphorus oxychloride (4.86 mL, 52.1 mmol, 65.7 equivalents). The reaction mixture was stirred at 100°C for 24 hours, then at 120°C for a further 24 hours. The reaction mixture was concentrated in vacuum and then diluted with ELISA (100 mL). The mixture was vigorously stirred, and saturated aqueous NaHCO3 was slowly added to bring the pH to >8. The organic phase was separated, and the aqueous phase was extracted with ELISA (2 × 50 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuum to obtain the marked compound (208 mg, yield 72%) as a light brown oily substance. LC-MS m / z 334.3[M+H] + ,ESI pos.

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

[0424] 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-chloro-4-methyl-1,2,4-triazine-5-one (Example 26, Step C) (209.0 mg, 0.58 mmol, 1.0 equivalent), 2-methoxy-4-(trifluoromethyl)-phenylboronic acid (CAS#312936-89-3, 139.36 mg, 0.63 mmol, 1.1 equivalent), and saturated Na2CO3 aqueous solution (0.5 mL) were suspended in 1,4-dioxane (4 mL), the reaction mixture was spurged with N2, then evacuated and refilled with N2 (3x). Xphos Pd G3 (48.8 mg, 0.06 mmol, 0.1 equivalent) was added, the reaction mixture was placed under N2, and then stirred at 80°C for 24 hours. The reaction mixture was partitioned into RINKAN (50 mL) and brine (50 mL). The organic phase was isolated, dried using a phase separator, and concentrated under vacuum to obtain the marked compound (310.0 mg, 0.65 mmol, yield 81%) 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-triazine-5-one

[0426] 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazine-5-one (Example 26, Step D) (186.1 mg, 0.38 mmol, 1.0 equivalent) was dissolved in MeOH (8 mL), and 20 wt% palladium hydroxide-supported carbon (50% in H2O) (80.1 mg, 0.060 mmol, 0.150 equivalents) was added, followed by formaldehyde (37 wt% in H2O) (0.28 mL, 3.8 mmol, 10 equivalents). The reaction mixture was stirred under 3 bar H2 for 72 hours. Next, an additional 20% by weight palladium hydroxide-supported carbon (50% in water) (91.9 mg, 0.07 mmol, 0.1 equivalent) was added, and the reaction mixture was stirred under 5 bar of H2 for 24 hours. The reaction mixture was filtered through a celite® pad, and the filtrate was concentrated under vacuum. The resulting residue was dissolved in DCM (10 mL), and boron tribromide (1 M in DCM) (3.27 mL, 3.27 mmol, 5.0 equivalent) was slowly added. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under 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 minutes, and then filtered, and the filtrate was concentrated under vacuum. The resulting residue was dissolved in 7.5 mL of DMSO, filtered, and then filtered again. 18Purification was performed by reverse-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, flow rate 40 mL-1, eluting with 0.3% ammonia in a water-MeCN gradient over 12.5 minutes using UV across all wavelengths with PDA, QDA, and ELS detectors. The at-column dilution pump provided 2 mL-1 of MeOH throughout the process, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, gradient from 5% MeCN to 30% MeCN; 10.5-10.6 min, gradient from 30% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. Evaporation of the clean fraction using Genevac yielded the marked compound (23.9 mg, 9% yield) as a white solid. LC-MS m / z 384.3[M+H] + ,ESI pos.

[0427] The following example "Ex." was synthesized using a method similar to that 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-triazine-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-triazine-5-one

[0429] 3-Chloro-6-[[(3R-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one (Example 2, Step D) (350 mg, 1.29 mmol, 1.0 equivalent), saturated sodium carbonate aqueous solution (1.5 mL, 5.50 mmol, 4.27 equivalents), 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 equivalent) were suspended in 1,4-dioxane (10 mL), N2 was spurged into the reaction mixture, then the system was evacuated and refilled with N2 (3x). Xphos Pd G3 (54.57 mg, 0.06 mmol, 0.05 equivalents) was added, and the reaction mixture was placed under N2 and stirred at 80°C for 18 hours. The reaction mixture was diluted with MeOH, then dry-loaded onto silica gel, and purified by silica gel column chromatography (12 g column, 0-10% (0.7 N NH3 in MeOH) / DCM) and chiral SFC with Waters preparative solution 15. UV detection was performed by DAD at 210-400 nm, 40°C, and 120 bar. The column was IH 10 x 250 mm, 5 μM, flow rate 15 mL / min, 10% MeOH (0.03% ammonia), 90% CO2. Two atropisomers were obtained:

[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 ¹H 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: Phenol OH was not 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 ¹H 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: The 1×N-CH signal is obscured by the water peak and therefore not observed.

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

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

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

[0435] A solution of p-toluenesulfonic acid (0.09 g, 0.52 mmol, 0.13 equivalents) and 3-(pentafluorothio)phenol (900.0 mg, 4.09 mmol, 1.0 equivalent) in MeOH (18 mL) was stirred at room temperature for 15 minutes. Then, the flask was covered with tin foil, and a solution of N-iodosuccinimide (3.0 g, 13.3 mmol, 3.26 equivalents) in MeOH (18 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, the mixture was redissolved in ELISA (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 obtain the marked 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 equivalents) was added to a stirred mixture of 2-iodo-5-(pentafluoro-λ6-sulfanyl)phenol (1.49 g, 4.19 mmol, 1.0 equivalent) and potassium carbonate (1.50 g, 10.9 mmol, 2.59 equivalents). The mixture was then heated at 56°C for 3 hours, and then heated at room temperature for 3 days. The reaction mixture was filtered and then concentrated to dryness. The resulting residue was partitioned into water (20 mL) and siRNA (40 mL). The organic layer was collected, and the aqueous layer was extracted with siRNA (2 × 15 mL). The combined organic layers were dried over (MgSO4), filtered, concentrated, and dried to obtain an orange oil. The crude product was purified by column chromatography (SiO2, 40 g cartridge, homogeneous concentration isohexane) to obtain the labeled compound (1.36 g, yield 87%) 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] Isopropyl magnesium chloride (2M in THF, 2.4 mL, 4.8 mmol, 1.44 equivalents) was added to a stirred solution of pentafluoro-(4-iodo-3-methoxyphenyl)-λ6-sulfan (1.2 g, 3.33 mmol, 1.0 equivalent) in THF (36 mL) cooled to 0°C. The mixture was stirred at 0°C for 30 minutes. Then, trimethyl borate (0.84 mL, 7.53 mmol, 2.26 equivalents) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated, then redissolved in DCM (20 mL), washed with 10% KH2PO3 aqueous solution (3 x 10 mL), and subsequently washed with brine (20 mL). The organic layer was dried with (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 minutes, then water (0.36 mL) and subsequently THF (1.2 mL) were added. The mixture was left to stir at room temperature for 18 hours. The reaction mixture was washed with 25 mL of 10% w / v KH2PO4 aqueous solution, the organic layer was dried with (MgSO4), filtered, and concentrated. The resulting solid was polished with isohexane (30 mL) to obtain the marked compound (576.0 mg, yield 62%) as a white powder. LC-MS: m / z 277.0 [MH] - ,ESI neg.

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

[0441] This process was carried out using a method similar 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-triazine-5-one [ka]

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

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

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

[0446] 6-[[(3R)-1-benzyl-3-piperidyl]amino]-3-[2-methoxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazine-5-one (Example 35, Step A) (186.1 mg, 0.38 mmol, 1.0 equivalent) was dissolved in MeOH (8 mL), and 20 wt% palladium hydroxide-supported carbon (50% in H2O) (80.08 mg, 0.06 mmol, 0.15 equivalents) was added, followed by formaldehyde (37 wt% in H2O) (0.28 mL, 3.80 mmol, 10.0 equivalents). The reaction mixture was stirred under 5 bar H2 for 24 hours. Next, 20% by weight of palladium hydroxide-supported carbon (50% in H2O) (91.9 mg, 0.070 mmol, 0.100 equivalents) was added, and the reaction mixture was stirred under 5 bar of H2 for 24 hours. The reaction mixture was filtered through a celite® pad, and the filtrate was concentrated under vacuum. The resulting residue was dissolved in DCM (10 mL), and boron tribromide (1 M in DCM) (1.9 mL, 1.90 mmol, 5.0 equivalents) was slowly added. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under 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 minutes, and then filtered, and the filtrate was concentrated under vacuum. The resulting residue was dissolved in 11 mL of DMSO, filtered, and then filtered again. 18 The samples were purified by reverse-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, flow rate 40 mL-1, and eluting over 12.5 minutes with 0.3% ammonia in a water-MeCN gradient using PDA, QDA, and ELS detectors with UV across all wavelengths. The at-column dilution pump was used throughout the process for 2 mL. -1This yields MeOH, which is included in the following percentage of MeCN. Gradient information: 0.0~0.5 min, 5% MeCN; 0.5~10.5 min, gradient from 5% MeCN to 30% MeCN; 10.5~10.6 min, gradient from 30% MeCN to 100% MeCN; 10.6~12.5 min, held at 100% MeCN. The clean fraction was evaporated using Genevac, yielding the marked compound (70.4 mg, yield 46%) 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-triazine-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 equivalent) and commercially available cyclopropylmethaneamine (CAS#2516-47-4, 0.95 mL, 10.9 mmol, 1.2 equivalents) in DCM (20 mL), DIPEA (2952.5 mg, 22.7 mmol, 2.5 equivalents), EDCI (2.09 g, 10.9 mmol, 1.2 equivalents), and HOBt (1.60 g, 11.8 mmol, 1.3 equivalents) were added. The resulting reaction mixture was stirred at 40°C for 2 hours. After the reaction was complete, water (50 mL) was added, and the solution was extracted with siRNA (20 mL x 3). The combined organic phase was washed with brine (100 mL), dried on 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 obtain the marked compound (2.10 g, yield 85%) as a yellow oily substance. 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-mentioned N-(cyclopropylmethyl)-2-methoxy-4-(trifluoromethyl)benzamide (Example 35, Step A) (2.10 g, 7.69 mmol, 1.0 equivalent) in THF (40 mL), Lawson's reagent (2.312 g, 4.61 mmol, 0.6 equivalent) was added. The mixture was stirred at 70°C for 2 hours, and then cooled to room temperature. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were 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 (petroleum ether:ethyl acetate = 1:0~10:1) to obtain the marked compound (2.20 g, yield 93%) as a yellow oil. LC-MS (Method 2): m / z 290 [M+H] + ,ESI pos.

[0452] Process 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 equivalent) in DMF (40 mL), DIEA (2.68 g, 20.74 mmol, 3.0 equivalents) was added at 20°C and stirred for 10 minutes. Then, MeI (1.67 g, 11.8 mmol, 1.7 equivalents) was added to the mixture. The mixture was stirred at 40°C for 2 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium phosphate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (C 18 The compound was purified using 120 g of water with 0.1% TFA / MeCN, then the desired fractions were combined and freeze-dried to obtain the marked compound (1.0 g, 48% yield) as a yellow oil. LC-MS (Method 2): m / z 303.9 [M+H] + ,ESI pos.

[0454] Process D: N"-(cyclopropylmethyl)-2-methoxy-4-(trifluoromethyl)benzimidohydrazide To a solution of methyl N-(cyclopropylmethyl)-2-methoxy-4-(trifluoromethyl)benzimidothioate (Example 35, Step C) (500.0 mg, 1.65 mmol, 1.0 equivalent) in ethanol (15 mL), hydrazine hydrate (835 mg, 16.7 mmol, 10.1 equivalents) was added. The mixture was stirred at 70°C for 6 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure. The crude product was subjected to column chromatography (C). 18 The compound was purified by 20 g of water with 0.1% NH3·H2O / MeCN, and then the desired fractions were combined and freeze-dried to obtain the marked compound (200 mg, yield 41%) 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-triazine-5(4H)-one

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

[0457] Process F: 6-Chloro-4-(cyclopropylmethyl)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine-5(4H)-one

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

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

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

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

[0462] To a solution of (R)-4-(cyclopropylmethyl)-6-((1-ethylpiperidine-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine-5(4H)-one (Example 35, Step F) (10.0 mg, 0.02 mmol, 1.0 equivalent) in DCM (1 mL), BBr3 (55.4 mg, 0.22 mmol, 10.0 equivalent) was added at -40°C, and the mixture was then stirred at 20°C for 1 hour. The reaction mixture was quenched with water (0.5 mL), then the pH was adjusted to approximately 8 with NH3.H2O, then concentrated under reduced pressure, the residue was dissolved in methanol (2 mL), and then preparative HPLC (column 3_Phenomenex Luna C) was performed. 18 The sample was purified using a 75×30mm×3μm sample (condition: 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 the solvent was removed by freeze-drying to obtain the marked compound (0.82 mg, yield 7%) as a white solid. LC-MS (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-triazine-5-one; 2,2,2-trifluoroacetic acid [ka]

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

[0465] 6-(((3R,5S)-5-fluoropiperidine-3-yl)amino)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one (Example 16, Step B) (20.0 mg, 0.05 mmol, 1.0 equivalent) and K2CO3 (66.4 mg, 0.48 mmol, 10.0 equivalents) were mixed in NMP (1 mL), to which benzenethiol (49 μL, 0.48 mmol, 10.0 equivalents) was added under N2 conditions, and the mixture was then stirred at 190°C for 30 minutes under microwave conditions. The reaction mixture was cooled to 20°C and subjected to column chromatography (C 18 The product was purified by 0.1% TFA / MeCN in water. The eluent was freeze-dried to obtain the product, which was then separated by preparative HPLC (column: 3_Phenomenex Luna C). 18 The compound was purified a second time using a 75×30mm×3μm filter under the following conditions: water (0.1% TFA)-MeCN, start B: 15; end B: 45, gradient time (min): 7; 100% B retention time (min): 2; flow rate (mL / min): 25. The desired fractions were combined and freeze-dried to obtain the marked compound (4.14 mg, yield 16%) as a yellow solid. LC-MS (Method 2): m / z 387.9[M+H]+, ESI pos.

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

[0467] RE-A was synthesized in the same manner as described in WO20200234715.

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

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

[0470] Example A The compound of formula I can be used as an active ingredient in a manner known to itself to produce tablets of the following composition: per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20 mg 425mg

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

Claims

1. Formula Ib 【Chemistry 1】 (In the formula, R １ However, H, acetyl, SF ５ , halo, alkyl, haloalkyl, haloalkoxy or nitrile; R ５ But is it H? Or, R １ and R ５ Furthermore, the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom which is optionally substituted with one or two substituents independently selected from halo or alkyl, or R １ and R ５ Furthermore, the atoms to which they are bonded form a 3-6 membered cycloalkyl ring, optionally substituted with one or two substituents independently selected from halo or alkyl; R ２ However, the compound is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, and the cycloalkyl or cycloalkylalkyl is optionally substituted with a halo; R ３ is H, alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl, where cycloalkyl or cycloalkylalkyl is optionally substituted with halo; Z is -O- or -NH-; R ４ However, halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO ２ A heterocycle optionally substituted with 1 to 3 substituents independently selected from H, cycloalkylalkyl, or cycloalkyl groups optionally substituted with halo; or R ４ However, it is a cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH; or R ４ (However, the substituent is an arylalkyl or heteroarylalkyl, and the arylalkyl or heteroarylalkyl has 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH.) Compounds thereof, or pharmaceutically acceptable salts thereof.

2. R ５ Is H or R １ and R ５ Furthermore, the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom, or R １ and R ５ The compound according to claim 1, wherein the atoms to which they are bonded form a 3- to 6-membered cycloalkyl ring.

3. R ５ Is H or R １ and R ５ The compound according to claim 1 or 2, wherein the atoms to which they are bonded form a five-membered heterocycle containing a single oxygen atom.

4. R １ However, acetyl, SF ５ The compound according to claim 1 or 2, wherein it is a halo, haloalkyl, haloalkoxy, or nitrile.

5. R １ The compound according to claim 1 or 2, wherein the compound is a halo, a haloalkyl, or a haloalkoxy.

6. R ２ The compound according to claim 1 or 2, wherein the compound is H or alkyl.

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

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

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

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

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

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

13. R １ However, acetyl, SF ５ , halo, haloalkyl, haloalkoxy or nitrile; R ５ But is it H? Or, R １ and R ５ Furthermore, the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom, or R １ and R ５ Furthermore, the atoms to which they are bonded form a 3-6 membered cycloalkyl ring, R ２ However, it is H or alkyl; R ３ However, it is H, alkyl, or cycloalkyl; Z is -NH-; R ４ However, it is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, or cycloalkylalkyl; or R ４ However, it is a cycloalkyl group optionally substituted with two substituents independently selected from alkyl and -OH; or R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is an arylalkyl group substituted with an OH group.

14. R １ However, acetyl, SF ５ , halo, haloalkyl, haloalkoxy or nitrile; R ５ But is it H? Or, R １ and R ５ Furthermore, the atoms to which they are bonded form a five-membered heterocycle containing a single oxygen atom. R ２ However, it is H or alkyl; R ３ However, it is H, alkyl, or cycloalkyl; Z is -NH-; R ４ However, it is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, or cycloalkylalkyl; or R ４ However, it is a cycloalkyl group optionally substituted with two substituents independently selected from alkyl and -OH; or R ４ The compound according to claim 1 or 13, or a pharmaceutically acceptable salt thereof, wherein the compound is an arylalkyl group substituted with an OH group.

15. The aforementioned compound, 6-((1-ethylpiperidine-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-3-piperidyl]amino]-1,2,4-triazine-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-triazine-5-one; (R)-6-((1-(cyclopropylmethyl)piperidine-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one; (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-one; 6-(1,2,3,5,6,7,8,8a-octahydroindolidine-8-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-1-propyl-3-piperidyl]amino]-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[(1,5,5-trimethyl-3-piperidyl)amino]-1,2,4-triazine-5-one; (R)-6-((1-cyclopropylpiperidine-3-yl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one; 6-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one; 6-[(1-tert-butyl-3-piperidyl)amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-(2-azabicyclo[2.2.1]heptan-6-ylamino)-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R,5S)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R,5R)-1-ethyl-5-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(5S)-5-fluoro-1-methyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R)-6,6-dimethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[(3-hydroxyphenyl)methylamino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 4-Cyclopropyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-fluoro-2-hydroxyphenyl)-4-methyl-1,2,4-triazine-5-one; 4-ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-1,2,4-triazine-5-one; 3-[4-(difluoromethoxy)-2-hydroxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 3-[4-(1,1-difluoroethyl)-2-hydroxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 3-(4-acetyl-2-hydroxyphenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-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-triazine-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-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(pentafluoro-λ6-sulfanyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-5-oxo-1,2,4-triazine-3-yl]-3-hydroxybenzonitrile; 3-(4-chloro-2-hydroxyphenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazine-5-one; 6-[[(3R,5S)-1-ethyl-5-fluoro-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4H-1,2,4-triazine-5-one A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the above.

16. The aforementioned compound, 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazine-5-one; (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazine-5-one; 3-[4-(difluoromethoxy)-2-hydroxyphenyl]-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 6-[[(3R)-1-ethyl-3-piperidyl]amino]-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-1,2,4-triazine-5-one; 3-(4-chloro-2-hydroxyphenyl)-6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazine-5-one; 3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-4-methyl-6-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazine-5-one A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the above.

17. 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-triazine-5-one or a pharmaceutically acceptable salt thereof.

18. a) A reaction in which a compound of formula XI is converted into a compound of formula XII; b) A reaction in which the compound of formula XII is converted to the compound of formula XIII (wherein R' is methyl); and c) Reaction to convert the compound of formula XIII to the compound of formula Ib 【Chemistry 2】 or a') A reaction in which the compound of formula XI is converted to the compound of formula XII; b') A reaction in which the compound of formula XII is converted to the compound of formula XIII (wherein R' is SEM); and c') Reaction to convert the compound of formula XIII to the compound of formula Ib 【Transformation 3】 or a'') A reaction in which the compound of formula XI is converted to the compound of formula XII; and b'') A reaction in which the compound of formula XII is converted to the compound of formula Ib (wherein R' is H). 【Chemistry 4】 (In the formula, R 1 , R 2 , R ３ , R ４ (R5 and Z are as described in claim 1) A method for preparing the compound according to claim 1 or 2, comprising the above.

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

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

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

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

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

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

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

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