Triazine Derivatives and Their Use in the Treatment of Cancer - Patent application

Abstract

The present invention relates to compounds of general formula Ib: TIFF2024522494000066.tif54165 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and Z is as described herein. The present invention relates to novel compounds having the formula:

Description

[Technical field]

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

[0002] The present invention relates to a compound of formula Ib: [ka] (In the formula, R 1 is H, halo, alkyl, haloalkyl, haloalkoxy or nitrile; R 5 is H, or R 1 and R 5 and the atoms to which they are attached form either a 4-6 membered heterocycle containing only one heteroatom O, optionally substituted with one or two substituents independently selected from halo or alkyl, or R 1 and R 5 and the atoms to which they are attached form a 3-6 membered cycloalkyl ring optionally substituted with 1 or 2 substituents independently selected from halo or alkyl; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo or haloalkoxy; R 3 is H, alkyl, haloalkyl, or cycloalkyl optionally substituted with halo; Z is -O-, -NH- or -NHCH 2 - and; R 4 is halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO 2 a heterocycle optionally substituted with 1-2 substituents independently selected from H, or cycloalkyl optionally substituted with halo; R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH. The present invention provides novel compounds of the formula:

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

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

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

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

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

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

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

[0010] The role of NLRP3 in diseases of the central nervous system is becoming clear, and lung diseases have also been shown to be influenced by NLRP3. In addition, NLRP3 plays a role in the development of liver disease, kidney disease and aging. Many of these associations are related to Nlrp3. - / - Although defined in mice, there are also insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

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

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

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

[0014] The present invention relates to a compound of formula Ib: [ka] (In the formula, R 1 is H, halo, alkyl, haloalkyl, haloalkoxy or nitrile; R 5 is H, or R 1 and R 5 and the atoms to which they are attached form either a 4-6 membered heterocycle containing only one heteroatom O, optionally substituted with one or two substituents independently selected from halo or alkyl, or R 1 and R 5 and the atoms to which they are attached form a 3-6 membered cycloalkyl ring optionally substituted with 1 or 2 substituents independently selected from halo or alkyl; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo or haloalkoxy; R 3 is H, alkyl, haloalkyl, or cycloalkyl optionally substituted with halo; Z is -O-, -NH- or -NHCH 2 - and; R 4 is halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO 2 a heterocycle optionally substituted with 1-2 substituents independently selected from H, or cycloalkyl optionally substituted with halo; R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH. The present invention provides novel compounds of the formula:

[0015] The term "alkyl" refers to a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl refers to a group having 1 to 6 carbon atoms (C 1~6 -alkyl) or 1 to 4 carbon atoms (C 1~4 -alkyl). 1~6 Examples of -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. Specific alkyl groups include methyl, ethyl and propyl. When an alkyl residue with a specific number of carbons is named, all geometric isomers with that number of carbons can be included. Thus, for example, "butyl" can include n-butyl, sec-butyl, isobutyl and t-butyl, and "propyl" can include n-propyl and isopropyl.

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

[0017] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise stated, a cycloalkyl contains 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, a cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. In other embodiments, a cycloalkyl contains one or more double bonds (e.g., a cycloalkyl fused to an aryl or heteroaryl ring, or a non-aromatic monocyclic hydrocarbon containing one or two double bonds). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, spiro[3.3]heptanyl, and the like. Bicyclic means a ring system consisting of two saturated carbocyclic rings with two shared carbon atoms. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, or cycloheptyl. Particular examples of "cycloalkyl" are cyclopropyl, cyclobutyl, and cyclopentyl.

[0018] The term "cycloalkylalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, and hydroxycyclopropylmethyl.

[0019] The terms "halogen", "halide" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo or iodo. Particular halogens include fluoro, chloro, and the like.

[0020] The term "haloalkyl" means C 1~6 - at least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom 1~6-represents an alkyl group. Particular examples are fluoromethyl, difluoromethyl and trifluoromethyl.

[0021] The term "haloalkoxy" means 1~6 - at least one hydrogen atom of an alkoxy group is replaced by the same or different halogen atom 1~6 -represents an alkoxy group. Examples of haloalkoxy are difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy. A particular example is trifluoromethoxy.

[0022] The term "heterocyclic" denotes a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 10 ring atoms or 4 to 9 ring atoms containing 1, 2 or 3 ring heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycles are oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or piperazinyl. Examples of partially unsaturated heterocycles are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl or dihydropyranyl. Particular examples of heterocycles are piperidinyl, furanyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl and 1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl.

[0023] The term "hydroxy" refers to an --OH group.

[0024] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, and dihydroxypropyl.

[0025] The term "nitrile" refers to the group -C≡N.

[0026] The term "pharmaceutically acceptable salt" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. Salts are formed with inorganic acids, such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. In addition, these salts can be prepared from the addition of inorganic or organic bases to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. Compounds of formula Ib may also exist in zwitterionic form. Particularly preferred pharma- ceutically acceptable salts of compounds of formula Ib are salts formed with formic acid and with hydrochloric acid to produce hydrochloride, dihydrochloride, or trihydrochloride salts.

[0027] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0028] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0029] The abbreviation ug means microgram and is equivalent to the symbol μg.

[0030] The compounds of formula Ib may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0031] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0032] One embodiment of the present invention also provides compounds according to formula Ib as described herein, and pharma- ceutically acceptable salts or esters thereof, particularly compounds according to formula Ib as described herein, and pharma- ceutically acceptable salts thereof, more particularly compounds according to formula Ib as described herein.

[0033] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, haloalkoxy, or nitrile; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form a five-membered heterocycle containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 4-5 membered cycloalkyl ring.

[0034] One embodiment of the present invention comprises: R 1 is haloalkyl or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing only one heteroatom O, or R 1and R 5 and the atoms to which they are attached form a 4-5 membered cycloalkyl ring.

[0035] One embodiment of the present invention comprises: R 1 is haloalkyl; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 4-membered cycloalkyl ring.

[0036] One embodiment of the present invention is 1 is H, halo, haloalkyl or cycloalkoxy.

[0037] One embodiment of the present invention is 1 is halo, alkyl, or haloalkyl.

[0038] One embodiment of the present invention is 1 F, Cl, OCF 3 , C.F. 3 or CH 3

[0023] The present invention provides a compound according to formula Ib described herein,

[0039] One embodiment of the present invention is 1 But CF 3

[0023] The present invention provides a compound according to formula Ib described herein,

[0040] One embodiment of the present invention is 2is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo.

[0041] One embodiment of the present invention is 2 is H, halo, alkyl, haloalkyl or cycloalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo.

[0042] One embodiment of the present invention is 2 is H, halo, alkyl or haloalkyl.

[0043] One embodiment of the present invention is 2 is H, halo, or alkyl.

[0044] One embodiment of the present invention is 2 is H or alkyl.

[0045] One embodiment of the present invention is 2 is alkyl.

[0046] One embodiment of the present invention is 2 is H.

[0047] One embodiment of the present invention is 3 is H, alkyl or haloalkyl.

[0048] One embodiment of the present invention is 3 is H or alkyl.

[0049] One embodiment of the present invention is 3 is H.

[0050] One embodiment of the present invention is 3 is alkyl.

[0051] One embodiment of the present invention is 3 is methyl.

[0052] One embodiment of the present invention is 4 but, 6-9 membered heterocycles containing 1 or 2 N heteroatoms; or a 6-membered heterocycle containing one heteroatom N, substituted with 1-2 substituents independently selected from alkyl and -OH; or Provided herein are compounds according to formula Ib, which is a 4-6 membered cycloalkyl substituted with 1-2 substituents independently selected from alkyl and -OH-.

[0053] One embodiment of the present invention is 4 but, a 9-membered heterocycle containing only one N heteroatom; or Compounds according to formula Ib as described herein are provided which are 6-membered heterocycles containing one heteroatom N, substituted with one alkyl substituent.

[0054] One embodiment of the present invention is 4 is methylpiperidyl or ethylpiperidyl.

[0055] One embodiment of the present invention is 4 is a heterocycle optionally substituted with alkyl, or a cycloalkyl ring optionally substituted with 1-2 substituents selected from alkyl and -OH.

[0056] One embodiment of the present invention is 4 is a heterocycle optionally substituted with alkyl.

[0057] One embodiment of the present invention is 4 is a heterocycle containing one heteroatom substituted with alkyl.

[0058] One embodiment of the present invention is 4 is either an ethylpiperidine or a cyclobutane substituted with alkyl and -OH.

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

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

[0061] One embodiment of the present invention provides a compound according to formula Ib described herein, wherein Z is -NH-.

[0062] One embodiment of the present invention is 1 and R 5 and the atom to which they are attached form a 4-6 membered heterocycle containing only one heteroatom O, optionally substituted with 1 or 2 substituents independently selected from halo or alkyl, or R 1 and R 5 and the atoms to which they are attached form a 3-6 membered cycloalkyl ring, optionally substituted with 1 or 2 substituents independently selected from halo or alkyl.

[0063] One embodiment of the present invention is 1 and R5 and the atoms to which they are attached form either a 4- to 6-membered heterocycle containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring.

[0064] One embodiment of the present invention is 1 and R 5 and the atom to which they are attached form a 5-membered heterocycle containing only one heteroatom O.

[0065] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, haloalkoxy, or nitrile; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form a five-membered heterocycle containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 4-5 membered cycloalkyl ring; R 2 is H, halo, or alkyl; R 3 is H, alkyl or haloalkyl; Z is -NH-; R 4 but, 6-9 membered heterocycles containing 1 or 2 N heteroatoms; or a 6-membered heterocycle containing one heteroatom N, substituted with 1-2 substituents independently selected from alkyl and -OH; or Provided herein are compounds according to formula Ib as described herein, which is 4-6 membered cycloalkyl substituted with 1-2 substituents independently selected from alkyl and -OH-, and pharma- ceutically acceptable salts thereof.

[0066] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, haloalkoxy, or nitrile; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form a five-membered heterocycle containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 4-5 membered cycloalkyl ring; R 2 but H; R 3 is alkyl; Z is -NH-; R 4 but, a 9-membered heterocycle containing only one N heteroatom; or Provided are compounds according to formula Ib as described herein, which are 6-membered heterocycles containing one heteroatom N, substituted with one alkyl substituent, and pharma- ceutically acceptable salts thereof.

[0067] One embodiment of the present invention comprises: R 1 is haloalkyl or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form a five-membered heterocycle containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 4-5 membered cycloalkyl ring; R 2 but H; R 3 is alkyl; Z is -NH-; R 4is methylpiperidyl or ethylpiperidyl, and pharma- ceutically acceptable salts thereof.

[0068] One embodiment of the present invention comprises: R 1 is haloalkyl; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form a five-membered heterocycle containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 4-membered cycloalkyl ring; R 2 but H; R 3 is alkyl; Z is -NH-; R 4 is ethyl piperidyl, and pharma- ceutically acceptable salts thereof.

[0069] One embodiment of the present invention comprises: R 1 and R 5 and the atom to which they are attached form a 4-6 membered heterocycle containing only one heteroatom O, optionally substituted with one or two substituents independently selected from halo or alkyl, or R 1 and R 5 and the atom to which they are attached form a 3-6 membered cycloalkyl ring optionally substituted with 1 or 2 substituents independently selected from halo or alkyl; R 2 but H; R 3 is methyl; Z is -NH-; R 4is a piperidine ring substituted with alkyl, and pharma- ceutically acceptable salts thereof.

[0070] One embodiment of the present invention comprises: R 1 and R 5 and the atoms to which they are attached form either a 4- to 6-membered heterocycle containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring: R 2 but H; R 3 is methyl; Z is -NH-; R 4 is a piperidine ring substituted with alkyl, and pharma- ceutically acceptable salts thereof.

[0071] One embodiment of the present invention provides a compound according to formula I, wherein the compound of formula I is a compound of formula Ib. [ka]

[0072] The compounds of formula Ib may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0073] Embodiments of the present invention also provide compounds according to formula I as described herein, and pharma- ceutically acceptable salts or esters thereof, particularly compounds according to formula I as described herein, and pharma- ceutically acceptable salts thereof, more particularly compounds according to formula I as described herein.

[0074] One embodiment of the present invention comprises: R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, or nitrile; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo or haloalkoxy; R 3 is H, alkyl, haloalkyl, or cycloalkyl optionally substituted with halo; Z is -O-, -NH- or -NHCH 2 - and; R 4 is halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO 2 a heterocycle optionally substituted with 1-2 substituents independently selected from H, or cycloalkyl optionally substituted with halo; R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH, and pharma- ceutically acceptable salts thereof.

[0075] One embodiment of the present invention comprises: R 1 is H, halo, alkyl, haloalkyl, or haloalkoxy; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo or haloalkoxy; R 3 is H, alkyl, haloalkyl, or cycloalkyl optionally substituted with halo; Z is -O-, -NH- or -NHCH 2 - and; R 4 is halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO2 a heterocycle optionally substituted with 1-2 substituents independently selected from H, or cycloalkyl optionally substituted with halo; R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH, and pharma- ceutically acceptable salts thereof.

[0076] One embodiment of the present invention is 1 is H, halo, haloalkyl or cycloalkoxy.

[0077] One embodiment of the present invention is 1 is halo, alkyl, or haloalkyl.

[0078] One embodiment of the present invention is 1 F, Cl, OCF 3 , C.F. 3 or CH 3

[0023] The present invention provides a compound according to formula I described herein,

[0079] One embodiment of the present invention is 1 But CF 3

[0023] The present invention provides a compound according to formula I described herein,

[0080] One embodiment of the present invention is 2 is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo.

[0081] One embodiment of the present invention is 2is H, halo, alkyl, haloalkyl, or cycloalkyl, wherein cycloalkyl or cycloalkylalkyl is optionally substituted with halo.

[0082] One embodiment of the present invention is 2 is H, halo, alkyl or haloalkyl.

[0083] One embodiment of the present invention is 2 is H or alkyl.

[0084] One embodiment of the present invention is 2 is alkyl.

[0085] One embodiment of the present invention is 2 is H.

[0086] One embodiment of the present invention is 3 is H, alkyl or haloalkyl.

[0087] One embodiment of the present invention is 3 is H or alkyl.

[0088] One embodiment of the present invention is 3 is H.

[0089] One embodiment of the present invention is 3 is methyl.

[0090] One embodiment of the present invention is 4is a heterocycle optionally substituted with alkyl, or a cycloalkyl ring optionally substituted with 1-2 substituents selected from alkyl and -OH.

[0091] One embodiment of the present invention is 4 is a heterocycle optionally substituted with alkyl.

[0092] One embodiment of the present invention is 4 is a heterocycle containing one heteroatom substituted with alkyl.

[0093] One embodiment of the present invention is 4 is either an ethylpiperidine or a cyclobutane substituted with alkyl and -OH.

[0094] One embodiment of the present invention is 4 is ethylpiperidine.

[0095] One embodiment of the present invention provides a compound according to formula I described herein, wherein Z is -O- or -NH-.

[0096] One embodiment of the present invention provides a compound according to formula I described herein, wherein Z is -NH-.

[0097] One embodiment of the present invention comprises: R 1 But Cl, OCF 3 , alkyl or haloalkyl; R 2 is H, halo, alkyl, haloalkyl or cycloalkyl optionally substituted with F; R 3 is H, alkyl, haloalkyl or cycloalkyl optionally substituted with F; Z is O, or -NH-; R 4 is halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO 2 a heterocycle optionally substituted with 1-2 substituents independently selected from H, or cycloalkyl optionally substituted with halo; R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH.

[0098] One embodiment of the present invention comprises: R 1 But Cl, CH 3 , OCF 3 , or CF 3 and; R 2 is H, halo, alkyl or haloalkyl; R 3 is H, alkyl or haloalkyl; Z is O, or -NH-; R 4 is halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO 2 a heterocycle containing 1 heteroatom optionally substituted with 1-2 substituents independently selected from H, or cycloalkyl optionally substituted with halo; or R 4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH.

[0099] One embodiment of the present invention comprises: R 1 But Cl, CH 3 , OCF 3 , or CF 3 and; R 2 is H, halo, alkyl or haloalkyl; R 3 is H, alkyl or haloalkyl; Z is O, or -NH-; R 4 is a heterocycle containing one heteroatom optionally substituted with 1-2 substituents independently selected from halo, alkyl, or haloalkyl.

[0100] One embodiment of the present invention comprises: R 1 But Cl, CH 3 , OCF 3 , or CF 3 and; R 2 is H, halo, alkyl or haloalkyl; R 3 is H, alkyl or haloalkyl; Z is -NH-; R 4 is a heterocycle containing one heteroatom optionally substituted with 1-2 substituents independently selected from halo, alkyl, or haloalkyl.

[0101] One embodiment of the present invention comprises: R 1 is halo or haloalkyl; R 2 is H or alkyl; R 3 is H or alkyl; Z is -NH-; R 4 is a heterocycle containing one heteroatom substituted with alkyl, or R 4 is a cycloalkyl ring substituted with 1 to 2 substituents independently selected from alkyl and -OH.

[0102] One embodiment of the present invention comprises: R 1 But halo or CF3 and; R 2 is H or methyl; R 3 is H or methyl; Z is -NH-; R 4 is a piperidine ring substituted with alkyl or a cyclobutane ring substituted with 1-2 substituents selected from alkyl and -OH.

[0103] One embodiment of the present invention comprises: R 1 But CF 3 or Cl; R 2 but H; R 3 is methyl, Z is -NH-; R 4 is an alkyl substituted piperidine ring.

[0104] One embodiment of the present invention comprises: R 1 But CF 3 and; R 2 but H; R 3 is methyl, Z is -NH-; R 4 is an alkyl substituted piperidine ring.

[0105] Particular examples of compounds of formula Ib described herein are 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-2-[3-[(1-ethyl-3-piperidyl)amino]-5-methyl-1,2,4-triazin-6-yl]phenol; 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[(3-hydroxy-3-methyl-cyclobutyl)amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 5-chloro-2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]phenol; 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-fluoro-phenol; 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol and pharma- ceutically acceptable salts thereof.

[0106] Other specific examples of compounds of formula Ib described herein are 3-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-3-fluoro-5-(trifluoromethyl)phenol; 2-[3-[[(3R or 3S)-1-tert-butyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(3S or 3R)-1-tert-butyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 4-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile; 2-[3-[[(3R,5S)-5-fluoro-1-methyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[5-methyl-3-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-ylamino)-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 5-Fluoro-2-[5-methyl-3-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]phenol; 5-Chloro-2-[5-methyl-3-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]phenol; 2-[5-methyl-3-[[(3R)-3-piperidyl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[5-methyl-3-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(1R,2R)-2-hydroxycyclohexyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethoxy)phenol; (3S,5R)-1-ethyl-5-[[6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl]amino]piperidin-3-ol; (3S,5R)-1-ethyl-5-[[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl]amino]piperidin-3-ol; 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]indan-4-ol 2-[5-methyl-3-[[rac-(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[5-methyl-3-[[rac-(8S,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(8R,8aS or 8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[3-[[(8S,8aR or 8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-(trifluoromethyl)-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(6S or 6R,8aS or 8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(6R or 6S,8aS or 8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(6S or 6R,8aR or 8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(6R or 6S, 8aR or 8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol and pharma- ceutically acceptable salts thereof.

[0107] A preferred example of a compound of formula Ib described herein is 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol, or a pharma- ceutically acceptable salt thereof.

[0108] Other preferred examples of compounds of formula Ib described herein are 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 5-chloro-2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]phenol; 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-fluoro-phenol; 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol; 3-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; 4-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile; 5-Chloro-2-[5-methyl-3-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]phenol; 2-[5-methyl-3-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethoxy)phenol; 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]indan-4-ol; 2-[3-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-3-methyl-5-(trifluoromethyl)phenol and pharma- ceutically acceptable salts thereof.

[0109] More preferred examples of compounds of formula Ib described herein are 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol; 3-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; 2-[5-methyl-3-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethoxy)phenol; 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]indan-4-ol and pharma- ceutically acceptable salts thereof.

[0110] The most preferred examples of compounds of formula Ib described herein are 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol; 3-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol and pharma- ceutically acceptable salts thereof.

[0111] Specific examples of compounds of formula I described herein are 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-2-[3-[(1-ethyl-3-piperidyl)amino]-5-methyl-1,2,4-triazin-6-yl]phenol; 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[(3-hydroxy-3-methyl-cyclobutyl)amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 5-chloro-2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]phenol; 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-fluoro-phenol and pharma- ceutically acceptable salts thereof.

[0112] Processes for the preparation of compounds of formula I described herein are the subject of the present invention.

[0113] The synthesis of compounds of formula I can be accomplished, for example, according to Scheme 1.

[0114] The processes for the preparation of compounds of formula Ib described herein are the subject of the present invention.

[0115] The synthesis of compounds of formula I can be accomplished, for example, according to Scheme 3.

[0116] General synthesis scheme for triazine compounds: Compounds of formula I can be prepared according to variations of the above methods and the following Scheme 1. Starting materials are commercially available or can be prepared according to known methods.

[0117] Scheme 1 [ka]

[0118] The compounds of formula I of the present invention can be synthesized according to the general synthesis shown in Scheme 1.

[0119] Commercially available building blocks of formula (III), where X is a halogen atom such as bromine, chlorine or iodine, more preferably chlorine, can be subjected to nucleophilic aromatic substitution to prepare compounds of formula (IV). The nucleophilic aromatic substitution is carried out by reacting a suitable amine ZR 4 (Wherein, Z and R 4has the meaning given for general formula I and is carried out in the presence of a base as N,N-diisopropylethylamine (DIEA) or trimethylamine, which is commonly known and / or commercially available to those skilled in the art. Usually, 1,4-dioxane was used as the solvent, but solvents such as dimethylsulfoxide (DMSO) or N-methyl-2-pyrrolidine (NMP) are also suitable. Other methods similar to the Buchwald-Hartwig amination can be used. The left side is added to a compound of general formula (IV) and a Suzuki cross-coupling is used according to standard conditions well known to those skilled in the art in the presence of a palladium catalyst and a boronic acid or a boronic acid pinacol ester, e.g. 4 or 4b, to form a compound of formula (V). In the final step, the methyl ether group is converted to a methyl ether group by the addition of boron tribromide (BBr) in dichloromethane. 3 ) to deliver the compound of general formula I. Specific examples of each of the exemplified compounds are described in more detail below.

[0120] Scheme 2 [ka]

[0121] X is NH 2 The building blocks of formula (II) were also prepared by a Sandmeyer type reaction to give building blocks (III) where X=Cl. Specific examples are given below for each exemplified compound.

[0122] In addition, Amine ZR 4 and R 4 contained, for example, a tert-butyloxycarbonyl (BOC) protecting group, an additional deprotection step was performed using TFA (trifluoroacetic acid) either at an early stage as described for Example 1 or at a final stage during the methyl ether cleavage.

[0123] Scheme 3 [ka]

[0124] The synthesis of the compound of formula Ib of the present invention is synthesized according to the general synthesis shown in Scheme 3, where R' can be H or a protecting group known to those skilled in the art, such as SEM, benzyl, or any other suitable protecting group for phenol. When R'=H, Va is equal to Ib.

[0125] The present invention therefore relates to the compounds according to the invention when prepared according to the process of the invention.

[0126] One embodiment of the present invention is the reaction of a compound of formula IV to a compound of formula V, in the presence of a palladium catalyst and a boronic acid or a boronic acid pinacol ester, 1 , R 2 , R 3 , R 4 and Z is as defined above. [ka]

[0127] One embodiment of the present invention is a process for preparing a compound of formula I as defined above, comprising reacting a compound of II to give a compound of III. [ka]

[0128] One embodiment of the present invention involves the reaction of a compound of formula IV to a compound of formula Va, in the presence of a palladium catalyst and a boronic acid or a boronic acid pinacol ester, 1 , R 2 , R 3 , R 4 , R 5 and Z is as defined above), to prepare a compound of formula Ib as defined above. [ka]

[0129] One embodiment of the present invention is a process for preparing a compound of formula Ib as defined above, comprising reacting a compound of II to give a compound of III. [ka]

[0130] Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing the compounds of the present invention and therapeutically inert carriers, diluents or excipients, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, the compounds of formula Ib can be formulated into galenic dosage forms by mixing at ambient temperature, at an appropriate pH, and at the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration employed. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compounds of formula Ib are formulated in acetate buffer at pH 5. In another embodiment, the compounds of formula Ib are sterile. The compounds can be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

[0131] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to physicians.

[0132] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural, and intranasal, and, where localized treatment is desired, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0133] The compounds of the present invention may be administered in any convenient dosage form, such as, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents and additional active agents.

[0134] Typical formulation is prepared by mixing the compound of the present invention and carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams&Wilkins,2004;Gennaro, Alfonso R., et al.Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams&Wilkins,2000;and Rowe, Raymond C.Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press,2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide proper presentation of the drug (i.e., a compound of the invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0135] The compound of formula Ib and its pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injection solutions or topical preparations.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

[0136] The compound of formula I and its pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injection solutions or topical preparations.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

[0137] Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid substances, and liquid polyols.

[0138] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugars, glucose etc.

[0139] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.

[0140] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols etc.

[0141] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrin, mannitol or many other carriers and excipients known in the art.

[0142] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents, or antioxidants. They may also contain still other therapeutically valuable substances.

[0143] The dosage may vary widely and may of course be adapted to the individual requirements in each particular case. In general, for oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g. about 300 mg per person), preferably divided into 1 to 3 individual administrations, which may, if appropriate, consist of, for example, equal amounts. For topical administration, the formulation may contain 0.001% to 15% by weight of the medicament, and the required dosage, which may be between 0.1 and 25 mg, may be administered either by a single administration per day or per week, by multiple administrations (2 to 4 times) per day, or by multiple administrations per week. However, it will be clear that the upper or lower limits given herein may be exceeded, where this is indicated.

[0144] One embodiment of the present invention is a compound according to formula Ib as described herein for use as a therapeutically active substance.

[0145] One embodiment of the present invention is a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein said disease, disorder or condition is responsive to NLRP3 inhibition.

[0146] One embodiment of the present invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition, wherein said disorder or condition is responsive to NLRP3 inhibition.

[0147] One embodiment of the present invention is a compound according to formula I as described herein for use as a therapeutically active substance.

[0148] One embodiment of the present invention is a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein said disease, disorder or condition is responsive to NLRP3 inhibition.

[0149] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition, wherein said disorder or condition is responsive to NLRP3 inhibition.

[0150] As used herein, the term "NLRP3 inhibition" refers to a complete or partial reduction in the activity level of NLRP3, including, for example, inhibition of active NLRP3 and / or inhibition of activation of NLRP3.

[0151] There is evidence for a role for NLRP3-induced IL-1 and IL-18 in the inflammatory responses associated with or resulting from a number of different disorders (Menu et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

[0152] In one embodiment, the disease, disorder or condition is selected from the following: (i) Inflammation; (ii) autoimmune diseases; (iii) Cancer (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) Lymphatic symptoms; (xiv) psychological disorders; (xv) graft-versus-host disease; (xvi) allodynia; (xvii) diabetes-related conditions; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0153] In another embodiment, the disease, disorder or condition is selected from the following: (i) Cancer (ii) infectious diseases; (iii) central nervous system disorders; (iv) cardiovascular disease; (v) liver disease; (vi) eye disease; or (vii) Skin diseases.

[0154] In a further exemplary embodiment of the invention, the disease, disorder or condition is inflammation. Examples of inflammation that may be treated or prevented include inflammatory responses associated with or resulting from: (i) Skin conditions such as contact sensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (ii) 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 conditions such as polymyositis or myasthenia gravis; (iv) gastrointestinal conditions such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), colitis, gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may have effects remote from the gut (e.g. migraine, rhinitis or eczema); (v) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust-induced asthma, especially chronic or refractory asthma, e.g. late stage asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, panlentic rhinitis, dry rhinitis, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis, e.g. hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, volcanic ash-induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (vi) vascular conditions such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (vii) autoimmune conditions such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes mellitus, idiopathic thrombocytopenic purpura, or Graves' disease; (viii) ocular conditions such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (ix) neurological conditions such as multiple sclerosis or encephalomyelitis; (x) an infection or infection-related condition such as acquired immune deficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, hemorrhagic dengue fever, leishmaniasis, streptococcal myositis, Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis / epidimitis, Legionnaires' disease, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (xi) renal conditions such as mesangial proliferative glomerulonephritis, renal syndrome, nephritis, glomerulonephritis, obesity-related glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritic syndrome, renal fibrosis including chronic crystal nephropathy, or renal hypertension; (xii) Lymphatic conditions such as Castleman's disease; (xiii) conditions of or involving the immune system, such as hyper-IgE syndrome, hepatoblastomatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (xiv) hepatic conditions such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcohol-induced hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, hepatic fibrosis, or liver failure; (xv) Cancer, including those listed above; (xvi) burns, wounds, trauma, hemorrhage or stroke; (xvii) radiation exposure; (xviii) metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or (xix) Pain such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.

[0155] One embodiment of the present invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) Lymphatic symptoms; (xiv) psychological disorders; (xv) graft-versus-host disease; (xvi) allodynia; (xvii) diabetes-related conditions; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0156] One embodiment of the present invention is the use of a compound according to formula Ib as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

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

[0158] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

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

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

[0161] One embodiment of the present invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0162] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0163] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0164] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0165] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to formula Ib as described herein.

[0166] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD, comprising administering an effective amount of a compound according to formula Ib as described herein.

[0167] One embodiment of the present invention is a method of treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), comprising administering an effective amount of a compound according to formula Ib as described herein.

[0168] One embodiment of the present invention relates to a method of inhibiting NLRP3 comprising administering an effective amount of a compound according to formula Ib described herein.

[0169] A compound of formula Ib as described herein when prepared according to any one of the processes described is also an embodiment of the present invention.

[0170] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to formula Ib described herein and a therapeutically inert carrier.

[0171] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) Lymphatic symptoms; (xiv) psychological disorders; (xv) graft-versus-host disease; (xvi) allodynia; (xvii) diabetes-related conditions; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0172] One embodiment of the present invention is the use of a compound according to formula I as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0173] One embodiment of the present invention is the use of a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0174] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0175] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0176] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0177] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0178] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to formula I as described herein.

[0179] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD, comprising administering an effective amount of a compound according to formula I as described herein.

[0180] One embodiment of the present invention relates to a method of inhibiting NLRP3, comprising administering an effective amount of a compound according to formula I described herein.

[0181] A compound of formula I as described herein when prepared according to any one of the processes described is also an embodiment of the present invention.

[0182] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to Formula I described herein and a therapeutically inert carrier.

[0183] Assay procedure NLRP3 and pyroptosis It is well established that activation of NLRP3 leads to cell pyroptosis, a hallmark that plays a key role in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016,59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Thus, inhibitors of NLRP3 are expected to block pyroptosis as well as the release of proinflammatory cytokines (e.g., IL-1β) from cells.

[0184] THP-1 cells: culture and preparation THP-1 cells (ATCC no. TIB-202) were grown in RPMI containing L-glutamine (Gibco no. 11835) supplemented with 1 mM sodium pyruvate (Sigma no. S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma no. P4333) in 10% fetal bovine serum (FBS) (Sigma no. F0804). Cells were passaged periodically and cultured until confluent (approximately 10 6The THP-1 cells were grown to a concentration of 625,000 cells / ml. On the day of the experiment, the THP-1 cells were harvested and resuspended in RPMI medium (without FBS). The cells were then counted and viability (>90%) was confirmed by trypan blue (Sigma #T8154). Appropriate dilutions were made to obtain a concentration of 625,000 cells / ml. LPS (Sigma #L4524) was added to this diluted cell solution to obtain a final assay concentration (FAC) of 1 μg / ml. 40 μl of the final preparation was dispensed into each well of a 96-well plate. The plates thus prepared were used for compound screening.

[0185] THP-1 cell pyroptosis assay For compound screening, the following method stepwise assay was followed. 1. Seed THP-1 cells (25,000 cells / well) in 40 μl of RPMI medium (without FBS) containing 1.0 μg / ml LPS in 96-well poly-D-lysine (VWR #734-0317) coated black-walled clear-bottom cell culture plates. 2. Add 5 μl of compound (8-point half-log dilutions with the highest dose at 10 μM) or vehicle (DMSO 0.1% FAC) to appropriate wells. 3. 37℃, 5% CO 2 Incubate for 3 hours at 4°C. 4. Add 5 μl of Nigericin (Sigma No. N7143) (FAC 5 μM) to all wells 5. 37℃, 5% CO 2 Incubate for 1 hour at 4°C. 6. At the end of the incubation period, spin the plate at 300xg for 3 minutes and remove the supernatant. 7. 50 μl of Resazurin (Sigma #R7017) (FAC 100 μM Resazurin in RPMI medium without FBS) is then added and the plate is incubated at 37° C. and 5% CO 2 and incubate for an additional 1-2 hours. 8. Plates were read on an Envision reader at Ex 560nm and Em 590nm. 9. IC50 Fit the data to a nonlinear regression equation (4-parameter log inhibitor vs. response variable slope)

[0186] The results of the pyroptosis assay were analyzed using THP IC 50 These are summarized in Table 1 below.

[0187] Human whole blood IL-1β release assay For systemic delivery, the ability of a compound to inhibit NLRP3 when present in the bloodstream is of great importance. For this reason, we investigated the NLRP3 inhibitory activity of a number of compounds in human whole blood according to the following protocol.

[0188] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor pool. 1. Plate out 80 μl of whole blood containing 1 μg / ml LPS into a 96-well flat-bottom cell culture plate (Corning #3585). 2. Add 10 μl of compound (8-point half log dilutions at the top dose of 10 μM) or vehicle (DMSO 0.1% FAC) to appropriate wells. 3. 37℃, 5% CO 2 Incubate for 3 hours at 4°C. 4. Add 10 μl of Nigericin (Sigma #N7143) (10 μM FAC) to all wells. 5. 37℃, 5% CO 2 Incubate for 1 hour at 4°C. 6. At the end of the incubation period, spin the plates at 300×g for 5 minutes to pellet the cells and remove 20 μl of supernatant and add to a 96-well v-bottom plate for IL-1β analysis (Note: these plates containing supernatants can be stored at -80° C. for analysis at a later date). 7. IL-1β was measured according to the manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000). 8. IC 50 Fit the data to a nonlinear regression equation (4-parameter log inhibitor vs. response variable slope)

[0189] Human whole blood assay results HWB IC 50 These are summarized in Table 1 below.

[0190] hERG Screening Assay cell

[0191] CHO-crelox hERG cell line (ATCC reference number PTA-6812, female Chinese hamster cells) was generated and validated at Roche. Ready-to-use frozen instant CHO-hERG cells were cryopreserved at Evotec (Germany) and used directly in the experiments.

[0192] Experimental solution The extracellular solution contained (in mM): NaCl 150; KCl 4; CaCl 2 1;MgCl 2 The internal solution contained (in mM): KCl, 10; KF, 100; NaCl, 10; HEPES, 10; EGTA, 20; pH = 7.0-7.4 with KOH, osmolarity 260-300 mOsm.

[0193] Electrophysiology The effects of compounds on hERG K+-current parameters will be evaluated at two concentrations in at least quadruplicate cells.

[0194] hERG studies are performed using the automated patch clamp system SynchroPatch® 384 (Nanion Technologies GmbH, Germany). K+ currents are measured using the patch voltage clamp technique in the whole-cell configuration at 35-37°C.

[0195] Cells were held at a resting voltage of -80 mV and stimulated with the voltage pattern shown in Figure 1 to activate hERG channels and conduct outward IKhERG currents at a stimulation frequency of 0.1 Hz (6 bpm).

[0196] Data analysis The IKhERG amplitude was recorded at each drug concentration and compared to vehicle control values ​​(set at 100%) to define fractional blocks. Concentration-response data were fitted with the following relationship: [Table 1]

[0197] Concentration-response curves were fitted by nonlinear regression analysis using the EworkBook suite (ID Business Solutions Ltd, UK). Data fitting was performed using a four-parameter logistic model (fit=(A+(B / (1+((x / C)^D)))), where A=0 and B=100). [Table 2] TIFF2024522494000014.tif215169 TIFF2024522494000015.tif250169 TIFF2024522494000016.tif250169 TIFF2024522494000017.tif202169 TIFF2024522494000018.tif233169 TIFF2024522494000019.tif171169 [Table 3]

[0198] The invention will now be illustrated by the following examples, which have no limiting character.

[0199] Where preparations are obtained as mixtures of enantiomers, the pure enantiomers may be obtained by methods described herein or known to those skilled in the art, such as chiral chromatography or crystallization.

[0200] Experimental Method Abbreviation: [Table 4]

[0201] Analysis method NMR spectra were run on a Bruker 400 MHz spectrometer using an ICON-NMR under TopSpin program control. Spectra were measured at 298 K and referenced to the solvent resonance unless otherwise stated.

[0202] LC-MS method: SHIMADZU LCMS-2020, Agilent 1200 LC / G1956A MSD and Agilent 1200\G6110A, Agilent 1200 LC&Agilent 6110 MSD. Mobile phase: A: 0.025% NH3·H2O in water (v / v); B: acetonitrile. Column: Kinetex EVO C18 2.1×30mm, 5μm.

[0203] Purification method (Step E) 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:75 * 30mm * 3um pH (water (0.1% TFA)-ACN): 3-4 Average particle size: 3μm Prior to use, the column was conditioned with 100% MeCN (2 min) followed by 1% MeCN (0.8 min). Flow rate = 25 mL / min.

[0204] Separation operation: [Table 5]

[0205] Purification method (Step F) 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:75 * 30mm * 3um pH (water (0.1% TFA)-ACN): 3-4 Average particle size: 3μm Prior to use, the column was conditioned with 100% MeCN (2 min) followed by 1% MeCN (0.8 min). Flow rate = 25 mL / min.

[0206] Separation operation: [Table 6] Detection wavelengths: 220 and 254 nm. Before each new run, the cartridge was cleaned using the conditioning method. [Brief description of the drawings]

[0207] [Figure 1] Pulse pattern used to elicit outward K+ currents at 35–37°C. EXAMPLES

[0208] Unless otherwise stated, all examples and intermediates were prepared under a nitrogen atmosphere.

[0209] Example 1: 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]-3-methyl-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid [ka]

[0210] Step A: 6-Bromo-3-chloro-1,2,4-triazine [ka]

[0211] To a solution of 6-bromo-1,2,4-triazin-3-amine (5.0 g, 29 mmol, 1 equiv.) in ACN (100 mL) was added tert-butyl nitrite (4.7 g, 46 mmol, 1.6 equiv.) and CuCl (3.7 g, 37 mmol, 1.3 equiv.). The mixture was stirred at 70 °C for 2 h. The residue was concentrated in vacuo and purified by column chromatography (PE:EtOAc = 1:0 to 10:1) to give the title compound (1.6 g, 29% yield) as a yellow oil.

[0212] Step B: (R)-tert-Butyl 3-((6-bromo-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate [ka]

[0213] To a solution of tert-butyl (3R)-3-aminopiperidine-1-carboxylate (620 mg, 3.1 mmol, 1.2 equiv.) in DMSO (5 mL) was added DIEA (1.0 mL, 5.7 mmol, 2.2 equiv.) and 6-bromo-3-chloro-1,2,4-triazine (500 mg, 2.6 mmol, 1 equiv.). The mixture was stirred at 20° C. for 2 h. The mixture was poured into water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was analyzed by preparative TLC (SiO 2 , PE / EtOAc=5 / 1) to give the title compound (590 mg, 64% yield) as a yellow solid. LCMS: m / z 304.0, [MC 4 H 9 +2+H]+,ESI pos.

[0214] Step C: 6-Bromo-N-[(3R)-3-piperidyl]-1,2,4-triazin-3-amine; 2,2,2-trifluoroacetic acid [ka]

[0215] tert-Butyl (3R)-3-[(6-bromo-1,2,4-triazin-3-yl)amino]piperidine-1-carboxylate (490 mg, 1.4 mmol, 1 equiv.) in CH 2 Cl 2 To a solution of (4 mL) was added TFA (1.0 mL). The mixture was stirred at 20° C. for 2 h. The reaction was concentrated under reduced pressure to give the title compound as a yellow gum (TFA salt, 500 mg). LCMS: m / z 258.0 [M+H] + ,ESI pos.

[0216] Step D: 6-Bromo-N-[(3R)-1-ethyl-3-piperidyl]-1,2,4-triazin-3-amine [ka]

[0217] A solution of 6-bromo-N-[(3R)-3-piperidyl]-1,2,4-triazin-3-amine in ACN (1 mL) containing 2,2,2-trifluoroacetic acid (100 mg, 0.3 mmol, 1 equiv.) was added to K 2 CO 3 (74 mg, 0.5 mmol, 2 equiv.) and ethyl bromide (0.02 mL, 0.3 mmol, 1.1 equiv.) were added. The reaction mixture was stirred at 20° C. for 16 h. Water (1 mL) was then added to the mixture and purified by reverse phase flash (0.1% TFA aqueous-ACN condition) to give the title compound (20 mg, 25% yield) as a yellow solid. LCMS: m / z 286.0 [M+H] + ,ESI pos.

[0218] Step E: N-[(3R)-1-ethyl-3-piperidyl]-6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1,2,4-triazin-3-amine; 2,2,2-trifluoroacetic acid [ka]

[0219] 2-[2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (320 mg, 1.0 mmol, 1.6 equiv.), 6-bromo-N-[(3R)-1-ethyl-3-piperidyl]-1,2,4-triazin-3-amine; 2,2,2-trifluoroacetic acid (250 mg, 0.6 mmol, 1 equiv.) and K in 1,4-dioxane (5 mL) and water (1 mL). 2 CO 3 A mixture of (463 mg, 4.4 mmol, 7 equiv.) was degassed and purged with nitrogen three times and treated with Pd(dppf)Cl 2 (153 mg, 0.2 mmol, 0.3 equiv) was added to the mixture. The mixture was stirred at 100° C. for 12 h. Then, water (1 mL) was added to the mixture. The residue was purified by reverse phase flash (0.1% TFA condition) twice and preparative HPLC (Method: Column 3_Phenomenex Luna C 18 75 * 30mm * 3um; Conditions: water (0.1% TFA)-ACN; Start B 28 End B 48; Gradient time (min): 7; 100% B; Hold time (min): 2; Flow rate (ml / min): 25) to give the title compound as a yellow solid (TFA salt, 12 mg, 4% yield). LCMS: m / z 396.3 [M+H] + ,ESI pos.

[0220] Step F: 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]-3-methyl-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid [ka]

[0221] N-[(3R)-1-Ethyl-3-piperidyl]-6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1,2,4-triazin-3-amine; CH 2 Cl 2 (1 mL) of solution of BBr 3 (0.07 mL, 0.8 mmol, 10 equiv.) was added at -70 °C. The mixture was stirred at 20 °C for 1 h. Then ice water (1 mL) was added to the mixture and NH 3 H 2 The pH was adjusted to approximately pH 8 with 2024 and the mixture was lyophilized. The residue was purified by preparative HPLC (column 3_Phenomenex Luna C 18 75 * 30mm * Purification by 3 μm; Conditions: water (0.1% TFA)-ACN; Start B 23 End B 43; Gradient time (min): 7; 100% B; Hold time (min): 2; Flow rate (mL / min): 25) afforded the title compound as a yellow solid (TFA salt, 25 mg, 63% yield). LCMS: m / z 382.2 [M+H] + ,ESI pos.

[0222] Example 2: 5-Chloro-2-[3-[(1-ethyl-3-piperidyl)amino]-5-methyl-1,2,4-triazin-6-yl]phenol (rac) [ka]

[0223] Step A: 6-chloro-N-(1-ethyl-3-piperidyl)-5-methyl-1,2,4-triazin-3-amine

[0224] To a mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (CAS no. 132434-82-3, 150 mg, 0.915 mmol, 1.0 equiv.) and 1-ethylpiperidin-3-amine (CAS no. 6789-94-2, 196 μL, 1.37 mmol, 1.5 equiv.) in 1,4-dioxane (3 mL) was added DIEA (160 μL, 1.37 mmol, 1.03 equiv.). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine. The aqueous layer was back-extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, EtOAc isocratic) to give the title compound (221 mg, traces of dichloromethane) as a pale yellow solid. m / z 256.1[M+H] + ,ESI pos.

[0225] Step B: 6-chloro-N-(1-ethyl-3-piperidyl)-5-methyl-1,2,4-triazin-3-amine (rac) [ka]

[0226] A mixture of the above 6-chloro-N-(1-ethyl-3-piperidyl)-5-methyl-1,2,4-triazin-3-amine (40 mg, 0.156 mmol, 1.0 equiv.), (4-chloro-2-hydroxy-phenyl)boronic acid (CAS number 1238196-66-1, 45.7 mg, 0.265 mmol, 1.7 equiv.), potassium carbonate (103 mg, 0.747 mmol, 4.8 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (14.8 mg, 0.018 mmol, 0.116 equiv.) in 1,4-dioxane (0.9 mL) and water (0.5 mL) was flushed with argon and stirred at 90° C. for 4 h. The reaction mixture was cooled to room temperature and extracted with EtOAc and water. The aqueous layer was back-extracted with EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered through a pad of Celite, and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Gemini NX, 12 nm, 5 μm, 100×30 mm; conditions: ACN / water+0.1% TEA; APS run time 15 min, gradient 20-40-55-100 ACN in water) to give the title compound (19.9 mg, 33% yield) as a grey solid. m / z 348.3 [M+H] + ,ESI pos.

[0227] Example 3: 2-[3-[(3-hydroxy-3-methyl-cyclobutyl)amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0228] Step A: 3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-1-methyl-cyclobutanol

[0229] As in Example 3: To a mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (CAS number 132434-82-3, 200 mg, 1.22 mmol, 1.0 equiv.) and 3-amino-1-methyl-cyclobutanol hydrochloride (CAS number 1820687-11-3, 251.7 mg, 1.83 mmol, 1.5 equiv.) in 1,4-dioxane (4 mL), DIEA (639 μL, 3.66 mmol, 3 equiv.) was added. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was extracted with EtOAc and water. The organic layer was washed with brine. The aqueous layer was back-extracted four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product (317 mg) was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, n-heptane / EtOAc, EtOAc gradient 0-80%) to give the title compound (159.4 mg, 90% purity) as a yellow solid. m / z 229.1 [M+H] + ,ESI pos.

[0230] Step B: 3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-1-methyl-cyclobutanol [ka]

[0231] A mixture of the above 3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-1-methyl-cyclobutanol (80 mg, 0.315 mmol, 1.0 equiv.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS number 1072951-50-8, 109.9 mg, 0.534 mmol, 1.7 equiv.) boronic acid, potassium carbonate (207.9 mg, 1.50 mmol, 4.8 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (29.7 mg, 0.036 mmol, 0.116 equiv.) in 1,4-dioxane (1.9 mL) and water (0.9 mL) was flushed with argon and stirred at 90° C. for 16 h. The reaction mixture was cooled to room temperature and extracted with EtOAc. The aqueous layer was back-extracted with EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered through a pad of Celite, and concentrated in vacuo. The crude product (297 mg) was purified by preparative HPLC (column: column achiral 100 PEI, 5 μm, 250×20 mm; conditions: 35% MeOH; SFC) to give the title compound (98.9 mg, 78% yield) as a grey solid. m / z 355.2 [M+H] + ,ESI pos.

[0232] Example 4: 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0233] Step A: 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine [ka]

[0234] To a mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (CAS no. 132434-82-3, 1.00 g, 6.1 mmol, 1.0 equiv.) and [(3R)-1-ethyl-3-piperidyl]amine (CAS no. 1020396-26-2, 1.24 g, 9.15 mmol, 1.5 equiv.) amine in 1,4-dioxane (20 mL) was added N,N-diisopropylethylamine (814 mg, 1.1 mL, 6.3 mmol, 1.03 equiv.). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was Extracted with dichloromethane and water. The organic layer was washed with brine. The aqueous layer was back-extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (1.32 g, 80% yield) as a green solid. m / z 256.3 [M+H]+, ESI pos.

[0235] Step B: 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0236] A mixture of the above 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine (Example 4, Step A) (280 mg, 1.04 mmol, 1.0 equiv.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS number 1072951-50-8, 365 mg, 1.77 mmol, 1.7 equiv.) boronic acid, potassium carbonate (690 mg, 4.99 mmol, 4.8 equiv.) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (98 mg, 0.120 mmol, 0.115 equiv.) in 1,4-dioxane (6 mL) and water (3 mL) was flushed with argon and stirred at 85° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with EtOAc and half-saturated NH 4 The mixture was extracted with aqueous Cl. The aqueous layer was back-extracted with EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 10% methanol in dichloromethane). The residue was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 100% (dichloromethane:methanol:NH 4 OH 9:1:0.05). All fractions containing the product were combined and concentrated in vacuo. The residue was triturated with EtOAc / heptane to give the title compound (246 mg, 61% yield) as an off-white powder. m / z 382.3[M+H]+,ESI pos.

[0237] Example 5: 5-Chloro-2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]phenol [ka]

[0238] A mixture of 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine (Example 4, Step A) (280 mg, 1.04 mmol, 1 equiv.), (4-chloro-2-hydroxyphenyl)boronic acid (CAS number 1238196-66-1, 305 mg, 1.77 mmol, 1.7 equiv.), potassium carbonate (690 mg, 4.99 mmol, 4.8 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (98 mg, 0.120 mmol, 0.115 equiv.) in 1,4-dioxane (6 mL) and water (3 mL) was flushed with argon and stirred overnight at 85° C. The reaction mixture was cooled to room temperature and diluted with EtOAc and half-saturated NH 4 The mixture was extracted with aqueous Cl. The aqueous layer was back-extracted with EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 10% methanol in dichloromethane). The residue was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 60% (dichloromethane:methanol:NH 4 OH 9:1:0.05). All fractions containing the product were combined and concentrated in vacuo. The residue was triturated with EtOAc / heptane to give the title compound (204 mg, 55% yield) as an off-white powder. m / z 348.3[M+H]+, ESI pos

[0239] Example 6: 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-fluoro-phenol [ka]

[0240] 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine as described above (Example 4, Step A)-5-methyl-1,2,4-triazin-3-amine (80 mg, 0.313 mmol, 1 equiv.), (4-fluoro-2-hydroxyphenyl)boronic acid (CAS no. 111-134-1) in 1,4-dioxane (1.8 mL) and water (0.900 mL). A mixture of No. 850568-00-2, 85 mg, 0.545 mmol, 1.74 equiv), potassium carbonate (205 mg, 1.48 mmol, 4.74 equiv) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (29 mg, 0.036 mmol, 0.114 equiv) was flushed with argon and stirred at 90°C for 2 h. The reaction mixture was cooled to room temperature and extracted with EtOAc and water. The aqueous layer was back extracted with EtOAc. The organic layer was washed twice with water and once with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% (methanol in dichloromethane) to give the title compound (50 mg, 46% yield) as a brown solid. m / z 332.3 [M+H]+, ESI pos

[0241] Example 7: 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol [ka]

[0242] Step A: 5-Bromo-2,3-dihydrobenzofuran-4-ol

[0243] To a solution of 2,3-dihydrobenzofuran-4-ol (CAS number 144822-82-2, 2.00 g, 14.7 mmol, 1 equiv.) in methanol (40 mL) was added pyridine tribromide (4.70 g, 14.7 mmol, 1 equiv.) at -40°C. The resulting mixture was stirred at -40°C for 0.5 h, then warmed to 20°C and stirred for 16 h. After completion of the reaction, the reaction mixture was dissolved in EtOAc (100 mL). The organic layer was washed with 1N hydrochloric acid (100 mL x 2), followed by brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , PE:EtOAc=15:1 to 10:1) to give the title compound (1.90 g, 60% yield) as a yellow solid. LCMS: m / z 212.8 [MH] - ,ESI neg.

[0244] Step B: 2-[(5-bromo-2,3-dihydrobenzofuran-4-yl)oxymethoxy]ethyl-trimethylsilane

[0245] To a solution of 5-bromo-2,3-dihydrobenzofuran-4-ol (Example 7, Step A) (1.00 g, 4.65 mmol, 1.0 equiv) in ACN (20 mL) was added K 2 CO 3 (1.29 g, 9.3 mmol, 2.0 equiv.) was added. The mixture was stirred at 20° C. for 0.5 h, and 2-(trimethylsilyl)ethoxymethyl chloride (0.99 mL, 5.58 mmol, 1.2 equiv.) was added dropwise to the mixture. The mixture was stirred at 20° C. for 2 h. TLC (PE:EtOAc=10:1) showed that the starting material was consumed and another major spot was formed. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL×3). The organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , PE:EtOAc=20:1 to 15:1) to give the title compound (1.30 g, 81% yield) as a yellow oil. 1H NMR (400MHz, DMSO-d 6 )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).

[0246] Step C: Trimethyl-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl]oxymethoxy]ethyl]silane

[0247] To a solution of 2-[(5-bromo-2,3-dihydrobenzofuran-4-yl)oxymethoxy]ethyl-trimethylsilane (1.20 g, 3.48 mmol, 1.0 equiv.) in isopropyl acetate (20 mL) was added bis(pinacolato)diboron (1.06 g, 4.17 mmol, 1.2 equiv.), anhydrous AcOK (0.75 g, 7.65 mmol, 2.2 equiv.), Xphos (166 mg, 0.350 mmol, 0.100 equiv.) and XPhos Pd G3 (295 mg, 0.350 mmol, 0.100 equiv.). The mixture was stirred at 40° C. for 2 h at 37° C. for 1 h at 37° C. for 2 h at 37° C. 2 Degas three times with N 2 The mixture was stirred at 80° C. for 12 h under reduced pressure. TLC (PE:EtOAc=20:1) showed that the starting material was consumed and one new spot was detected. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL×3). The organic phase was washed with brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was first purified by column chromatography (SiO2, PE:EtOAc=80:1-50:1) followed by reverse phase flash (CombiFlash 0.1% NH 3 .H 2 Purification by HCl (aqueous ACN) followed by lyophilization afforded the title compound (288.3 mg, 20% yield) as a colorless oil. LCMS: m / z 393.1 [M+H] + ,ESI pos.

[0248] Step D: N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-6-[4-(2-trimethylsilylethoxymethoxy)-2,3-dihydrobenzofuran-5-yl]-1,2,4-triazin-3-amine

[0249] The above 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine (Example 4, Step A) (25 mg, 0.098 mmol, 1.0 equiv.), trimethyl-[2-[[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl]oxymethoxy]ethane in 1,4-dioxane (1 mL) and water (0.5 mL). A mixture of [ethyl]silane (53.7 mg, 0.137 mmol, 1.4 equiv.), potassium carbonate (60.8 mg, 0.440 mmol, 4.5 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (CAS no. 95464-05-4, 9.58 mg, 0.012 mmol, 0.120 equiv.) was flushed with argon and stirred at 90° C. for 6 h and at 23° C. for 10 h. The reaction mixture was cooled to room temperature, quenched with water (10 mL) and saturated aqueous NH4Cl (10 mL), then extracted with dichloromethane (2×40 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was obtained as a brown oil (85 mg, 70% pure) and used directly in the next step without further purification. LCMS: m / z 486.4[M+H] + ,ESI pos.

[0250] Step E: 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol

[0251] To a solution of N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-6-[4-(2-trimethylsilylethoxymethoxy)-2,3-dihydrobenzofuran-5-yl]-1,2,4-triazin-3-amine (85 mg, 0.123 mmol, 1 equiv.) in dichloromethane, extra dry (5 mL) and methanol (1 mL) was added 4M HCl in dioxane (123 μL, 0.49 mmol, 4 equiv.) at room temperature. The mixture was stirred at 23° C. for 2 hours. After completion of the reaction, the mixture was washed with dichloromethane (20 mL), ice water (20 mL) and saturated NaHCO 3 (20 mL). It was then extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated in vacuo. The crude brown material was purified using RP HPLC (column: Gemini NX, 12 nm, 5 μm, 100×30 mm, acetonitrile / water+0.1 triethylamine) to give the title compound (12 mg, 27%) as a pale yellow amorphous lyophilized solid. LCMS: m / z 356.3 [M+H] + ,ESI pos.

[0252] Example 8: 3-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol [ka]

[0253] Step A: 2-[(3-bromo-2-bicyclo[4.2.0]octa-1,3,5trienyl)oxymethoxy]ethyl-trimethyl-silane

[0254] To a solution of 3-bromobicyclo[4.2.0]octa-1,3,5trien-2-ol (WO2021150574, 195 mg, 0.98 mmol, 1.0 equiv.) in DMF (5 mL) was added potassium carbonate (302 mg, 2.19 mmol, 2.20 equiv.) at room temperature. The resulting mixture was sonicated, then 2-(trimethylsilyl)ethoxymethyl chloride (200 μL, 1.13 mmol, 1.15 equiv.) was added and the reaction mixture was stirred at room temperature for 16 h. Potassium carbonate (140 mg, 1.01 mmol, 1.03 equiv.) was then added, followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.1 mL, 0.570 mmol, 0.58 equiv.) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and 50v% brine (100 mL) and the separated aqueous layer was further extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 50v% brine (100 mL), dried (MgSO4), filtered and concentrated. The crude reaction mixture was purified by column chromatography on silica gel (40 g, 0-20% MTBE:isohexane) to afford the title compound (345.0 mg, 100% yield) as a colorless oil. 1 H NMR(500MHz,DMSO)δ 7.39(d,1H),6.67(d,1H),5.27(s,2H),3.72(dd,2H),3.28(dd,2H),3.05(dd,2H),0.91-0.85(m,2H),-0.05(s,9H).LCMS No ionization.

[0255] Step B: Trimethyl-[2-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-bicyclo[4.2.0]octa-1,3,5trienyl]oxymethoxy]ethyl]silane

[0256] 2-[(3-Bromo-2-bicyclo[4.2.0]octa-1,3,5trienyl)oxymethoxy]ethyl-trimethyl-silane (103.0 mg, 0.270 mmol, 1 equiv.), bis(pinacolato)diboron (81.0 mg, 0.320 mmol, 1.2 equiv.) and potassium acetate (111.0 mg, 1.13 mmol, 4.25 equiv.) in isopropyl acetate (8 mL) were sparged (nitrogen was bubbled through for 10 min while sonicating). XPhos Pd G3 (46.0 mg, 0.05 mmol, 0.05 equiv.) and XPhos (11.0 mg, 0.02 mmol, 0.02 equiv.) were added and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated and the resulting residue was purified by silica gel chromatography (40 g, 0-20% MTBE:isohexane) to afford the title compound (199 mg, 41% yield) as a pale yellow oil. 1 H NMR (500 MHz, CDCl 3 ) δ 7.57(d,1H), 6.71(d,1H), 5.25(s,2H), 3.81-3.71(m,2H), 3.30(dd,2H), 3.18-3.05(m,2H), 1.33(s,12H), 0.97-0.92(m,2H), -0.03(s,9H). LCMS no ionization.

[0257] Step C: N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-6-[2-(2-trimethylsilylethoxymethoxy)-3-bicyclo[4.2.0]octa-1(6),2,4-trienyl]-1,2,4-triazin-3-amine A mixture of the above 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine (Example 4, Step A) (53 mg, 0.197 mmol, 1.0 equiv.), trimethyl-[2-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-bicyclo[4.2.0]octa-1(6),2,4-trienyl]oxymethoxy]ethyl]silane (Example 4, Step B) (103.74 mg, 0.276 mmol, 1.4 equiv.), potassium carbonate (122.4 mg, 0.886 mmol, 4.5 equiv.) in 1,4-dioxane (2.52 mL) and water (1.26 mL). The mixture was flushed with argon and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (CAS number 95464-05-4, 24.1 mg, 0.030 mmol, 0.120 equiv.) was flushed again with argon. The resulting mixture was stirred at 90° C. for 5 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL) and saturated NH 4 The mixture was quenched with aqueous Cl (10 mL) and then extracted with dichloromethane (2×40 mL). The combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated in vacuo. The crude product (200 mg) was purified by flash chromatography (SiO 2 , 12 g, heptane:EtOAc=0-50% EtOAc, followed by EtOAc:MeOH=9:1) to give the title compound (75 mg, 78%) as a light brown oil. LCMS: m / z 470.7 [M+H] + ,ESI pos.

[0258] Step D: 3-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol

[0259] To a solution of N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-6-[4-(2-trimethylsilylethoxymethoxy)-2,3-dihydrobenzofuran-5-yl]-1,2,4-triazin-3-amine (75 mg, 0.160 mmol, 1 equiv.) in dichloromethane (4 mL) and methanol (1 mL) was added 4M HCl in dioxane (399.2 μL, 1.60 mmol, 10 equiv.) at room temperature. The mixture was stirred at 23° C. for 16 h. After completion of the reaction, the mixture was washed with dichloromethane (20 mL), ice water (20 mL) and saturated NaHCO 3 (20 mL). The combined organic extracts were diluted with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated in vacuo. The crude material (77 mg) was purified by RP HPLC (column: YMC-triart C 18 , 12 nm, 5 μm, 100×30 mm, acetonitrile / water+0.1 triethylamine) to give the title compound (32 mg, 59%) as an off-white amorphous lyophilized solid. LCMS: m / z 340.2 [M+H] + ,ESI pos.

[0260] Example 9: 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-3-fluoro-5-(trifluoromethyl)phenol [ka]

[0261] Step A: 2-Bromo-6-fluoro-4-(trifluoromethyl)aniline

[0262] To a solution of commercially available 2-fluoro-4-(trifluoromethyl)aniline (25.0 g, 140 mmol, 1.00 equiv.) in DMF (300 mL) was added NBS (26.1 g, 147 mmol, 1.05 equiv.) at -10°C. The mixture was stirred at 25°C for 12 h. The reaction mixture was diluted with EtOAc (500 mL) and extracted. The organic phase was washed with brine (500 mL x 3) and diluted with Na 2 SO4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0-10 / 1) to give the title compound (36.0 g, 99.9% yield) as a yellow oil. LCMS: m / z 257.9 [M+H] + ,ESI pos.

[0263] Step B: 2-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[0264] A solution of the compound 2-bromo-6-fluoro-4-(trifluoromethyl)aniline (30.0 g, 116 mmol, 1.00 equiv.) in dioxane (500 mL) was treated with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (59.1 g, 233 mmol, 2.00 equiv.), KOAc (28.5 g, 291 mmol, 2.50 equiv.) and Pd(dppf)Cl 2 .CH 2 Cl 2 (9.50 g, 11.6 mmol, 0.10 equiv.) was dissolved in N 2 The mixture was stirred at 100° C. for 3 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc (1000 mL) and extracted. The organic phase was washed with brine (1000 mL) and diluted with Na 2 SO 4 It was dried over, filtered and concentrated in vacuo to give the title compound (45.0 g) as a black oil which was used directly in the next step. LCMS: m / z 306.1 [M+H] + ,ESI pos.

[0265] Step D: 2-Amino-3-fluoro-5-(trifluoromethyl)phenol

[0266] To a solution of the above 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (45.0 g, 148 mmol, 1.00 equiv.) in THF (600 mL) was added NaOH (2 M, 221 mL, 3.00 equiv.) and H 2 O 2 (100 g, 885 mmol, 85.0 mL, 30.0% purity, 6.00 equiv) was added at 0° C. and the reaction was stirred at 25° C. for 3 h. The reaction was diluted with EtOAc (1500 mL) and extracted. The organic phase was washed with Na 2 SO 3 Wash with aqueous solution (1500 mL x 3) and add Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% formic acid condition) to give the title compound (11.0 g, 38% yield) as a brown solid. LCMS: m / z 196.0 [M+H] +, ESI pos.

[0267] Step E: 3-Fluoro-2-iodo-5-(trifluoromethyl)phenol

[0268] The compound 2-amino-3-fluoro-5-(trifluoromethyl)phenol (11.0 g, 56.4 mmol, 1.00 equiv.) and H 2 SO 4 (40.5 g, 404 mmol, 22.0 mL, 7.17 equiv.) of H 2 To a solution of NaNO in 20O (200 mL) and acetone (50.0 mL), 2 (7.78 g, 113 mmol, 2.00 equiv.) was added at 0° C. and the reaction was stirred at 0° C. for 30 min. Then CuI (26.8 g, 141 mmol, 2.50 equiv.) and NaI (21.1 g, 141 mmol, 2.50 equiv.) were added to the reaction at 0° C. and the reaction was stirred at 0° C. for 1.5 h. After the reaction was completed, water (500 mL) was added to the reaction mixture. The aqueous phase was washed with EtOAc (300 mL×2). The combined organic layer was washed with brine (300 mL×2) and Na 2 SO 4The mixture was dried over ice, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0-10 / 1) to give the title compound (20.0 g) as a brown oil. 1 H NMR (400 MHz, CDCl 3 )δ=7.04(s,1H),6.89(dd,1H),6.76(s,1H).

[0269] Step F: 1-(ethoxymethoxy)-3-fluoro-2-iodo-5-(trifluoromethyl)benzene

[0270] To a solution of the compound 3-fluoro-2-iodo-5-(trifluoromethyl)phenol (20.0 g, 65.4 mmol, 1.00 equiv.) and chloromethoxyethane (9.27 g, 98.0 mmol, 9.09 mL, 1.50 equiv.) in DMF (200 mL), Cs 2 CO 3 (31.9 g, 98.0 mmol, 1.50 equiv) was added and the mixture was stirred at 25° C. for 2 h. After the reaction, EtOAc (500 mL) was added, the phases were separated and extracted. The organic phase was washed with brine (500 mL×3) and added with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0-10 / 1) to give the title compound (10.0 g, yield 42%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ):δ=7.15(s,1H),7.00(dd,1H),5.36(s,2H),3.78(q,2H),1.24(t,3H).

[0271] Step G: 2-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0272] To a solution of 1-(ethoxymethoxy)-3-fluoro-2-iodo-5-(trifluoromethyl)benzene (10.0 g, 27.5 mmol, 1.00 equiv) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.3 g, 82.4 mmol, 16.8 mL, 3.00 equiv) in THF (100 mL) was added n-BuLi (2.50 M, 27.5 mL, 2.50 equiv) at -70 °C and the reaction was stirred at -70 °C for 1 h. After completion of the reaction, NH 4 Aqueous Cl (300 mL) was added, the mixture was stirred for 10 min, and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (300 mL) and Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250 * 50 * 10 μm; mobile phase: [hexane-EtOH]; B%: 0%-0%, 7 min) to give the title compound (7.00 g, 60% yield, 86.3% purity) as a white solid. 1 H NMR (400 MHz, CDCl 3 ):δ=7.10(s,1H),6.94(d,1H),5.24(s,2H),3.73(q,2H),1.39(s,12H),1.22(t,3H).

[0273] Step H: 6-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine

[0274] A mixture of the above 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine (Example 4, Step A) (67 mg, 0.262 mmol, 1 eq.), 2-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (221.9 mg, 0.524 mmol, 2 eq.), potassium carbonate (144.8 mg, 1.05 mmol, 4 eq.) in 1,4-dioxane (1.6 mL) and water (0.4 mL). The mixture was flushed with argon for 5 min and SPhos Pd G3 (CAS number 1445085-82-4, 0.66 mg, 0.039 mmol, 0.150 eq.) was flushed with argon again. The mixture was stirred in a microwave at 120° C. for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with water (30 mL) and saturated NH 4 The mixture was quenched with aqueous Cl (30 mL) and then extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine (30 mL) and diluted with Na 2 SO 4 It was dried over, filtered and concentrated in vacuo. The crude product (140 mg, brown oil, 80% purity) was taken onto the next step. LCMS: m / z 458.5 [M+H] + ,ESI pos.

[0275] Step I: 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-3-fluoro-5-(trifluoromethyl)phenol

[0276] To a solution of the above 6-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine (Example 9, step H) (140 mg, 0.245 mmol, 1 equiv.) and dichloromethane (5 mL) was added TFA (566 μL, 7.34 mmol, 30 equiv.) dropwise under ice cooling. The reaction mixture was stirred at 0° to +23° C. for 4 h. After complete conversion, the solvent was evaporated. The obtained residue was dissolved in saturated dichloromethane (30 mL). NaHCO 3 Solution (30 mL) was added and extracted. The organic phase was separated and washed with water (20 mL) and brine (20 mL). The aqueous phase was back-extracted with dichloromethane (2×30 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over silica gel, filtered and concentrated in vacuo. The residue (190 mg) was purified by flash chromatography (SiO 2 , 12 g, gradient 0% to 100% in dichloromethane (dichloromethane:MeOH:NH 4 After purification by preparative RP-HPLC (column: YMC-Triart C 18 , 12 nm, 5 μm, 100×30 mm, acetonitrile / water+0.1 triethylamine) to give the title compound (51 mg, 50%) as an off-white amorphous lyophilized solid. LCMS: m / z 400.4 [M+H] + ,ESI pos.

[0277] Examples 10 and 11: 2-[3-[[(3R)-1-tert-butyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol and 2-[3-[[(3S)-1-tert-butyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0278] Step A: (rac)-N-(1-tert-butyl-3-piperidyl)-6-chloro-5-methyl-1,2,4-triazin-3-amine

[0279] To a mixture of commercially available 3,6-dichloro-5-methyl-1,2,4-triazine (CAS number 132434-82-3, 250 mg, 1.45 mmol, 1.0 equiv.) and commercially available (1-tert-butyl-3-piperidyl)amine; hydrochloride (CAS number 2243513-25-7, 418.7 mg, 2.17 mmol, 1.50 equiv.) in 1,4-dioxane (4.75 mL) was added N,N-diisopropylethylamine (514 μL, 2.94 mmol, 2.03 equiv.). The reaction mixture was stirred at room temperature for 1 h and then at 80° C. for 22 h. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with dichloromethane and water. The organic layer was washed with water and brine. The combined organic layer was washed with NaCl. 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient 0% to 10% methanol in dichloromethane) to give the title product (273 mg, 66%) as a green viscous oil. LCMS: m / z 284.3 [M+H] + ,ESI pos.

[0280] Step B: 2-[3-[(1-tert-butyl-3-piperidyl)amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol

[0281] A mixture of the above (rac)-N-(1-tert-butyl-3-piperidyl)-6-chloro-5-methyl-1,2,4-triazin-3-amine (273 mg, 0.962 mmol, 1.0 equiv.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (336.8 mg, 1.64 mmol, 1.7 equiv.), potassium carbonate (638.1 mg, 4.62 mmol, 4.8 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (90.3 mg, 0.111 mmol, 0.115 equiv.) in 1,4-dioxane (5.5 mL) and water (2.75 mL) was flushed with argon and stirred at 85° C. for 5 h. After complete conversion, the reaction mixture was cooled to room temperature and dissolved in ethyl acetate (30 mL) and half-saturated NH 4 The mixture was extracted with 100 mL of NaCl solution. The aqueous layer was back-extracted with ethyl acetate (30 mL). The organic layer was washed with water (4 mL) and brine (4 mL). The combined organic layers were washed with Na 2 SO 4 The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, MeOH 0-10% in dichloromethane) to give the title product (316 mg, 80%) as a light brown solid. LCMS: m / z 410.5 [M+H] + ,ESI pos.

[0282] The crude material was subjected to chiral HPLC (column: chiralcel OJ, MeOH 5%+0.2% trimethylamine, SFC) to give the first enantiomer 10 as a light brown solid (144 mg, 100% ee, containing 6% MeOH) and the second enantiomer 11 as a light brown solid (116 mg, 90% ee, containing 10% MeOH).

[0283] Optical rotation: Example 10: [α] 20 D=-17.47 (c=0.161 g / 100 mL, MeOH) Example 11: [α] 20 D = +18.58 (c = 0.120 g / 100 mL, MeOH)

[0284] Example 12: 4-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile [ka]

[0285] A mixture of the above 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine (Example 4, Step A) (120 mg, 0.469 mmol, 1 equiv.), commercially available 4-cyano-2-hydroxy-phenyl)boronic acid (CAS number n / a, 130.29 mg, 0.800 mmol, 1.7 equiv.), potassium carbonate (311.3 mg, 2.25 mmol, 4.8 equiv.) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (44.2 mg, 0.054 mmol, 0.115 equiv.) in 1,4-dioxane (2.8 mL) and water (1.4 mL) was flushed with argon and stirred at 85° C. overnight. The reaction mixture was cooled to room temperature and diluted with about 15 mL of EtOAc and about 15 mL of half-saturated NH 4 Cl solution. The aqueous layer was back extracted with ca. 15 mL EtOAc. The organic layer was washed with ca. 10 mL water and ca. 10 mL brine. The combined organic layers were dried over Ns2SO4, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 4 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (120 mg, 72%) as a light brown powder. LCMS: m / z 333.9 [M+H] + ,ESI pos.

[0286] Example 13: 2-[3-[[(3R,5S)-5-fluoro-1-methyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0287] Step A: N-[(3R,5S)-5-fluoro-1-methyl-3-piperidyl]carbamic acid tert-butyl ester

[0288] To a solution of commercially available N-[(3R,5S)-5-fluoro-3-piperidyl]carbamic acid tert-butyl ester (CAS number 1363378-08-8, 469 mg, 2.15 mmol, 1.0 equiv.) in tetrahydrofuran, extra dry (10 mL) N,N-diisopropylethylamine (938 μL, 5.37 mmol, 2.5 equiv.) was added, followed by the dropwise addition of iodomethane (161.2 μL, 2.58 mmol, 1.2 equiv.). The solution was stirred overnight at 40 °C. The reaction mixture was washed with ice water (10 mL) and saturated NaHCO 3 (30 mL) solution and extracted with ethyl acetate (2×80 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic extracts were washed with Na 2 SO 4 It was dried over hexane, filtered off and concentrated in vacuo to give the desired crude product (461 mg, 88%) as a pale yellow solid which was used as such in the next step. LCMS: m / z 233.1 [M+H]+, ESI pos.

[0289] Step B: [(3R,5S)-5-Fluoro-1-methyl-3-piperidyl]amine

[0290] To a solution of the above N-[(3R,5S)-5-fluoro-1-methyl-3-piperidyl]carbamic acid tert-butyl ester (Example 13, Step A) (461 mg, 1.89 mmol, 1 equiv.) in dichloromethane (10 mL) and methanol (5 mL) was added dropwise 4M HCl in dioxane (3.77 mL, 15.1 mmol, 8 equiv.). The pale yellow reaction solution was stirred at 23° C. for 16 h. The reaction mixture was then concentrated in vacuo and dried under high vacuum at 50° C. for 1 h to give the desired title compound (369 mg, 1:1 hydrogen chloride) as a pale yellow solid, which was used directly in the next step. LCMS: m / z 133.1 [M+H] + ,ESI pos.

[0291] Step C: 6-chloro-N-[(3R,5S)-5-fluoro-1-methyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine

[0292] To a mixture of the aforementioned [(3R,5S)-5-fluoro-1-methyl-3-piperidyl]amine; hydrochloride salt in 1,4-dioxane (Example 13, Step B) (359.9 mg, 2.13 mmol, 1.4 eq.), extra dry (10 mL) and N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (1.33 mL, 7.62 mmol, 5.0 eq.) at ambient temperature to give a pale yellow solution. After stirring for 10 minutes at 23° C., commercially available 3,6-dichloro-5-methyl-1,2,4-triazine (CAS number 132434-82-3, 250 mg, 1.52 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 23° C. for 60 hours. After completion of the reaction, the main amount of solvent was evaporated and the reaction mixture was then diluted with half-saturated NaHCO 3 3 The mixture was quenched with ethyl acetate (80 mL) and extracted with ethyl acetate (2×80 mL). The organic layer was washed with water (60 mL) and brine (60 mL). The combined organic extracts were washed with Na 2 SO 4It was dried over ice, filtered and concentrated in vacuo. The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, 0-50% ethyl acetate in heptane; then ethyl acetate:methanol 9:1) to give the title compound (271 mg, 65%) as a pale yellow solid. LCMS: m / z 260.2 [M+H] + ,ESI pos.

[0293] Step D: 2-[3-[[(3R,5S)-5-fluoro-1-methyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol

[0294] A mixture of the above 6-chloro-N-[(3R,5S)-5-fluoro-1-methyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine (Example 13, Step C)-5-methyl-1,2,4-triazin-3-amine (72 mg, 0.277 mmol, 1.0 equiv.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (91.3 mg, 0.444 mmol, 1.6 equiv.), potassium carbonate (1.25 mmol, 4.5 equiv.) in 1,4-dioxane (1.9 mL) and water (0.9 mL) was flushed with argon for 2 minutes, followed by 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (27.2 mg, 0.033 mmol, 0.120 equiv.). The resulting mixture was stirred at 90° C. for 16 h. After complete conversion, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (2×20 mL) and half-saturated NH 4 The mixture was extracted with Cl solution (20 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic layer was washed with Na 2 SO 4The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, 0-50% ethyl acetate in heptane; then ethyl acetate:methanol 9:1) followed by crystallization with ethyl acetate / heptane 1:1 to give the title product (39 mg, 35%) as a white solid. LCMS: m / z 386.2 [M+H] + ,ESI pos.

[0295] Example 14: 2-[5-Methyl-3-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-ylamino)-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0296] Step A: (6-chloro-5-methyl-1,2,4-triazin-3-yl)-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)amine

[0297] To a mixture of commercially available 3,6-dichloro-5-methyl-1,2,4-triazine (CAS no. 132434-82-3, 71 mg, 0.433 mmol, 1 equiv.) and commercially available 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-ylamine; dihydrochloride salt (CAS no. 2408962-15-0, 136.45 mg, 0.649 mmol, 1.5 equiv.) in 1,4-dioxane, extra dry (2 mL) was added N-ethyldiisopropylamine (233.8 μL, 1.34 mmol, 3.1 equiv.) at room temperature. The reaction mixture was stirred at 23 °C for 16 h. No product was formed so the reaction mixture was heated at 80 °C for 2 h. LCMS showed minimal conversion so the mixture was transferred to a sealed tube and subjected to microwave reaction at 100 °C for 1 h. LCMS showed product but still mainly starting material. Therefore, more N-ethyldiisopropylamine (233.8 μL, 1.34 mmol, 3.1 equiv) was added and the mixture was then microwaved at 120° C. for 90 min and then 120° C. for 60 min. More conversion to product was formed so the reaction was stopped. The reaction mixture was extracted with dichloromethane (30 mL) and water (30 mL). The organic layer was washed with brine (30 mL). The aqueous layer was back extracted with dichloromethane (2×30 mL). The combined organic layers were washed with NaCl. 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (23 mg, 20%) as a brown solid. LCMS: m / z 265.1 ([{35Cl}M+H]+), 267.1 ([{37Cl}M+H]+), ESI pos.

[0298] Step B: 2-[5-methyl-3-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-ylamino)-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol

[0299] A mixture of the above (6-chloro-5-methyl-1,2,4-triazin-3-yl)-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)amine (Example 14, Step A) (23 mg, 86.9 μmol, 1.0 eq.) and [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (30.4 mg, 147.7 μmol, 1.7 eq.) and potassium carbonate (48.0 mg, 347.6 μmol, 4.0 eq.) was dissolved in 1,4-dioxane (1000 μL) and water (500 μL). The sealable tube was flushed with argon and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (8.51 mg, 10.4 μmol, 0.120 eq.) was added. Flushed again with argon and stirred the sealed tube at 90° C. for 6 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL) and saturated NH 4 The mixture was quenched with Cl sol (10 mL) and then extracted with dichloromethane (2×40 mL). The organic layer was washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried over hexane, filtered off and concentrated in vacuo. The crude material was purified by preparative RP HPLC (column: YMC-Triart C 18 , 12 nm, 5 μm, 100×30 mm, eluent: acetonitrile / water+0.1 HCOOH) followed by overnight lyophilization afforded the desired title compound (3.5 mg, 10%) as a white amorphous lyophilized solid. LCMS: m / z 391.3 [M+H] + ,ESI pos.

[0300] Example 15: 5-Fluoro-2-[5-methyl-3-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]phenol [ka]

[0301] Step A: 6-chloro-5-methyl-N-[(3R)-1-methyl-3-piperidyl]-1,2,4-triazin-3-amine

[0302] To a mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (CAS no. 132434-82-3, 400 mg, 2.44 mmol, 1.0 equiv.) and (3R)-1-methylpiperidin-3-amine (CAS no. 1001353-92-9, 418 mg, 3.66 mmol, 1.5 equiv.) in 1,4-dioxane (8.0 mL) was added N,N-diisopropylethylamine (326 mg, 0.440 mL, 2.52 mmol, 1.03 equiv.). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with dichloromethane and water. The organic layer was washed with brine. The aqueous layer was back-extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 5% methanol in dichloromethane) to give the title compound (290 mg, 47% yield) as a brown solid. LCMS: m / z 242.2 [M+H] + ,ESI pos.

[0303] Step B: 5-fluoro-2-[5-methyl-3-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]phenol

[0304] A mixture of 6-chloro-5-methyl-N-[(3R)-1-methyl-3-piperidyl]-1,2,4-triazin-3-amine (Example 15, Step A) (80 mg, 0.31 mmol, 1.0 equiv), (4-fluoro-2-hydroxyphenyl)boronic acid (CAS number 850568-00-2, 77 mg, 0.49 mmol, 1.57 equiv), cesium carbonate (326 mg, 1.00 mmol, 3.18 equiv) and XPhos Pd G3 (30 mg, 0.04 mmol, 0.11 equiv) in 1,4-dioxane (1.2 mL) and water (0.300 mL) was flushed with argon and stirred at 90° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and half-saturated NH 4The mixture was extracted with aqueous Cl. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 20% methanol in dichloromethane). All fractions containing product were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 50% (dichloromethane:methanol:NH 4 OH 9:1:0.05)) to give the title compound (42 mg, 40% yield) as a yellow solid. LCMS: m / z 318.3 [M+H] + ,ESI pos.

[0305] Example 16: 5-Chloro-2-[5-methyl-3-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]phenol [ka]

[0306] A mixture of 6-chloro-5-methyl-N-[(3R)-1-methyl-3-piperidyl]-1,2,4-triazin-3-amine (Example 15, Step A) (95 mg, 0.37 mmol, 1.0 equiv.), (4-chloro-2-hydroxyphenyl)boronic acid (CAS number 1238196-66-1, 109 mg, 0.63 mmol, 1.69 equiv.), potassium carbonate (248 mg, 1.79 mmol, 4.81 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (35 mg, 0.04 mmol, 0.11 equiv.) in 1,4-dioxane (2.2 mL) and water (1.1 mL) was flushed with argon and stirred at 90° C. for 5 h and at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and half-saturated NH 4Cl aq. The aqueous layer was back-extracted twice with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane). The residue was adsorbed onto ISOLUTE HM-N and repurified by flash chromatography (Si-amine, 12 g, gradient 0% to 10% methanol in ethyl acetate) to give the title compound (71 mg, 54% yield) as a light brown solid. LCMS: m / z 334.3 [M+H] + ,ESI pos.

[0307] Example 17: 2-[5-methyl-3-[[(3R)-3-piperidyl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0308] Step A: tert-Butyl (3R)-3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]piperidine-1-carboxylate

[0309] To a mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (CAS no. 132434-82-3, 180 mg, 1.10 mmol, 1.0 equiv.) and commercially available tert-butyl (3R)-3-aminopiperidine-1-carboxylate (CAS no. 188111-79-7, 330 mg, 1.65 mmol, 1.5 equiv.) in 1,4-dioxane (3.6 mL) was added N,N-diisopropylethylamine (148 mg, 0.200 mL, 1.15 mmol, 1.04 equiv.). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with dichloromethane and water. The organic layer was washed with brine. The aqueous layer was back-extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 40% ethyl acetate in heptane). All fractions containing the product were combined and concentrated in vacuo to give the title compound (351 mg, 93% yield) as a yellow oil. LCMS: m / z 328.3 [M+H] + ,ESI pos.

[0310] Step B: tert-Butyl (3R)-3-[[6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4 triazin-3-yl]amino]piperidine-1-carboxylate

[0311] A mixture of tert-butyl (3R)-3-[(6-chloro-5-methyl-1,2,4 triazin-3-yl)amino]piperidine-1-carboxylate (Example 17, Step A) (100 mg, 0.29 mmol, 1.0 equiv.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS number 1072951-50-8, 115 mg, 0.56 mmol, 1.93 equiv.), potassium carbonate (220 mg, 1.59 mmol, 5.49 equiv.) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (30 mg, 0.04 mmol, 0.13 equiv.) in 1,4-dioxane (2.0 mL) and water (1.0 mL) was flushed with argon and stirred at 90° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and half-saturated NH 4 Cl aq. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed once with water and once with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 40% ethyl acetate in heptane). All fractions containing product were combined and concentrated to give the title compound (105 mg, 76% yield) as a yellow foam. LCMS: m / z 454.4 [M+H] + ,ESI pos.

[0312] Step C: 2-[5-methyl-3-[[(3R)-3-piperidyl]amino]-1,2,4 triazin-6-yl]-5-(trifluoromethyl)phenol

[0313] To a solution of tert-butyl (3R)-3-[[6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4 triazin-3-yl]amino]piperidine-1-carboxylate (Example 17, Step B) (100 mg, 0.21 mmol, 1.0 equiv.) in dichloromethane (0.55 mL) and methanol (0.27 mL) was added dropwise 4M aqueous HCl in dioxane (528 mg, 0.440 mL, 1.76 mmol, 8.4 equiv.). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was extracted with a mixture of dichloromethane / methanol (19:1) and saturated aqueous NaHCO3 solution. The aqueous layer was back-extracted twice with a mixture of dichloromethane / methanol (19:1) and three times with a mixture of dichloromethane / methanol (9:1). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (70 mg, 85% yield) as a yellow foam. LCMS: m / z 354.3 [M+H] + ,ESI pos.

[0314] Example 18: 2-[5-methyl-3-[[(3R)-1-methyl-3-piperidyl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0315] A mixture of 6-chloro-5-methyl-N-[(3R)-1-methyl-3-piperidyl]-1,2,4-triazin-3-amine (Example 15, Step A) (90 mg, 0.35 mmol, 1.0 equiv.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS no. 1072951-50-8, 124 mg, 0.60 mmol, 1.7 equiv.), potassium carbonate (235 mg, 1.7 mmol, 4.81 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (34 mg, 0.04 mmol, 0.12 equiv.) in 1,4-dioxane (2.0 mL) and water (1.0 mL) was flushed with argon and stirred at 90° C. for 16 h. The reaction mixture was diluted with ethyl acetate and half-saturated NH 4 Extraction with aqueous Cl. The aqueous layer was back-extracted twice with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane). All fractions containing product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate / heptane (ca. 1:1) to give the title compound (24 mg, 18% yield) as an off-white powder. LCMS: m / z 368.3 [M+H] + ,ESI pos.

[0316] Example 19: 2-[3-[[(1R,2R)-2-hydroxycyclohexyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0317] Step A: (1R,2R)-2-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexanol

[0318] To a mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (CAS no. 132434-82-3, 200 mg, 1.22 mmol, 1.0 equiv.) and commercially available (1R,2R)-2-aminocyclohexanol hydrochloride (CAS no. 13374-31-7, 277 mg, 1.83 mmol, 1.5 equiv.) in 1,4-dioxane (4.0 mL), N,N-diisopropylethylamine (636 mg, 0.860 mL, 4.92 mmol, 4.04 equiv.) was added. The reaction mixture was stirred at room temperature for 5 days. The reaction mixture was extracted with dichloromethane and water. The organic layer was washed with brine. The aqueous layer was back-extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 5% methanol in dichloromethane) to give the title compound (178 mg, 57% yield) as a light brown solid. LCMS: m / z 243.1 [M+H] + ,ESI pos.

[0319] Step B: 2-[3-[[(1R,2R)-2-hydroxycyclohexyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol

[0320] A mixture of (1R,2R)-2-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexanol (Example 19, Step A) (96 mg, 0.38 mmol, 1.0 equiv.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS no. 1072951-50-8, 132 mg, 0.64 mmol, 1.71 equiv.), potassium carbonate (250 mg, 1.81 mmol, 4.81 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (36 mg, 0.04 mmol, 0.12 equiv.) in 1,4-dioxane (2.2 mL) and water (1.1 mL) was flushed with argon and stirred at 85° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and half-saturated NH 4Extraction with aqueous Cl. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 5% methanol in dichloromethane). All fractions containing product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate to give the title compound (87 mg, 60% yield) as an off-white powder. LCMS: m / z 369.2 [M+H] + ,ESI pos.

[0321] Example 21: 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-3-methyl-5-(trifluoromethyl)phenol [ka]

[0322] A mixture of 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine (Example 4, Step A) (60 mg, 0.22 mmol, 1.0 equiv), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS number 2557358-38-8, 100 mg, 0.33 mmol, 1.49 equiv), cesium carbonate (220 mg, 0.68 mmol, 3.03 equiv) and XPhos Pd G3 (20 mg, 0.02 mmol, 0.11 equiv) in 1,4-dioxane (0.80 mL) and water (0.20 mL) was flushed with argon and stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and half-saturated NH 4The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane:methanol:NH in dichloromethane). The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane:methanol:NH in dichloromethane). 4 OH 9:1:0.05) to give the title compound (67 mg, 72% yield) as a brown foam. LCMS: m / z 396.3 [M+H] + ,ESI pos.

[0323] Example 22: 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethoxy)phenol [ka]

[0324] A mixture of 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine (Example 4, Step A) (70 mg, 0.26 mmol, 1.0 equiv.), [2-hydroxy-4-(trifluoromethoxy)phenyl]boronic acid (CAS number 1309768-22-6, 90 mg, 0.41 mmol, 1.56 equiv.), cesium carbonate (257 mg, 0.79 mmol, 3.03 equiv.) and XPhos Pd G3 (24 mg, 0.03 mmol, 0.11 equiv.) in 1,4-dioxane (1.2 mL) and water (0.30 mL) was flushed with argon and stirred at 100° C. for 3 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane:methanol:NH 4 OH 9:1:0.05). All fractions containing the product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate / heptane to give the title compound (28 mg, 26% yield) as a pale yellow powder. LCMS: m / z 398.3 [M+H] + ,ESI pos.

[0325] Example 23: (3S,5R)-1-Ethyl-5-[[6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl]amino]piperidin-3-ol [ka]

[0326] Step A: tert-Butyl (3R,5S)-3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-5-hydroxy-piperidine-1-carboxylate

[0327] To a mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (CAS number 132434-82-3, 250 mg, 1.52 mmol, 1.0 equiv.) and tert-butyl (3R,5S)-3-amino-5-hydroxypiperidine-1-carboxylate (CAS number 1932513-59-1, 396 mg, 1.83 mmol, 1.2 equiv.) in 1,4-dioxane (5.0 mL), N,N-diisopropylethylamine (204 mg, 0.275 mL, 1.57 mmol, 1.03 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture, N,N-dimethylformamide (0.50 mL) was added. The reaction was stirred at room temperature for 16 hours. The reaction mixture was extracted with dichloromethane and water. The organic layer was washed with brine. The aqueous layer was back-extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, gradient 0% to 100% ethyl acetate in heptane) to give the title compound (443 mg, 80% yield) as a yellow oil. LCMS: m / z 344.2 [M+H] + ,ESI pos.

[0328] Step B: (3S,5R)-5-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]piperidin-3-ol hydrochloride

[0329] To a solution of tert-butyl (3R,5S)-3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-5-hydroxy-piperidine-1-carboxylate (Example 23, Step A) (338 mg, 0.93 mmol, 1.0 equiv) in dichloromethane (3.6 mL) and methanol (1.8 mL) was added dropwise 4M HCl in dioxane (3.0 mL, 12 mmol, 12.85 equiv). The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give the title compound (388 mg, 96% yield, 65% purity) as a yellow foam which was used without further purification LCMS: m / z 244.1 [M+H] + ,ESI pos.

[0330] Step C: (3S,5R)-5-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-1-ethyl-piperidin-3-ol

[0331] To a suspension of (3S,5R)-5-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]piperidin-3-ol hydrochloride (Example 23, Step B) (385 mg, 0.89 mmol, 1.0 eq, 65% purity) in dichloromethane (3.9 mL) was added sodium acetate (149 mg, 1.82 mmol, 2.03 eq) followed by acetaldehyde (101 mg, 0.130 mL, 2.3 mmol, 2.58 eq) under ice bath cooling. Sodium triacetoxyborohydride (285 mg, 1.34 mmol, 1.51 eq) was added at 0° C. and the reaction mixture was stirred at 0° C. for 15 min and at room temperature for 4 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was carefully basified with dichloromethane and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, dichloromethane 0% to 10% methanol) to give the title compound (85 mg, 33% yield) as an orange foam. LCMS: m / z 272.1 [M+H] + ,ESI pos.

[0332] Step D: (3S,5R)-1-Ethyl-5-[[6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl]amino]piperidin-3-ol

[0333] To a solution of (3S,5R)-5-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-1-ethyl-piperidin-3-ol (Example 23, step C) (85 mg, 0.30 mmol, 1.0 eq.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS number 1072951-50-8, 105 mg, 0.51 mmol, 1.72 eq.) and potassium carbonate (198 mg, 1.43 mmol, 4.82 eq.) in 1,4-dioxane (1.32 mL) and water (0.33 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (28 mg, 0.03 mmol, 0.12 eq.). Stir under argon at 90° C. for 16 h. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate and half-saturated NH 4 The crude product was adsorbed onto ISOLUTE-HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane:methanol:NH in dichloromethane). The aqueous layer was back-extracted twice with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE-HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane:methanol:NH in dichloromethane). 4 OH 9:1:0.05). All fractions containing the product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate / heptane to give the title compound (51 mg, 41% yield) as a light brown powder. LCMS: m / z 398.3 [M+H] + ,ESI pos.

[0334] Example 24: (3S,5R)-1-Ethyl-5-[[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl]amino]piperidin-3-ol [ka]

[0335] A mixture of (3S,5R)-5-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-1-ethyl-piperidin-3-ol (Example 23, Step C) (55 mg, 0.18 mmol, 1.0 equiv), [2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (CAS number 2557358-06-0, 60 mg, 0.26 mmol, 1.42 equiv), cesium carbonate (179 mg, 0.55 mmol, 3.02 equiv) and XPhos Pd G3 (18 mg, 0.021 mmol, 0.12 equiv) in 1,4-dioxane (0.80 mL) and water (0.20 mL) was flushed with argon and stirred at 100 °C for 2.75 h. To the reaction mixture was added [2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (CAS no. 2557358-06-0, 21 mg, 0.09 mmol, 0.50 equiv.) and XPhos Pd G3 (6 mg, 0.01 mmol, 0.04 equiv.) at room temperature. The mixture was flushed with argon and stirred at 100 °C for 1.25 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane:methanol:NH) in dichloromethane. 4 OH 9:1:0.05) to give the title compound (49 mg, 59% yield, 90% purity) as an orange solid. LCMS: m / z 412.3 [M+H] + ,ESI pos.

[0336] Example 25: 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]indan-4-ol [ka]

[0337] Step A: 2-(4-benzyloxyindan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0338] To a solution of 4-benzyloxy-5-bromo-indane (CAS no. 2676863-60-6, 538 mg, 1.51 mmol, 1.00 equiv, 85% purity) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (465 mg, 0.510 mL, 2.5 mmol, 1.66 equiv) in tetrahydrofuran (6.5 mL) was added a 1.6 M solution of n-butyllithium in hexanes (1.9 mL, 3.04 mmol, 2.02 equiv) dropwise at -76 °C (maintaining internal temperature below -68 °C). Stir at -76 °C for 3 h. Warm the reaction mixture to -60 °C and add saturated NH 4 Quench with aqueous Cl at -60 °C, warm to room temperature, then add ethyl acetate and saturated NH 4 Extraction with aqueous Cl. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 10% ethyl acetate in heptane) to afford the title compound (391 mg, 70% yield) as a colorless oil. LCMS: m / z 351.2 [M+H] + ,ESI pos.

[0339] Step B: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-4-ol

[0340] A solution of the above 2-(4-benzyloxyindan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example 25, Step A) (388 mg, 1.05 mmol, 1.00 equiv) in ethyl acetate (4.8 mL) was alternately evacuated and flushed with argon three times. Palladium on activated carbon, 10% Pd basic (39 mg, 0.037 mmol, 0.04 equiv) was carefully added. The reaction flask was evacuated, flushed with argon, evacuated, and flushed with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 16 hours. The reaction mixture was filtered and rinsed thoroughly with ethyl acetate / methanol. The filtrate was concentrated in vacuo to give the title compound (286 mg, quantitative yield) as an off-white solid. LCMS: m / z 261.2 [M+H] + ,ESI pos.

[0341] Step C: 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]indan-4-ol

[0342] 6-Chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine (Example 4, Step A) (80 mg, 0.29 mmol, 1.00 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-4-ol (exemplified) in 1,4-dioxane (1.8 mL) and water (0.90 mL). A mixture of Example 25, step B) (129 mg, 0.47 mmol, 1.60 equiv), potassium carbonate (187 mg, 1.35 mmol, 4.60 equiv) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (36 mg, 0.044 mmol, 0.15 equiv) was flushed with argon and stirred at 100°C for 2.5 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane). The residue was triturated with ethyl acetate / heptane. The filtrate was concentrated in vacuo to give the title compound (69 mg, 63% yield) as a brown solid. LCMS: m / z 354.3 [M+H] + ,ESI pos.

[0343] Examples 26 and 27: 2-[5-methyl-3-[[rac-(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol and 2-[5-methyl-3-[[rac-(8S,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0344] Step A: (6-chloro-5-methyl-1,2,4 triazin-3-yl)-indolizidin-8-yl-amine

[0345] To a solution of commercially available 3,6-dichloro-5-methyl-1,2,4-triazine (CAS number 132434-82-3, 277 mg, 1.69 mmol, 1.0 equiv.) and commercially available indolizidin-8-ylamine (374 mg, 2.53 mmol, 1.5 equiv.) in 1,4-dioxane, extra dry (6 mL) was added at room temperature to give a brown clear solution. The reaction mixture was stirred at 23° C. for 16 h. After completion of the reaction, the reaction mixture was extracted with dichloromethane (30 mL) and water (30 mL). The organic layer was washed with brine (30 mL). The aqueous layer was back extracted with dichloromethane (2×30 mL). The combined organic layers were washed with NaCl. 2 SO 4 The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound in two fractions: the first fraction (255 mg, 55%) as a light brown gum and the second fraction (37 mg, 8%) as a light brown oil. LCMS: m / z 268.2 ([{35Cl}M+H]+), 270.1 ([{37Cl}M+H]+), ESI pos.

[0346] Step B: 2-[5-methyl-3-[[rac-(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0347] A mixture of (6-chloro-5-methyl-1,2,4-triazin-3-yl)-indolizidin-8-yl-amine (255 mg, 0.952 mmol, 1.00 equiv.) and [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (333 mg, 1.62 mmol, 1.70 equiv.) and potassium carbonate (632 mg, 4.57 mmol, 4.80 equiv.) as described above (Example 26 / 27, Step A, Fraction 1) was dissolved in 1,4-dioxane (6 mL) and water (3 mL). The sealable tube was flushed with argon and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (93 mg, 0.114 mmol, 0.120 equiv.) was added. The sealed tube was flushed again with argon and stirred at 90° C. for 3 h. The reaction mixture was cooled to room temperature and added water (10 mL) and saturated NH 4 The mixture was quenched with Cl solution (10 mL) and then extracted with dichloromethane (2×40 mL). The organic layer was washed with brine (20 mL) and diluted with Na 2 SO 4 The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient 0% to 10% methanol in dichloromethane) and then triturated in tert-butyl methyl ether (5 mL) to give the title compound (Example 26) (226 mg, 57% yield) as an off-white solid. LCMS: m / z 394.1 [M+H] + ,ESI pos.

[0348] Step C: 2-[5-methyl-3-[[rac-(8S,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0349] A mixture of (6-chloro-5-methyl-1,2,4-triazin-3-yl)-indolizidin-8-yl-amine (37 mg, 138.2 μmol, 1.00 equiv.) and [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (48.4 mg, 235 μmol, 1.70 equiv.) and potassium carbonate (91.7 mg, 663.3 μmol, 4.80 equiv.) was dissolved in 1,4-dioxane (871 μL) and water (435 μL). The sealable tube was flushed with argon and 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (13.5 mg, 16.6 μmol, 0.120 equiv.) was added. Flush again with argon and stir the sealed tube at 90° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL) and saturated NH 4 The mixture was quenched with Cl sol (10 mL) and then extracted with dichloromethane (2×40 mL). The organic layer was washed with brine (20 mL) and diluted with Na 2 SO 4 The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane) followed by preparative HPLC to give the title compound (Example 27) (22 mg, 38%) as a light brown foam. The relative stereochemistry was assigned but not verified at this point.

[0350] Examples 28 and 29: 2-[3-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol and 2-[3-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0351] The above-mentioned title compound (Example 26) (92 mg, 0.234 mmol, 1.00 equivalent) was purified by chiral preparative HPLC (SFC, column chiral Lux C 4 , 5 μm, 250 × 20 mm; Method: 25% iPrOH+DEA; BPR at 120 bar, 90 mL / min) gave two fractions: enantiopure Example 28 as an off-white solid (41 mg, rt = 1.706 min, 100% ee) and enantiopure Example 29 as an off-white solid (38 mg, rt = 2.184 min, 100% ee).

[0352] Example 30: 2-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-(trifluoromethyl)-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid [ka]

[0353] Step A: 5-(trifluoromethyl)-1,2,4-triazin-3-amine

[0354] To a solution of NaOAc (9.53 g, 70.0 mmol, 2.1 equiv) in water (36 mL) was added commercially available 1,1-dibromo-3,3,3-trifluoroacetone (CAS no. 431-67-4, 9.0 g, 33.4 mmol, 1.0 equiv), then stirred at 100° C. for 30 min, then cooled to 20° C., and commercially available [(E)-aminocarbonohydrazonoyl]ammonium;hydrone;carbonate (CAS no. 2582-30-1, 4.54 g, 33.4 mmol, 1.0 equiv) was added in small portions at 20° C. and stirred for 3 h at 20° C. NaOH (16.7 mL, 66.7 mmol, 2.0 equiv, 4 M in water) was added (adjusting the pH to about 10) and then stirred at 20° C. for 36 h. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column (silica gel, petroleum ether:ethyl acetate = 1:0 to 3:1) to give the title compound (500 mg, yield 9%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.07(s,1H),8.00(br.s,2H).

[0355] Step B: 6-Bromo-5-(trifluoromethyl)-1,2,4-triazin-3-amine

[0356] To a solution of 5-(trifluoromethyl)-1,2,4-triazin-3-amine (300.0 mg, 1.83 mmol, 1.0 equiv.) in DMF (6 mL) was added NBS (388.1 mg, 2.19 mmol, 1.2 equiv.) and then stirred at 20° C. for 2 h. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column (silica gel, petroleum ether:EtOAc=1:0-2:1) to give the title compound (220 mg, 50% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3)δ 5.94(br.s,2H).

[0357] Step C: 2-(3-amino-5-(trifluoromethyl)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0358] To a solution of 6-bromo-5-(trifluoromethyl)-1,2,4-triazin-3-amine (170 mg, 0.7 mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) and water (0.500 mL) was added (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (172.9 mg, 0.84 mmol, 1.2 equiv.), Na 2 CO 3 (185.4 mg, 1.75 mmol, 2.5 equiv.), followed by Pd(dppf)Cl 2 (102.4 mg, 0.14 mmol, 0.2 equiv.) was added. The reaction mixture was diluted with N 2 The mixture was stirred at 100°C under atmospheric pressure for 2 hours. The reaction mixture was cooled to 25°C, diluted with water (50mL) and extracted with ethyl acetate (20mL x 3). The combined organic phase was washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column (silica gel, petroleum ether:ethyl acetate = 1:0 to 2:1) to give the title compound (180mg, yield 79%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ 10.50(br.s,1H),8.08(br.s,2H),7.54(d,1H),7.27(dd,1H),7.18(s,1H).

[0359] Step D: 2-(3-chloro-5-(trifluoromethyl)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0360] To a mixture of 2-(3-amino-5-(trifluoromethyl)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (90.0 mg, 0.28 mmol, 1.0 equiv), CuCl (82.5 mg, 0.83 mmol, 3.0 equiv), LiCl (23.5 mg, 0.56 mmol, 2.0 equiv), benzyl(triethyl)azanium chloride (240.3 mg, 1.05 mmol, 3.8 equiv) in MeCN (3 mL) was added tert-butyl nitrite (143.1 mg, 1.39 mmol, 5.0 equiv) at 25 °C, and the mixture was then cooled to 5 °C with 5% CO. 2 The mixture was stirred at 70° C. for 1 hour under reduced pressure. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate=4:1, Rf=0.5) to give the title compound (20.0 mg, 21% yield) as a yellow oil. LCMS: m / z 436.3 [M+H] + ,ESI pos.

[0361] Examples 31, 32, 33 and 34: 2-[3-[[(6S or 6R, 8aS or 8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(6R or 6S, 8aS or 8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(6S or 6R,8aR or 8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol and 2-[3-[[(6R or 6S,8aR or 8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [ka]

[0362] Step A: N-(6-chloro-5-methyl-1,2,4-triazin-3-yl)-1,2,3,5,6,7,8,8a-octahydroindolizine-6-amine

[0363] To a mixture of commercially available 3,6-dichloro-5-methyl-1,2,4-triazine (CAS no. 132434-82-3, 260 mg, 1.51 mmol, 1.00 equiv.) and commercially available indolizidine-6-amine (1824202-77-8, 316.8 mg, 2.26 mmol, 1.50 equiv.) in 1,4-dioxane (4.9 mL) was added N,N-diisopropylethylamine (201 mg, 272 μL, 1.56 mmol, 1.033 equiv.). The reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with dichloromethane and water. The organic layer was washed with brine. The aqueous layer was back-extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound in two fractions: the first fraction (124 mg, 29% yield) as a green solid and the second fraction (80 mg, 19% yield) as a pale green powder. LCMS: m / z 268.3 [M+H] + ,ESI pos.

[0364] Step B: 2-[3-[[(6S or 6R, 8aS or 8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol; 2-[3-[[(6R or 6S, 8aS or 8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol 2-[3-[[(6S or 6R,8aR or 8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol and 2-[3-[[(6R or 6S,8aR or 8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol

[0365] To a solution of the above N-(6-chloro-5-methyl-1,2,4-triazin-3-yl)-indolizidin-6-yl-amine (Step A, Fraction 1) (124 mg, 0.463 mmol, 1.00 equiv.) and [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (138.3 mg, 0.672 mmol, 1.45 equiv.) in 1,4-dioxane was added extra dry (1.8 mL) and and water (0.45 mL) were added under argon cesium carbonate (434.6 mg, 1.33 mmol, 2.88 equiv), followed by the addition of methanesulfonate (2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (38.4 mg, 0.045 mmol, 0.098 equiv). The reaction mixture was flushed with argon and stirred at 100 °C for 1 h. The color changed from dark green to dark brown. The reaction mixture was cooled to room temperature and extracted with about 5 mL of EtOAc and about 5 mL of water. The aqueous layer was back extracted with about 5 mL of EtOAc. The organic layer was washed with about 5 mL of water and about 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, 0-5% MeOH in DCM) to give two fractions of a yellow powder: the first (56 mg, 31%) and the second (24 mg, 13%). LCMS (both fractions): m / z 394.3 [M+H] + ,ESI pos.

[0366] In a separate flask: To a solution of N-(6-chloro-5-methyl-1,2,4-triazin-3-yl)-indolizidin-6-yl-amine (80 mg, 0.284 mmol, 1.0 equiv.) and [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (84.8 mg, 0.412 mmol, 1.45 equiv.) from above (Step A, Fraction 2) in 1,4-dioxane was added extra dry (0.95 mL ) and water (0.24 mL) were added under argon and cesium carbonate (266.3 mg, 0.817 mmol, 2.88 equiv) was added followed by methanesulfonate (2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (23.5 mg, 0.028 mmol, 0.098 equiv). The reaction mixture was flushed with argon and stirred at 90 °C for 18 h. The color changed from brown to dark brown. The reaction mixture was cooled to room temperature and extracted with about 5 mL of ethyl acetate and about 5 mL of water. The aqueous layer was back extracted with about 5 mL of ethyl acetate. The organic layer was washed with about 5 mL of water and about 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 4 g, heptane / MeOH 0-10% in DCM) to give the title compound in two fractions as a yellow powder: the first fraction (37 mg, 33% yield) and the second fraction (18 mg, 16% yield). LCMS: m / z 394.4 [M+H] + ,ESI pos.

[0367] In the final step, the above two fractions (37 mg) and (56 mg) were combined and subjected to SFC separation (column Chiral O JH, 5 μm, 250×20 mm; 10% iPrOH+0.2% diethylamine) to give two new enantiomeric fractions: the first one, Example 31, as an off-white powder (30 mg, 51%), and the second one, Example 32, as a white powder (35 mg, 60%). The relative stereochemistry was not investigated at this stage.

[0368] Additionally, the other two left fractions (24 mg) and (18 mg) mentioned above were combined and subjected to RP separation (column: Gemini NX, 12 nm, 5 μM, 100×30 mm; CAN / water+0.1% trimethylamine) to give two further enantiomerically pure fractions as both white powders Example 34 (8 mg, 13%) and Example 33 (12 mg, 20%). At this stage, the relative stereochemistry was not investigated.

[0369] Reference Example RE-A: 2-[6-[(1-ethyl-3-piperidyl)amino]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol

[0370] RE-A was synthesized as described in WO20200234715.

[0371] Example A' The compound of formula Ib can be used in a manner known per se as active ingredient to produce tablets of the following composition: Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0372] Example B' The compound of formula Ib can be used in a manner known per se as active ingredient to produce capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0373] Example A The compounds of formula I can be used in a manner known per se as active ingredient to produce tablets of the following composition: Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0374] Example B The compounds of formula I can be used in a manner known per se as active ingredient to prepare capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Formula Ib: 【Chemistry 1】 (In the formula, R １ and R ５ and the atoms to which they are attached form either a 4-6 membered heterocycle containing only one heteroatom O, optionally substituted with one or two substituents independently selected from halo or alkyl, or R １ and R ５ and the atoms to which they are attached form a 3-6 membered cycloalkyl ring optionally substituted with 1 or 2 substituents independently selected from halo or alkyl; R ２ is H; R ３ is methyl; Z is -NH-; R ４ is an alkyl-substituted piperidine ring. and pharma- ceutically acceptable salts thereof.

2. R 1 and R 5 and the atoms to which they are attached form either a 4- to 6-membered heterocycle containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R 2 is H; R 3 is methyl; Z is -NH-; R 4 is an alkyl-substituted piperidine ring; The compound of claim 1.

3. A compound which is 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol, or a pharma- ceutically acceptable salt thereof.

4. A compound which is 3-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol, or a pharma- ceutically acceptable salt thereof.

5. A compound which is 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]indan-4-ol, or a pharma- ceutically acceptable salt thereof.

6. A compound according to any one of claims 1 to 5 for use as a therapeutically active substance.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and a therapeutically inert carrier.

8. A compound according to any one of claims 1 to 5 for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

9. A compound according to any one of claims 1 to 5 for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

12. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

13. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

14. An NLRP3 inhibitor comprising a compound described in any one of claims 1 to 5.

Images