Triazine derivatives and their use in the treatment of cancer

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, particularly compounds that regulate NLRP3 inhibition.

[0002] The present invention relates to formula Ib:

Chemical Formula

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

Background Art

[0004] The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its abnormal activation is pathogenic in genetic disorders such as cryopyrin-associated periodic syndromes (CAPS), 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 factors, environmental factors, and host-derived factors. When activated, NLRP3 binds to apoptosis-associated speck-like proteins containing caspase activation and recruitment domain (ASC). Subsequently, ASC polymerizes to form large aggregates known as ASC specks. The polymerized ASC then interacts with the cysteine protease caspase-1 to form a complex called the inflammasome. This leads to the activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (called 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. The ASC speck can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 to cause apoptotic cell death.

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

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

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

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

[0010] The role of NLRP3 in central nervous system diseases is becoming clear, and it has also been shown that lung diseases are also affected by NLRP3. Furthermore, NLRP3 plays a role in the development of liver diseases, kidney diseases and aging. Many of these associations are related to Nlrp3 - / - defined using mice, but there is also insight into the specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), the 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. Glibenclamide inhibits IL-1β production at micromolar concentrations in response to NLRP3 activation, but does not respond to the activation of NLRC4 or NLRP1. Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene and dimethyl sulfoxide (DMSO), but these agents have limited potency and are non-specific.

[0012] Current treatments for NLRP3-related diseases include biological 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 the treatment of CAPS, and these biological agents are being used in clinical trials for other IL-1β-related diseases.

[0013] There is a need to provide compounds with improved pharmacological and / or physiological and / or physicochemical properties, and / or compounds that are useful alternatives to known compounds. SUMMARY OF THE INVENTION

[0014] The present invention relates to formula Ib:

Chemical formula

[0015] The term "alkyl" represents a monovalent straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, unless otherwise described, alkyl has 1 to 6 carbon atoms (C 1~6 -alkyl) or 1 to 4 carbon atoms (C 1~4 -alkyl). Examples of C 1~6 -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 having a specific number of carbons is named, all geometric isomers having that number of carbons can be included. Thus, for example, "butyl" can include n-butyl, sec-butyl, iso-butyl, and t-butyl, and "propyl" can include n-propyl and isopropyl.

[0016] The term "alkoxy" represents a group of the formula -O-R', where R' is a C 1~6 -alkyl group. Examples of C 1~6 -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, and tert-butoxy. Specific 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 specified, cycloalkyl contains 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. In other embodiments, cycloalkyl contains one or more double bonds (e.g., 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 carbon rings having two shared carbon atoms. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutanil, cyclopentyl, cyclohexyl or cycloheptyl. Specific 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 represent fluoro, chloro, bromo or iodo. Specific halogens include fluoro, chloro, and the like.

[0020] The term "haloalkyl" refers to a C 1~6 -alkyl group in which at least one hydrogen atom is replaced by the same or different halogen atoms C 1~6- represents an alkyl group. Specific examples are fluoromethyl, difluoromethyl and trifluoromethyl.

[0021] The term "haloalkoxy" refers to a C 1~6 -alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by the same or different halogen atoms, representing a C 1~6 -alkoxy group. Examples of haloalkoxy are difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy. A specific example is trifluoromethoxy.

[0022] The term "heterocyclic" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 10 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. Specific 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" represents an -OH group.

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

[0025] The term "nitrile" represents a -C≡N group.

[0026] The term "pharmaceutically acceptable salt" refers to salts of the free base or free acid that retain the biological effectiveness and properties of the free base or free acid and are not biologically or otherwise undesirable. The salts are formed from 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 an inorganic base or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium. Salts derived from organic bases include 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, salts of polyamine resins, but are not limited to these. The compounds of formula Ib may also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula Ib are salts formed with formic acid and salts formed with hydrochloric acid that yield a hydrochloride, dihydrochloride or trihydrochloride.

[0027] The abbreviation uM means micromole 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] 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, racemates of diastereoisomers or mixtures of racemates of diastereoisomers.

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

[0032] One embodiment of the invention also provides a compound according to formula Ib described herein, and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula Ib described herein, and a pharmaceutically acceptable salt thereof, more specifically, a compound according to formula Ib described herein.

[0033] One embodiment of the invention is 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 any of a 5-membered heterocyclic ring containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 4- to 5-membered cycloalkyl ring, a compound according to formula Ib described herein.

[0034] One embodiment of the invention is 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 any of a 5-membered heterocyclic ring containing only one heteroatom O, or R 1and R 5 and the atoms to which they are attached form a 4- to 5-membered cycloalkyl ring, to provide a compound according to formula Ib described herein.

[0035] One embodiment of the present invention is R 1 is haloalkyl; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any of a 5-membered heterocyclic ring 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, to provide a compound according to formula Ib described herein.

[0036] One embodiment of the present invention is that R 1 is H, halo, haloalkyl or cycloalkoxy, to provide a compound according to formula Ib described herein.

[0037] One embodiment of the present invention is that R 1 is halo, alkyl, or haloalkyl, to provide a compound according to formula Ib described herein.

[0038] One embodiment of the present invention is that R 1 is F, Cl, OCF3, CF3 or CH3, to provide a compound according to formula Ib described herein.

[0039] One embodiment of the present invention is that R 1 is CF3, to provide a compound according to formula Ib described herein.

[0040] One embodiment of the present invention is that R 2is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, wherein the cycloalkyl or cycloalkylalkyl is optionally substituted with halo, and provides a compound according to formula Ib described herein.

[0041] One embodiment of the present invention is R 2 is H, halo, alkyl, haloalkyl or cycloalkyl, wherein the cycloalkyl or cycloalkylalkyl is optionally substituted with halo, and provides a compound according to formula Ib described herein.

[0042] One embodiment of the present invention is R 2 is H, halo, alkyl or haloalkyl, and provides a compound according to formula Ib described herein.

[0043] One embodiment of the present invention is R 2 is H, halo, or alkyl, and provides a compound according to formula Ib described herein.

[0044] One embodiment of the present invention is R 2 is H or alkyl, and provides a compound according to formula Ib described herein.

[0045] One embodiment of the present invention is R 2 is alkyl, and provides a compound according to formula Ib described herein.

[0046] One embodiment of the present invention is R 2 is H, and provides a compound according to formula Ib described herein.

[0047] One embodiment of the present invention is R 3 is H, alkyl or haloalkyl, and provides a compound according to formula Ib described herein.

[0048] One embodiment of the present invention is R 3 is H or alkyl, and provides a compound according to formula Ib described herein.

[0049] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 3 is H.

[0050] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 3 is alkyl.

[0051] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 3 is methyl.

[0052] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 4 is a 6- to 9-membered heterocyclic ring containing one or two heteroatoms N; or a 6-membered heterocyclic ring containing one heteroatom N, substituted with one or two substituents independently selected from alkyl and -OH; or a 4- to 6-membered cycloalkyl substituted with one or two substituents independently selected from alkyl and -OH-.

[0053] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 4 is a 9-membered heterocyclic ring containing only one heteroatom N; or a 6-membered heterocyclic ring containing one heteroatom N, substituted with one alkyl substituent.

[0054] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 4 is methylpiperidyl or ethylpiperidyl.

[0055] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 4 is a heterocyclic ring optionally substituted with alkyl, or a cycloalkyl ring optionally substituted with one or two substituents selected from alkyl and -OH.

[0056] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 4 is a heterocyclic ring optionally substituted with alkyl.

[0057] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 4 is a heterocyclic ring containing one heteroatom substituted with alkyl.

[0058] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 4 is either ethylpiperidine or cyclobutane substituted with alkyl and -OH.

[0059] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 4 is ethylpiperidine.

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

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

[0062] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 1 and R 5 , and the atoms to which they are attached, together form any of a 4- to 6-membered heterocyclic ring 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, together form a 3- to 6-membered cycloalkyl ring optionally substituted with one or two substituents independently selected from halo or alkyl.

[0063] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein R 1 and R5 and the atoms to which they are attached form any of a 4- to 6-membered heterocyclic ring containing only one heteroatom O, or R 1 and R 5 provide a compound of formula Ib as described herein, wherein the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring.

[0064] One embodiment of the invention provides a compound of formula Ib as described herein, wherein R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocyclic ring containing only one heteroatom O.

[0065] One embodiment of the invention is 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 any of a 5-membered heterocyclic ring containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 4- to 5-membered cycloalkyl ring; R 2 is H, halo or alkyl; R 3 is H, alkyl or haloalkyl; Z is -NH-; R 4 is a 6- to 9-membered heterocyclic ring containing one or two heteroatoms N; or a 6-membered heterocyclic ring containing one heteroatom N substituted with one or two substituents independently selected from alkyl and -OH; or a 4- to 6-membered cycloalkyl substituted with one or two substituents independently selected from alkyl and -OH-. Also provided are compounds of formula Ib as described herein and pharmaceutically acceptable salts thereof.

[0066] One embodiment of the present invention is that 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 any of a 5-membered heterocyclic ring containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 4- to 5-membered cycloalkyl ring; R 2 is H; R 3 is alkyl; Z is -NH-; R 4 is a 9-membered heterocyclic ring containing only one heteroatom N; or a 6-membered heterocyclic ring containing one heteroatom N substituted with one alkyl substituent, a compound of formula Ib described herein, and a pharmaceutically acceptable salt thereof are provided.

[0067] One embodiment of the present invention is that 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 any of a 5-membered heterocyclic ring containing only one heteroatom O, or R 1 and R 5 and the atoms to which they are attached form a 4- to 5-membered cycloalkyl ring; R 2 is H; R 3 is alkyl; Z is -NH-; R 4Provided are compounds of formula Ib described herein, and pharmaceutically acceptable salts thereof, wherein R is methylpiperidyl or ethylpiperidyl.

[0068] One embodiment of the invention is R 1 is haloalkyl; R 5 is H; or R 1 and R 5 together with the atoms to which they are attached form any of a 5-membered heterocyclic ring containing only one heteroatom O, or R 1 and R 5 together with the atoms to which they are attached form a 4-membered cycloalkyl ring; R 2 is H; R 3 is alkyl; Z is -NH-; R 4 is ethylpiperidyl, provided are compounds of formula Ib described herein, and pharmaceutically acceptable salts thereof.

[0069] One embodiment of the invention is R 1 and R 5 together with the atoms to which they are attached form any of a 4- to 6-membered heterocyclic ring containing only one heteroatom O optionally substituted with one or two substituents independently selected from halo or alkyl, or R 1 and R 5 together with the atoms to which they are attached form a 3- to 6-membered cycloalkyl ring optionally substituted with one or two substituents independently selected from halo or alkyl; R 2 is H; R 3 is methyl; Z is -NH-; R 4Provided are compounds of formula Ib as described herein, and pharmaceutically acceptable salts thereof, wherein the piperidine ring is substituted with alkyl.

[0070] One embodiment of the invention is R 1 and R 5 such that the atoms to which they are attached form any of a 4- to 6-membered heterocyclic ring containing only one heteroatom O, or 1 R 5 and R R 2 is H; R 3 is methyl; Z is -NH-; R 4 Provided are compounds of formula Ib as described herein, and pharmaceutically acceptable salts thereof, wherein the piperidine ring is substituted with alkyl.

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

Chemical formula

[0072] 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, racemates of diastereoisomers or mixtures of racemates of diastereoisomers.

[0073] Also, embodiments of the invention provide compounds of formula I as described herein, and pharmaceutically acceptable salts or esters thereof, particularly compounds of formula I as described herein, and pharmaceutically acceptable salts thereof, more particularly compounds of formula I as described herein.

[0074] One embodiment of the invention is R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, or nitrile; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl, wherein the 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 -NHCH2-; R 4 is a heterocycle optionally substituted with one or two substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO2H, or cycloalkyl optionally substituted with halo, or R 4 is cycloalkyl optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl and -OH, a compound according to formula I described herein, and a pharmaceutically acceptable salt thereof are provided.

[0075] One embodiment of the present invention is R 1 is H, halo, alkyl, haloalkyl, or haloalkoxy; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl, wherein the 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 -NHCH2-; R 4is a heterocyclic ring optionally substituted with 1 to 2 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO2H, 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, a compound according to formula I as described herein, and a pharmaceutically acceptable salt thereof are provided.

[0076] One embodiment of the present invention provides a compound according to formula I as described herein, wherein 1 R is H, halo, haloalkyl, or cycloalkoxy.

[0077] One embodiment of the present invention provides a compound according to formula I as described herein, wherein 1 R is halo, alkyl, or haloalkyl.

[0078] One embodiment of the present invention provides a compound according to formula I as described herein, wherein 1 R is F, Cl, OCF3, CF3, or CH3.

[0079] One embodiment of the present invention provides a compound according to formula I as described herein, wherein 1 R is CF3.

[0080] One embodiment of the present invention provides a compound according to formula I as described herein, wherein 2 R is H, halo, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl, and the cycloalkyl or cycloalkylalkyl is optionally substituted with halo.

[0081] One embodiment of the present invention provides a compound according to formula I as described herein, wherein 2 R is H, halo, alkyl, haloalkyl, or cycloalkyl, and the cycloalkyl or cycloalkylalkyl is optionally substituted with halo.

[0082] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 2 is H, halo, alkyl or haloalkyl.

[0083] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 2 is H or alkyl.

[0084] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 2 is alkyl.

[0085] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 2 is H.

[0086] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 3 is H, alkyl or haloalkyl.

[0087] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 3 is H or alkyl.

[0088] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 3 is H.

[0089] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 3 is methyl.

[0090] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 4 is a heterocyclic ring optionally substituted with alkyl, or a cycloalkyl ring optionally substituted with 1 to 2 substituents selected from alkyl and -OH.

[0091] One embodiment of the present invention provides a compound of formula I as described herein, wherein R4 Provided is a compound according to formula I herein, which is a heterocyclic ring optionally substituted with alkyl.

[0092] One embodiment of the present invention is R 4 Provided is a compound according to formula I herein, which is a heterocyclic ring containing one heteroatom substituted with alkyl.

[0093] One embodiment of the present invention is R 4 Provided is a compound according to formula I herein, which is either ethylpiperidine or cyclobutane substituted with alkyl and -OH.

[0094] One embodiment of the present invention is R 4 Provided is a compound according to formula I herein, which is ethylpiperidine.

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

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

[0097] One embodiment of the present invention is R 1 is Cl, OCF3, alkyl or haloalkyl; R 2 is H optionally substituted with F, halo, alkyl, haloalkyl or cycloalkyl; R 3 is H optionally substituted with F, alkyl, haloalkyl or cycloalkyl; Z is O, or -NH-; R 4 is a heterocyclic ring optionally substituted with 1 to 2 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO2H, or cycloalkyl optionally substituted with halo, or R4 is cycloalkyl optionally substituted with 1 to 3 substituents independently selected from alkyl, halo, haloalkyl, and -OH, and provides a compound according to formula I described herein.

[0098] One embodiment of the present invention is R 1 is Cl, CH3, OCF3, or CF3; R 2 is H, halo, alkyl, or haloalkyl; R 3 is H, alkyl, or haloalkyl; Z is O or -NH-; R 4 is a heterocyclic ring containing 1 heteroatom optionally substituted with 1 to 2 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO2H, 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, and provides a compound according to formula I described herein.

[0099] One embodiment of the present invention is R 1 is Cl, CH3, OCF3, or CF3; R 2 is H, halo, alkyl, or haloalkyl; R 3 is H, alkyl, or haloalkyl; Z is O or -NH-; R 4 is a heterocyclic ring containing 1 heteroatom optionally substituted with 1 to 2 substituents independently selected from halo, alkyl, or haloalkyl, and provides a compound according to formula I described herein.

[0100] One embodiment of the present invention is R1 is Cl, CH3, OCF3, or CF3; R 2 is H, halo, alkyl or haloalkyl; R 3 is H, alkyl or haloalkyl; Z is -NH-; R 4 is a heterocyclic ring containing one heteroatom optionally substituted with one or two substituents independently selected from halo, alkyl or haloalkyl, and provides a compound according to formula I described herein.

[0101] One embodiment of the present invention is 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 heterocyclic ring containing one heteroatom substituted with alkyl or R 4 is a cycloalkyl ring substituted with one or two substituents independently selected from alkyl and -OH, and provides a compound according to formula I described herein.

[0102] One embodiment of the present invention is R 1 is halo or CF3; 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 one or two substituents selected from alkyl and -OH, and provides a compound according to formula I described herein.

[0103] One embodiment of the present invention is R1 is CF3 or Cl; R 2 is H; R 3 is methyl, Z is -NH-; R 4 is a piperidine ring substituted with alkyl, and provides a compound according to formula I described herein.

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

[0105] Specific examples of the 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 are selected from pharmaceutically acceptable salts thereof.

[0106] Other specific examples of the 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 are selected from those pharmaceutically acceptable salts thereof.

[0107] Preferred examples of the compound of formula Ib described herein are 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol, or a pharmaceutically acceptable salt thereof.

[0108] Other preferred examples of the compound 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 are selected from those pharmaceutically acceptable salts thereof.

[0109] More preferred examples of the compound 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 are selected from those pharmaceutically acceptable salts thereof.

[0110] The most preferred examples of the compound 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 are selected from those pharmaceutically acceptable salts thereof.

[0111] Specific examples of the 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 are selected from those pharmaceutically acceptable salts thereof.

[0112] The method for the production of the compounds of formula I described herein is an object of the present invention.

[0113] The synthesis of the compound of formula I can be achieved, for example, according to Scheme 1.

[0114] The method for the production of the compound of formula Ib described herein is an object of the present invention.

[0115] The synthesis of the compound of formula I can be achieved, for example, according to Scheme 3.

[0116] General synthetic scheme of triazine compounds: The compound of formula I can be prepared according to a modification of the above method and according to Scheme 1 below. The starting materials can be commercially available or prepared according to known methods.

[0117] Scheme 1

Chemical formula

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

[0119] Commercially available components of formula (III) in which X is a halogen atom such as bromine, chlorine or iodine, more preferably chlorine, can be subjected to nucleophilic aromatic substitution to prepare a compound of formula (IV). The nucleophilic aromatic substitution is carried out with a suitable amine Z-R 4 (wherein Z and R 4has the meaning given for general formula I and is carried out in the presence of a base such as N,N - diisopropylethylamine (DIEA) or trimethylamine which is common, known to those skilled in the art, and / or commercially available). Usually, 1,4 - dioxane is used as the solvent, but solvents such as dimethyl sulfoxide (DMSO) or N - methyl - 2 - pyrrolidine (NMP) are also suitable. Other methods similar to Buchwald - Hartwig amination can be used. The compound of general formula (IV) is added to the left side, and the compound of formula (V) is formed using Suzuki cross - coupling according to standard conditions well - known to those skilled in the art in the presence of a palladium catalyst and a boronic acid or boronic acid pinacol ester, for example 4 or 4b. In the final step, the methyl ether group is cleaved with boron tribromide (BBr3) in dichloromethane 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

Chemical formula

[0121] When X is NH2, the component of formula (II) was also prepared by a Sandmeyer - type reaction to obtain the component (III) where X = Cl. Specific examples are described below for each of the exemplified compounds.

[0122] Furthermore, when the amine Z - R 4 and R 4 contain, for example, a tert - butyloxycarbonyl (BOC) protecting group, trifluoroacetic acid (TFA) was used to perform an additional deprotection step either at the initial stage described for Example 1 or at the final stage during the cleavage of the methyl ether.

[0123] Scheme 3

Chemical formula

[0124] The synthesis of the compound of formula Ib of the present invention is synthesized according to the general synthesis shown in Scheme 3, wherein 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] Accordingly, the present invention relates to the compounds according to the present invention when produced according to the methods of the present invention.

[0126] One embodiment of the present invention is a 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 boronic acid pinacol ester (wherein R 1 , R 2 , R 3 , R 4 and Z are as defined above), a method for preparing a compound of formula I as defined above.

Chemical formula

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

Chemical formula

[0128] One embodiment of the present invention is a method for preparing a compound of formula Ib as defined above, comprising a 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 boronic acid pinacol ester (wherein R 1 , R 2 , R 3 , R 4 , R 5 and Z are as defined above).

Chemical formula

[0129] One embodiment of the present invention is a method for preparing a compound of formula Ib as defined above, which comprises a reaction of a compound of II to a compound of III.

Chemical formula

[0130] Another embodiment of the present invention provides a pharmaceutical composition or medicament containing a compound of the present invention and a therapeutically inert carrier, diluent or excipient, and a method of using a compound of the present invention for preparing such a composition and medicament. In one example, a compound of formula Ib can be formulated into a galenic dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used, at ambient temperature, at an appropriate pH, and with the desired degree of purity. The pH of the formulation mainly depends on the particular use and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, a compound of formula Ib is formulated in an acetate buffer of pH 5. In another embodiment, a compound of formula Ib is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0131] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to the physician.

[0132] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intralung, intradermal, intrathecal and epidural, and intranasal, and, if local treatment is desired, intralesional administration. Parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

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

[0134] Typical formulations are prepared by mixing the compounds of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in 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 formulations can also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opaquing agents, flow promoters, processing aids, coloring agents, sweeteners, fragrances, flavoring agents, diluents, and other known additives to provide accurate presentation of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or to assist in the manufacture of a pharmaceutical product (i.e., a medicine).

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

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

[0137] Adjuvants suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols, etc.

[0138] Adjuvants suitable for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0139] Adjuvants suitable for injection solutions are, for example, water, alcohol, polyols, glycerol, vegetable oils, etc.

[0140] Adjuvants suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0141] Adjuvants suitable for topical ophthalmic preparations are, for example, cyclodextrin, mannitol or many other carriers and excipients known in the art.

[0142] Furthermore, the pharmaceutical preparation may contain a preservative, solubilizer, viscosity increasing substance, stabilizer, wetting agent, emulsifier, sweetening agent, coloring agent, flavoring agent, salt for changing the osmotic pressure, buffer, masking agent, or antioxidant. They may also contain still other therapeutically valuable substances.

[0143] The dosage can be varied widely and can, of course, be adapted to the individual requirements in each particular case. Generally, in the case of 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 (for example, about 300 mg per person), is preferably divided into 1 to 3 individual administrations, which can, if appropriate, consist of, for example, the same amounts. In the case of topical administration, the preparation may contain 0.001% to 15% by weight of the medicament, and the required dosage, which can be between 0.1 and 25 mg, can be administered either by a single administration per day or per week, by multiple administrations per day (2 to 4 times), or by multiple administrations per week. However, it will be apparent that this can exceed the upper or lower limits given herein if so indicated.

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

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

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

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

[0148] One embodiment of the invention is a compound of 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 invention is a compound of 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 decrease in the activity level of NLRP3 and includes, for example, inhibition of active NLRP3 and / or inhibition of NLRP3 activation.

[0151] There is evidence regarding the role of 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: (i) Inflammation; (ii) Autoimmune disease; (iii) Cancer (iv) Infectious disease; (v) Central nervous system disease; (vi) Metabolic disease; (vii) Cardiovascular disease; (viii) Respiratory disease; (ix) Liver disease; (x) Kidney disease; (xi) Eye disease; (xii) Skin disease; (xiii) Lymphatic conditions; (xiv) Psychological disorders; (xv) Graft-versus-host disease; (xvi) Allodynia; (xvii) Symptoms associated with diabetes; 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 symptom is selected from: (i) Cancer (ii) Infectious disease; (iii) Central nervous system diseases; (iv) Cardiovascular diseases; (v) Liver diseases; (vi) Eye diseases; or (vii) Skin diseases.

[0154] In a further exemplary embodiment of the invention, the disease, disorder or symptom is an inflammation. Examples of inflammation that can be treated or prevented include inflammatory reactions associated with or resulting from the following: (i) Skin symptoms such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (ii) Joint symptoms such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or seronegative spondyloarthropathies (e.g., ankylosing spondylitis, psoriatic arthritis or Reiter's disease); (iii) Muscle symptoms such as polymyositis or myasthenia gravis; (iv) Gastrointestinal symptoms such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), colitis, gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that can affect areas away from the intestine (e.g., migraine, rhinitis or eczema); (v) Respiratory symptoms such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust asthma, especially chronic or refractory asthma, such as late-stage asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, catarrhal rhinitis, hypertrophic rhinitis, panrental rhinitis, dry rhinitis, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis, such as 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 symptoms such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (vii) Autoimmune symptoms such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease; (viii) Eye symptoms such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (ix) Neurological symptoms such as multiple sclerosis or encephalomyelitis; (x) Infectious or infection-related symptoms such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infections, acute or chronic parasitic infections, acute or chronic viral infections, acute or chronic fungal infections, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, laryngotracheitis, malaria, hemorrhagic dengue fever, leishmaniasis, streptococcal myositis, mycobacterium tuberculosis (including co-infection with mycobacterium tuberculosis and HIV), mycobacterium avium intracellulare, pneumocystis carinii pneumonia, orchitis / epididymitis, legionella, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (xi) Renal symptoms such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, obesity-related glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritic syndrome, renal fibrosis including chronic crystalline nephropathy, or renal hypertension; (xii) Lymphatic symptoms such as Castleman's disease; (xiii) Symptoms of the immune system, or symptoms involved therewith, such as hyper IgE syndrome, bacillary angiomatosis, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (xiv) Liver symptoms such as chronic active hepatitis, non-alcoholic fatty liver disease (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, liver fibrosis, or liver failure; (xv) Cancers including the above cancers; (xvi) Burns, wounds, traumas, bleeding or strokes; (xvii) Radiation exposure; (xviii) Metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or (xix) Pains 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 described herein for the treatment or prevention of a disease, disorder or symptom selected from the following: (i) Inflammation; (ii) Autoimmune diseases; (iii) Cancers; (iv) Infectious diseases; (v) Central nervous system diseases; (vi) Metabolic diseases; (vii) Cardiovascular diseases; (viii) Respiratory diseases; (ix) Liver diseases; (x) Kidney diseases; (xi) Eye diseases; (xii) Skin diseases; (xiii) Lymphatic symptoms; (xiv) Psychological disorders; (xv) Graft-versus-host disease; (xvi) Allodynia; (xvii) Symptoms related to diabetes; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0156] One embodiment of the invention is the use of a compound of formula Ib 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 invention is the use of a compound of formula Ib 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 invention is the use of a compound of formula Ib 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 invention is a compound of formula Ib 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 invention is a compound of formula Ib described herein for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0161] One embodiment of the invention is a compound of formula Ib 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 invention is the use of a compound of formula Ib 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 described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or symptom selected from asthma or COPD.

[0164] One embodiment of the present invention is the use of a compound according to formula Ib described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or symptom selected from inflammatory bowel 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 symptom selected from Alzheimer's disease and Parkinson's disease, the method comprising administering an effective amount of a compound according to formula Ib described herein.

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

[0167] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder or symptom selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), the method comprising administering an effective amount of a compound according to formula Ib 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 described herein, when manufactured according to any one of the methods 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 of formula I described herein for the treatment or prevention of a disease, disorder or condition selected from the following: (i) Inflammation; (ii) Autoimmune disease; (iii) Cancer; (iv) Infectious disease; (v) Central nervous system disease; (vi) Metabolic disease; (vii) Cardiovascular disease; (viii) Respiratory disease; (ix) Liver disease; (x) Kidney disease; (xi) Eye disease; (xii) Skin disease; (xiii) Lymphatic conditions; (xiv) Psychological disorders; (xv) Graft-versus-host disease; (xvi) Allodynia; (xvii) Conditions associated with diabetes; 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 of formula I 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 of formula I 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 of formula I 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 of formula I 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 of 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 of 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, the method comprising administering an effective amount of a compound of 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, the method comprising administering an effective amount of a compound of 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 of formula I as described herein.

[0181] A compound of formula I as described herein, when manufactured 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 of formula I as described herein and a therapeutically inert carrier.

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

[0184] THP-1 cells: Culture and preparation THP-1 cells (ATCC number TIB-202) were grown in RPMI supplemented with 10% fetal bovine serum (FBS) (Sigma number F0804), 1 mM sodium pyruvate (Sigma number S8636), and L-glutamine (Gibco number 11835) supplemented with penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma number P4333). Cells were passaged regularly and confluent (about 10 6The cells were grown to a density of [[[number of cells]]] cells / ml. On the day of the experiment, THP-1 cells were harvested and resuspended in RPMI medium (without FBS). The cells were then counted, and the viability (>90%) was confirmed using trypan blue (Sigma number T8154). Appropriate dilution was performed to obtain a concentration of 625,000 cells / ml. Lipopolysaccharide (LPS, Sigma number 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 plate thus prepared was used for compound screening.

[0185] THP-1 Cell Pyroptosis Assay For compound screening, a stepwise assay of the following method was followed. 1. Seed THP-1 cells (25,000 cells / well) containing 1.0 μg / ml of LPS in 40 μl of RPMI medium (without FBS) in a black-walled clear-bottom cell culture plate coated with 96-well poly-D-lysine (VWR number 734-0317). 2. Add 5 μl of the compound (8-point log dilution using a maximum dose of 10 μM) or vehicle (0.1% FAC DMSO) to the appropriate wells. 3. Incubate at 37 °C, 5% CO2 for 3 hours. 4. Add 5 μl of nigericin (Sigma number N7143) (FAC 5 μM) to all wells. 5. Incubate at 37 °C, 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plate at 300 x g for 3 minutes and remove the supernatant. 7. Then add 50 μl of resazurin (Sigma number R7017) (FAC 100 μM resazurin in RPMI medium without FBS) and incubate the plate at 37 °C and 5% CO2 for an additional 1 - 2 hours. 8. Read the plate on an Envision reader at Ex 560 nm and Em 590 nm. 9. IC 50Fit the data to a non-linear regression equation (log inhibitor vs. response variable slope 4-parameter)

[0186] Summarize the results of the pyroptosis assay as THP IC 50 in Table 1 below.

[0187] Human whole blood IL-1β release assay For systemic delivery, the ability of the compound to inhibit NLRP3 when present in the bloodstream is highly important. Therefore, the NLRP3 inhibitory activity of a number of compounds in human whole blood was examined according to the following protocol.

[0188] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor population. 1. Plate out 80 μl of whole blood containing 1 μg / ml of LPS in a 96-well flat-bottom cell culture plate (Corning number 3585). 2. Add 10 μl of the compound (8-point semi-log dilution at a maximum dose of 10 μM) or vehicle (0.1% DMSO in FAC) to the appropriate wells. 3. Incubate at 37 °C, 5% CO2 for 3 hours. 4. Add 10 μl of nigericin (Sigma number N7143) (10 μM in FAC) to all wells. 5. Incubate at 37 °C, 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plate at 300 × g for 5 minutes to pellet the cells, remove 20 μl of the supernatant, and add it to a 96-well v-bottom plate for IL-1β analysis (Note: These plates containing the supernatant can be stored at -80 °C for later analysis). 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 non-linear regression equation (log inhibitor vs. response variable slope 4-parameter)

[0189] The results of the human whole blood assay are summarized in Table 1 below as HWB IC 50 as follows.

[0190] hERG screening assay Cells

[0191] The CHO Clerox hERG cell line (ATCC reference number PTA-6812, female Chinese hamster cells) was generated and verified by Roche. Immediately available cryopreserved CHO-hERG cells were cryopreserved by Evotec (Germany) and used directly in the experiment.

[0192] Experimental solutions The extracellular solution contained (in mM units) NaCl 150; KCl 4; CaCl2 1; MgCl2 1; HEPES 10, with a pH of 7.2 - 7.4 adjusted with NaOH and an osmolarity of 290 - 330 mOsm. The internal solution contained (in mM units): KCl, 10; KF, 100; NaCl, 10; HEPES, 10; EGTA, 20, with a pH = 7.0 - 7.4 adjusted with KOH and an osmolarity of 260 - 300 mOsm.

[0193] Electrophysiology The effect of the compound on hERG K+-current parameters will be evaluated at two concentrations in at least four cells.

[0194] The hERG test is performed using an automated patch-clamp system SynchroPatch® 384 (Nanion Technologies GmbH, Germany). The K+ current is measured using the patch voltage-clamp method 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 the hERG channel at a stimulation frequency of 0.1 Hz (6 bpm) and conduct an outward IKhERG current.

[0196] Data analysis The amplitude of IKhERG was recorded at each drug concentration, and the fractional block was defined by comparison with the vehicle control value (set as 100%). The concentration-response data were fitted according to the following relationship: [Table 1]

[0197] The concentration-response curve was fitted by non-linear 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] TIFF0007705963000013.tif215169 TIFF0007705963000014.tif250169 TIFF0007705963000015.tif250169 TIFF0007705963000016.tif202169 TIFF0007705963000017.tif233169 TIFF0007705963000018.tif171169 [Table 3]

[0198] The present invention will now be described by the following examples, which have no limiting features.

[0199] When the preparation example is obtained as a mixture of enantiomers, the pure enantiomers can be obtained by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography or crystallization.

[0200] Experimental methods Abbreviations:

Table 4

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

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

[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 photometric detector unit, and a Gilson-281 fraction collector. Phenomenex Gemini: 75 * 30 mm * 3 μm pH (water (0.1% TFA)-ACN): 3 - 4 Average particle size: 3 μm The column was conditioned with 100% MeCN for 2 minutes before use and then changed to 1% MeCN for 0.8 minutes. 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 Before use, the column was conditioned with 100% MeCN (for 2 minutes), and then changed to 1% MeCN (for 0.8 minutes). Flow rate = 25 mL / min

[0206] Separation operation:

Table 6

Brief Description of the Drawings

[0207]

Figure 1

Examples

[0208] Unless otherwise specified, 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

Chemical

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

Chem.

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

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

Chem.

[0213] To a solution of DMSO (5 mL) containing tert-butyl (3R)-3-aminopiperidine-1-carboxylate (620 mg, 3.1 mmol, 1.2 eq.) was added DIEA (1.0 mL, 5.7 mmol, 2.2 eq.) and 6-bromo-3-chloro-1,2,4-triazine (500 mg, 2.6 mmol, 1 eq.). 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 purified by preparative TLC (SiO2, PE / EtOAc = 5 / 1) to give the title compound (590 mg, yield 64%) as a yellow solid. LCMS: m / z 304.0, [M-C4H9+2+H]+, ESI pos.

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

Chem.

[0215] To a solution of tert-butyl (3R)-3-[(6-bromo-1,2,4-triazin-3-yl)amino]piperidine-1-carboxylate (490 mg, 1.4 mmol, 1 equiv) in CH2Cl2 (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 afford the title compound as a yellow gum (TFA salt, 500 mg). LCMS: m / z 258.0 [M+H] + , ESI pos.

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

Chem.

[0217] To 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) were added K2CO3 (74 mg, 0.5 mmol, 2 equiv) and ethyl bromide (0.02 mL, 0.3 mmol, 1.1 equiv). The reaction mixture was stirred at 20 °C for 16 h. Then, water (1 mL) was added to the mixture and purified by reverse-phase flash (0.1% TFA aqueous-ACN conditions) to afford the title compound (20 mg, 25% yield) as a yellow solid. LCMS: m / z 286.0 [M+H] + , ESI pos.

[0218] Project 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

Chem.

[0219] A mixture of 2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (320 mg, 1.0 mmol, 1.6 eq), 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 eq) and K2CO3 (463 mg, 4.4 mmol, 7 eq) in 1,4-dioxane (5 mL) and water (1 mL) was degassed and purged with nitrogen three times, and Pd(dppf)Cl2 (153 mg, 0.2 mmol, 0.3 eq) 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 * 30 mm * 3 um; condition: 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, yield 4%). LCMS: m / z 396.3 [M+H] + , ESI pos.

[0220] Project 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

Chem.

[0221] N-[(3R)-1-Ethyl-3-piperidyl]-6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1,2,4-triazin-3-amine; To a solution of CH2Cl2 (1 mL) containing 2,2,2-trifluoroacetic acid (40 mg, 0.08 mmol, 1 equiv), BBr3 (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, the pH was adjusted to about pH 8 using NH3·H2O, and the mixture was lyophilized. The residue was purified by preparative HPLC (column 3_Phenomenex Luna C 18 75 * 30 mm * 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) to give 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)

Chemical formula

[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 eq) and 1-ethylpiperidin-3-amine (CAS No. 6789-94-2, 196 μL, 1.37 mmol, 1.5 eq) in 1,4-dioxane (3 mL) was added DIEA (160 μL, 1.37 mmol, 1.03 eq). 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, isocratic EtOAc) to afford the title compound (221 mg, trace 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-triazine-3-amine (rac)

Chemical Structure

[0226] A mixture of the above-mentioned 6-chloro-N-(1-ethyl-3-piperidyl)-5-methyl-1,2,4-triazine-3-amine (40 mg, 0.156 mmol, 1.0 eq), (4-chloro-2-hydroxy-phenyl)boronic acid (CAS No. 1238196-66-1, 45.7 mg, 0.265 mmol, 1.7 eq), potassium carbonate (103 mg, 0.747 mmol, 4.8 eq) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (14.8 mg, 0.018 mmol, 0.116 eq) 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, yield 33%) 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

Chemical formula

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

[0229] Similar to Example 3: 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 eq) and 3-amino-1-methyl-cyclobutanol hydrochloride (CAS No. 1820687-11-3, 251.7 mg, 1.83 mmol, 1.5 eq) in 1,4-dioxane (4 mL) was added DIEA (639 μL, 3.66 mmol, 3 eq). 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 4 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, purity 90%) 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

Chemical formula

[0231] A mixture of the above-mentioned 3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-1-methyl-cyclobutanol (80 mg, 0.315 mmol, 1.0 eq), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS No. 1072951-50-8, 109.9 mg, 0.534 mmol, 1.7 eq), potassium carbonate (207.9 mg, 1.50 mmol, 4.8 eq) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (29.7 mg, 0.036 mmol, 0.116 eq) 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: Chiralpak 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

Chemical Structure

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

Chemical Structure

[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 eq) and [(3R)-1-ethyl-3-piperidyl]amine (CAS No. 1020396-26-2, 1.24 g, 9.15 mmol, 1.5 eq) in 1,4-dioxane (20 mL) was added N,N-diisopropylethylamine (814 mg, 1.1 mL, 6.3 mmol, 1.03 eq). 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% - 10% methanol in dichloromethane) to afford 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

Chemical Structure

[0236] A mixture of the above-mentioned 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazine-3-amine (Example 4, Step A) (280 mg, 1.04 mmol, 1.0 equiv), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS No. 1072951-50-8, 365 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 at 85 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with EtOAc and semi-saturated aqueous NH4Cl solution. 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% - 10% methanol in dichloromethane). The residue was adsorbed onto ISOLUTE HM-N and re-purified by flash chromatography (silica gel, 25 g, gradient 0% - 100% (dichloromethane:methanol:NH4OH 9:1:0.05) in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. Trituration of the residue with EtOAc / heptane afforded 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

Chemical Structure

[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 No. 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 at 85 °C overnight. The reaction mixture was cooled to room temperature and extracted with EtOAc and half-saturated aqueous NH4Cl solution. 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% - 10% methanol in dichloromethane). The residue was adsorbed onto ISOLUTE HM-N and re-purified by flash chromatography (silica gel, 12 g, gradient 0% - 60% (dichloromethane:methanol:NH4OH 9:1:0.05) in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. Trituration of the residue with EtOAc / heptane afforded 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

Chemical Structure

[0240] A mixture of the above-mentioned 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazine-3-amine (Example 4, Step A)-5-methyl-1,2,4-triazine-3-amine (80 mg, 0.313 mmol, 1 equiv), (4-fluoro-2-hydroxyphenyl)boronic acid (CAS 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) in 1,4-dioxane (1.8 mL) and water (0.900 mL) 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% - 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

Chemical Structure

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

[0243] A solution of 2,3-dihydrobenzofuran-4-ol (CAS No. 144822-82-2, 2.00 g, 14.7 mmol, 1 equiv) in methanol (40 mL) was added with pyridinium 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 1 N hydrochloric acid (100 mL × 2), followed by brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EtOAc = 15:1~10:1) to obtain the title compound (1.90 g, yield 60%) as a yellow solid. LCMS: m / z 212.8 [M-H] - ,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 K2CO3 (1.29 g, 9.3 mmol, 2.0 equiv). The mixture was stirred at 20 °C for 0.5 h, and 2-(trimethylsilyl)ethoxymethyl chloride (0.99 mL, 5.58 mmol, 1.2 equiv) was added dropwise to the mixture. The mixture was stirred at 20 °C for 2 h. TLC (PE:EtOAc = 10:1) indicated that the starting material was consumed and another main 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 (SiO2, PE:EtOAc = 20:1~15:1) to obtain the title compound (1.30 g, yield 81%) as a yellow oil. 11H NMR (400 MHz, DMSO-d6) δ = 7.30 (d, 1H), 6.49 (d, 1H), 5.19 (s, 2H), 4.54 (t, 2H), 3.87 - 3.74 (m, 2H), 3.32 - 3.26 (m, 2H), 0.94 - 0.86 (m, 2H), -0.01 - -0.05 (m, 9H).

[0246] Process 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) were added bis(pinacolato)diboron (1.06 g, 4.17 mmol, 1.2 equiv), anhydrous AcOK (0.75 g, 7.65 mmol, 2.2 equiv), Xphos (166 mg, 0.350 mmol, 0.100 equiv) and XPhos Pd G3 (295 mg, 0.350 mmol, 0.100 equiv). The mixture was degassed three times with N2 and stirred at 80 °C for 12 h under N2. TLC (PE:EtOAc = 20:1) indicated 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% NH3.H2O aqueous ACN), and then lyophilized to give the title compound (288.3 mg, yield 20%) as a colorless oil. LCMS: m / z 393.1 [M+H] + , ESI pos.

[0248] Project 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] A mixture of the aforementioned 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 equivalent), trimethyl-[2-[[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl]oxymethoxy]ethyl]silane (53.7 mg, 0.137 mmol, 1.4 equivalents), potassium carbonate (60.8 mg, 0.440 mmol, 4.5 equivalents) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (CAS No. 95464-05-4, 9.58 mg, 0.012 mmol, 0.120 equivalent) in 1,4-dioxane (1 mL) and water (0.5 mL) was flushed with argon and stirred at 90 °C for 6 hours and at 23 °C for 10 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL) and saturated aqueous NH4Cl solution (10 mL), and 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, purity 70%) 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] 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 was added with extra dry (5 mL) and methanol (1 mL), and 4 M HCl in dioxane (123 μL, 0.49 mmol, 4 equiv) was added at room temperature. The mixture was stirred at 23 °C for 2 h. After completion of the reaction, the mixture was diluted with dichloromethane (20 mL), ice water (20 mL) and saturated NaHCO3 (20 mL). Then, it was extracted with dichloromethane (3 × 20 mL). The combined organic extracts were dried over Na2SO4, 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 afford the title compound (12 mg, 27%) as a pale yellow amorphous freeze-dried 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

Chemical formula

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

[0254] A solution of 3-bromobicyclo[4.2.0]octa-1,3,5-trien-2-ol (International Publication No. 2021150574, 195 mg, 0.98 mmol, 1.0 equiv) in DMF (5 mL) was added with potassium carbonate (302 mg, 2.19 mmol, 2.20 equiv) at room temperature. The resulting mixture was sonicated and 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. Subsequently, potassium carbonate (140 mg, 1.01 mmol, 1.03 equiv) and then 2-(trimethylsilyl)ethoxymethyl chloride (0.1 mL, 0.570 mmol, 0.58 equiv) were added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and 50 v% brine (100 mL), and the separated aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with 50 v% brine (100 mL), dried (MgSO4), filtered, and concentrated. The crude reaction mixture was purified by silica gel column chromatography (40 g, 0 - 20% MTBE:isohexane) to obtain the title compound (345.0 mg, yield 100%) as a colorless oil. 1 H NMR (500 MHz, 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-1,3,5-trienyl]oxymethoxy]ethyl]silane

[0256] 2-[(3-Bromo-2-bicyclo[4.2.0]octa-1,3,5-trienyl)oxymethoxy]ethyl-trimethyl-silane (103.0 mg, 0.270 mmol, 1 equiv), bis(pinacolato)diborane (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 for 10 min with sonication). 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 give the title compound (199 mg, 41% yield) as a pale yellow oil. 1 H NMR (500 MHz, CDCl3) 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 The mixture of the aforementioned 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazine-3-amine (Example 4, Step A) (53 mg, 0.197 mmol, 1.0 eq), 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 eq), and potassium carbonate (122.4 mg, 0.886 mmol, 4.5 eq) 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 No. 95464-05-4, 24.1 mg, 0.030 mmol, 0.120 eq) was flushed again with argon. The resulting mixture was stirred at 90 °C for 5 h. The reaction mixture was cooled to room temperature, quenched with water (10 mL) and saturated aqueous NH4Cl solution (10 mL), and then extracted with dichloromethane (2 × 40 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product (200 mg) was purified by flash chromatography (SiO2, 12 g, heptane:EtOAc = 0 - 50% EtOAc, followed by EtOAc:MeOH = 9:1) to obtain 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] 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 diluted with dichloromethane (20 mL), ice water (20 mL) and saturated NaHCO3 (20 mL). The combined organic extracts were dried over Na2SO4, 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 freeze-dried 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

Chemical formula

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

[0262] A solution of commercially available 2-fluoro-4-(trifluoromethyl)aniline (25.0 g, 140 mmol, 1.00 equiv) in DMF (300 mL) was added with 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×3), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 - 10 / 1) to afford the title compound (36.0 g, yield 99.9%) 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] To a solution of compound 2-bromo-6-fluoro-4-(trifluoromethyl)aniline (30.0 g, 116 mmol, 1.00 equiv) in dioxane (500 mL) were added 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)Cl2·CH2Cl2 (9.50 g, 11.6 mmol, 0.10 equiv) under N2. 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), dried over Na2SO4, filtered, and concentrated in vacuo to afford 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 eq) in THF (600 mL) were added NaOH (2 M, 221 mL, 3.00 eq) and H2O2 (100 g, 885 mmol, 85.0 mL, purity 30.0%, 6.00 eq) at 0 °C, and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with EtOAc (1500 mL) and extracted. The organic phase was washed with aqueous Na2SO3 solution (1500 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by reverse-phase HPLC (under 0.1% formic acid conditions) 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] To a solution of compound 2-amino-3-fluoro-5-(trifluoromethyl)phenol (11.0 g, 56.4 mmol, 1.00 eq) and H2SO4 (40.5 g, 404 mmol, 22.0 mL, 7.17 eq) in H2O (200 mL) and acetone (50.0 mL) was added NaNO2 (7.78 g, 113 mmol, 2.00 eq) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. Then, CuI (26.8 g, 141 mmol, 2.50 eq) and NaI (21.1 g, 141 mmol, 2.50 eq) were added to the reaction mixture at 0 °C, and the reaction mixture was stirred at 0 °C for 1.5 h. After completion of the reaction, water (500 mL) was added to the reaction mixture. The aqueous phase was washed with EtOAc (300 mL × 2). The combined organic layers were washed with brine (300 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 - 10 / 1) to give the title compound (20.0 g) as a brown oil. 11H NMR (400 MHz, CDCl3) 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 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) was added Cs2CO3 (31.9 g, 98.0 mmol, 1.50 equiv), 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), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to afford the title compound (10.0 g, yield 42%) as a colorless oil. 1 1H NMR (400 MHz, CDCl3): 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] A solution of 1-(ethoxymethoxy)-3-fluoro-2-iodo-5-(trifluoromethyl)benzene (10.0 g, 27.5 mmol, 1.00 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.3 g, 82.4 mmol, 16.8 mL, 3.00 eq) in THF (100 mL) was added with n-BuLi (2.50 M, 27.5 mL, 2.50 eq) at -70 °C, and the reaction mixture was stirred at -70 °C for 1 h. After completion of the reaction, an aqueous NH4Cl solution (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), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 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 obtain the title compound (7.00 g, yield 60%, purity 86.3%) as a white solid. 1 1H NMR (400 MHz, CDCl3): 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 aforementioned 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 equivalent), 2-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (221.9 mg, 0.524 mmol, 2 equivalents), and potassium carbonate (144.8 mg, 1.05 mmol, 4 equivalents) in 1,4-dioxane (1.6 mL) and water (0.4 mL). The mixture was flushed with argon for 5 minutes, and SPhos Pd G3 (CAS No. 1445085-82-4, 0.66 mg, 0.039 mmol, 0.150 equivalent) was flushed with argon again. The mixture was stirred in a microwave at 120 °C for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water (30 mL) and saturated aqueous NH4Cl solution (30 mL), and then extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product (140 mg, brown oil, purity 80%) was subjected to 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] A solution of the above 6-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazine-3-amine (Example 9, Step H) (140 mg, 0.245 mmol, 1 equivalent) and dichloromethane (5 mL) was added dropwise with TFA (566 μL, 7.34 mmol, 30 equivalents) under ice-cooling. The reaction mixture was stirred at 0° to +23 °C for 4 hours. After complete conversion, the solvent was evaporated. The obtained residue was dissolved in saturated dichloromethane (30 mL). A NaHCO3 solution (30 mL) was added and extraction was carried out. 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 dried over Na2SO4, filtered, and concentrated in vacuo. The residue (190 mg) was purified by flash chromatography (SiO2, 12 g, gradient 0% to 100% in dichloromethane (dichloromethane:MeOH:NH4OH 110:10:1)) and then further purified by preparative RP-HPLC (column: YMC-Triart C 18 , 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1 triethylamine) to obtain the title compound (51 mg, 50%) as an off-white amorphous freeze-dried 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

Chemical Structure

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

[0279] A mixture of commercially available 3,6-dichloro-5-methyl-1,2,4-triazine (CAS No. 132434-82-3, 250 mg, 1.45 mmol, 1.0 equiv) and commercially available (1-tert-butyl-3-piperidyl)amine; hydrochloride (CAS No. 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 hour and then at 80 °C for 22 hours. 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 layers were dried over Na2SO4, 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% - 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-triazine-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 extracted with ethyl acetate (30 mL) and semi-saturated NH4Cl solution (4 mL). 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 dried over Na2SO4, filtered and concentrated in vacuo. 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] When the crude material was subjected to chiral HPLC (column: chiralcel OJ, MeOH 5% + 0.2% trimethylamine, SFC), the first enantiomer 10 was obtained as a light brown solid (144 mg, 100% ee, containing 6% MeOH), and the second enantiomer 11 was obtained 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

Chemical formula

[0285] A mixture of the above-mentioned 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazine-3-amine (Example 4, Step A) (120 mg, 0.469 mmol, 1 equivalent), commercially available 4-cyano-2-hydroxy-phenyl)boronic acid (CAS number n / a, 130.29 mg, 0.800 mmol, 1.7 equivalents), potassium carbonate (311.3 mg, 2.25 mmol, 4.8 equivalents) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (44.2 mg, 0.054 mmol, 0.115 equivalents) 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 extracted with about 15 mL of EtOAc and about 15 mL of semi-saturated NH4Cl solution. The aqueous layer was back-extracted with about 15 mL of EtOAc. The organic layer was washed with about 10 mL of water and about 10 mL of 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% - 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

Chemical formula

[0287] Process A: tert-Butyl N-[(3R,5S)-5-fluoro-1-methyl-3-piperidyl]carbamate

[0288] To a solution of commercially available tert-butyl N-[(3R,5S)-5-fluoro-3-piperidyl]carbamate (CAS No. 1363378-08-8, 469 mg, 2.15 mmol, 1.0 eq) in tetrahydrofuran were added extra dry (10 mL), N,N-diisopropylethylamine (938 μL, 5.37 mmol, 2.5 eq), followed by dropwise addition of iodomethane (161.2 μL, 2.58 mmol, 1.2 eq). The solution was stirred at 40 °C overnight. The reaction mixture was poured into ice water (10 mL) and saturated NaHCO3 (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 dried over Na2SO4, 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] Process B: [(3R,5S)-5-Fluoro-1-methyl-3-piperidyl]amine

[0290] To a solution of the above tert-butyl N-[(3R,5S)-5-fluoro-1-methyl-3-piperidyl]carbamate (Example 13, Process A) (461 mg, 1.89 mmol, 1 eq) in dichloromethane (10 mL) and methanol (5 mL) was added dropwise 4 M HCl in dioxane (3.77 mL, 15.1 mmol, 8 eq). The pale yellow reaction solution was stirred at 23 °C for 16 h. Then the reaction mixture was concentrated in vacuo and dried at 50 °C for 1 h under high vacuum 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] Project C: 6-chloro-N-[(3R,5S)-5-fluoro-1-methyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine

[0292] To the aforementioned mixture of [(3R,5S)-5-fluoro-1-methyl-3-piperidyl]amine, hydrochloride in 1,4-dioxane (Example 13, Step B) (359.9 mg, 2.13 mmol, 1.4 equivalents), extra dry (10 mL) and N,N-dimethylformamide (2 mL) were added to N,N-diisopropylethylamine (1.33 mL, 7.62 mmol, 5.0 equivalents) at ambient temperature to obtain a pale yellow solution. After stirring at 23 °C for 10 minutes, commercially available 3,6-dichloro-5-methyl-1,2,4-triazine (CAS number 132434-82-3, 250 mg, 1.52 mmol, 1.0 equivalent) was added and the reaction mixture was stirred at 23 °C for 60 hours. After completion of the reaction, the major amount of the solvent was evaporated and then the reaction mixture was quenched with semi-saturated NaHCO3 solution (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 dried over Na2SO4, 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 obtain the title compound (271 mg, 65%) as a pale yellow solid. LCMS: m / z 260.2 [M+H] + ,ESI pos.

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

[0294] 6-Chloro-N-[(3R,5S)-5-fluoro-1-methyl-3-piperidyl]-5-methyl-1,2,4-triazine-3-amine (Example 13, Step C)-5-methyl-1,2,4-triazine-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), and potassium carbonate (1.25 mmol, 4.5 equiv) in 1,4-dioxane (1.9 mL) and water (0.9 mL) were flushed with argon for 2 minutes, followed by flushing with 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 hours. After complete conversion, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 × 20 mL) and semi-saturated NH4Cl solution (20 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The 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 using 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

Chemical formula

[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 in 1,4-dioxane (CAS No. 2408962-15-0, 136.45 mg, 0.649 mmol, 1.5 equiv), 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. Since no product was formed, 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 a microwave reaction at 100 °C for 1 h. LCMS showed the product but still mainly showed the starting material. Therefore, additional N-ethyldiisopropylamine (233.8 μL, 1.34 mmol, 3.1 equiv) was added, and then the mixture was irradiated with microwaves at 120 °C for 90 min and further at 120 °C for 60 min. Since more conversion to the product was formed, 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 dried over Na2SO4, 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% - 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] The 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 equivalent), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (30.4 mg, 147.7 μmol, 1.7 equivalents) and potassium carbonate (48.0 mg, 347.6 μmol, 4.0 equivalents) was dissolved in 1,4-dioxane (1000 μL) and water (500 μL). A 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 equivalent) was added. After flushing with argon again, the sealed tube was stirred at 90 °C for 6 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL) and saturated NH4Cl sol (10 mL), and then extracted with dichloromethane (2 × 40 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, 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 lyophilization overnight to give 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

Chemical formula

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

[0302] 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 to 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, 0% - 5% methanol in gradient dichloromethane) to afford 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] 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 eq), (4-fluoro-2-hydroxyphenyl)boronic acid (CAS No. 850568-00-2, 77 mg, 0.49 mmol, 1.57 eq), cesium carbonate (326 mg, 1.00 mmol, 3.18 eq) and XPhos Pd G3 (30 mg, 0.04 mmol, 0.11 eq) in 1,4-dioxane (1.2 mL) and water (0.300 mL) were flushed with argon and stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and semi-saturated aqueous NH4Cl. 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% - 20% methanol in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and re-purified by flash chromatography (silica gel, 12 g, gradient 0% - 50% (dichloromethane:methanol:NH4OH 9:1:0.05)) to afford 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

Chemical Structure

[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 No. 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 extracted with ethyl acetate and semi-saturated aqueous NH4Cl solution. 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% - 10% methanol in dichloromethane). The residue was adsorbed onto ISOLUTE HM-N and re-purified by flash chromatography (Si-amine, 12 g, gradient 0% - 10% methanol in ethyl acetate) to afford 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

Chemical formula

[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 eq) and commercially available tert-butyl (3R)-3-aminopiperidine-1-carboxylate (CAS No. 188111-79-7, 330 mg, 1.65 mmol, 1.5 eq) in 1,4-dioxane (3.6 mL) was added N,N-diisopropylethylamine (148 mg, 0.200 mL, 1.15 mmol, 1.04 eq). 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% - 40% ethyl acetate in heptane). Combining all fractions containing the product and concentrating in vacuo gave 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 No. 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 extracted with ethyl acetate and half-saturated aqueous NH4Cl solution. 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% - 40% ethyl acetate in heptane). All fractions containing the 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] 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 eq) in dichloromethane (0.55 mL) and methanol (0.27 mL) was added dropwise with 4M aqueous HCl solution in dioxane (528 mg, 0.440 mL, 1.76 mmol, 8.4 eq). The reaction mixture was stirred at room temperature for 2 hours. 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, concentrated in vacuo, and the title compound (70 mg, 85% yield) was obtained 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

Chemical Structure

[0315] 6-Chloro-5-methyl-N-[(3R)-1-methylpiperidin-3-yl]-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) were flushed with argon and stirred at 90 °C for 16 h. The reaction mixture was extracted with ethyl acetate and semi-saturated aqueous NH4Cl. The aqueous layer was back-extracted twice with ethyl acetate. The organic layers were 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% - 10% methanol in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate / heptane (ca. 1:1) to afford 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 [Chemical formula]

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

[0318] 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) was added N,N-diisopropylethylamine (636 mg, 0.860 mL, 4.92 mmol, 4.04 equiv). 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% - 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] (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) were flushed with argon and stirred at 85 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and semi-saturated aqueous NH4Cl. 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% - 5% methanol in dichloromethane). All fractions containing the 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

Chemical Structure

[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 No. 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 extracted with ethyl acetate and semi-saturated aqueous NH4Cl solution. 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% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)) to afford 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

Chemical Structure

[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 eq), [2-hydroxy-4-(trifluoromethoxy)phenyl]boronic acid (CAS No. 1309768-22-6, 90 mg, 0.41 mmol, 1.56 eq), cesium carbonate (257 mg, 0.79 mmol, 3.03 eq) and XPhos Pd G3 (24 mg, 0.03 mmol, 0.11 eq) 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 layers were 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% - 10% methanol in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and re-purified by flash chromatography (silica gel, 12 g, gradient 0% - 100% (dichloromethane:methanol:NH4OH 9:1:0.05) in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate / heptane to afford 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

Chem.

[0326] Project 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 No. 132434-82-3, 250 mg, 1.52 mmol, 1.0 eq) and tert-butyl (3R,5S)-3-amino-5-hydroxypiperidine-1-carboxylate (CAS No. 1932513-59-1, 396 mg, 1.83 mmol, 1.2 eq) in 1,4-dioxane (5.0 mL) was added N,N-diisopropylethylamine (204 mg, 0.275 mL, 1.57 mmol, 1.03 eq). The reaction mixture was stirred at room temperature for 16 h. To the reaction mixture was added N,N-dimethylformamide (0.50 mL). The reaction 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, 24 g, gradient 0% - 100% ethyl acetate in heptane) to afford the title compound (443 mg, 80% yield) as a yellow oil. LCMS: m / z 344.2 [M+H] + , ESI pos.

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

[0329] 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 eq) in dichloromethane (3.6 mL) and methanol (1.8 mL) was added dropwise with 4M HCl in dioxane (3.0 mL, 12 mmol, 12.85 eq). The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo to afford the title compound (388 mg, yield 96%, purity 65%) 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] (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, purity 65%) in dichloromethane (3.9 mL) was suspended and cooled in an ice bath. Sodium acetate (149 mg, 1.82 mmol, 2.03 eq) was added, followed by acetaldehyde (101 mg, 0.130 mL, 2.3 mmol, 2.58 eq). 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 carefully basified with saturated NaHCO3 solution 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, 0% - 10% methanol in dichloromethane) to afford the title compound (85 mg, yield 33%) as an orange foam. LCMS: m / z 272.1 [M+H] + , ESI pos.

[0332] Project 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] (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 No. 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) were added to 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (28 mg, 0.03 mmol, 0.12 eq). The mixture was stirred at 90 °C for 16 h under argon. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and semi-saturated aqueous NH4Cl. 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% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). All fractions containing the product were combined and concentrated in vacuo. Trituration of the residue with ethyl acetate / heptane gave 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

Chemical formula

[0335] (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) in 1,4-dioxane (0.80 mL) and water (0.20 mL), [2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (CAS No. 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) were flushed with argon and stirred at 100 °C for 2.75 h. To the reaction mixture were added at room temperature [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). 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% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)) to give the title compound (49 mg, yield 59%, purity 90%) 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

Chemical Structure

[0337] Project 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 eq., purity 85%) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (465 mg, 0.510 mL, 2.5 mmol, 1.66 eq.) in tetrahydrofuran (6.5 mL) was added dropwise a 1.6 M hexane solution of n-butyllithium (1.9 mL, 3.04 mmol, 2.02 eq.) at -76 °C (maintaining the internal temperature below -68 °C). Stir at -76 °C for 3 h. Warm the reaction mixture to -60 °C, quench at -60 °C with saturated aqueous NH4Cl, warm to room temperature, and then extract with ethyl acetate and saturated aqueous NH4Cl. Back-extract the aqueous layer with ethyl acetate. Wash the organic layer with brine. Combine the organic layers, dry over sodium sulfate, filter, and concentrate in vacuo. Adsorb the crude product onto ISOLUTE HM-N and purify by flash chromatography (silica gel, 25 g, gradient 0% - 10% ethyl acetate in heptane) to obtain the title compound (391 mg, yield 70%) as a colorless oil. LCMS: m / z 351.2 [M+H] + ,ESI pos.

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

[0340] A solution of the above-mentioned 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 equivalent) in ethyl acetate (4.8 mL) was flushed with argon three times, except alternately. Palladium on activated carbon, 10% Pd basis (39 mg, 0.037 mmol, 0.04 equivalent) was carefully added. The reaction flask was evacuated, flushed with argon, evacuated again, and flushed with hydrogen. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere (balloon). The reaction mixture was filtered and thoroughly washed with ethyl acetate / methanol. Concentration of the filtrate in vacuo gave 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-triazine-3-amine (Example 4, Step A) (80 mg, 0.29 mmol, 1.00 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-4-ol (Example 25, Step B) (129 mg, 0.47 mmol, 1.60 eq), potassium carbonate (187 mg, 1.35 mmol, 4.60 eq) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (36 mg, 0.044 mmol, 0.15 eq) in 1,4-dioxane (1.8 mL) and water (0.90 mL) were flushed with argon and stirred at 100 °C for 2.5 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% - 10% methanol in dichloromethane). The residue was triturated with ethyl acetate / heptane. Concentration of the filtrate in vacuo gave 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

Chemical formula

[0344] Project 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 No. 132434-82-3, 277 mg, 1.69 mmol, 1.0 eq) and commercially available indolizidin-8-ylamine (374 mg, 2.53 mmol, 1.5 eq) in 1,4-dioxane (6 mL) at room temperature was added extra-dry (6 mL) and N-ethyldiisopropylamine (303 μL, 1.74 mmol, 1.03 eq), and a brown clear solution was obtained. 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 dried over Na2SO4, 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% - 10% methanol in dichloromethane) to give the title compound as a light brown gum in two fractions: the first fraction (255 mg, 55%) 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] Project B: 2-[5-Methyl-3-[[rac-(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizidin-8-yl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol

Chemical Structure

[0347] The mixture of the foregoing (Example 26 / 27, Step A, Fraction 1) (6-chloro-5-methyl-1,2,4-triazin-3-yl)-indolizidin-8-yl-amine (255 mg, 0.952 mmol, 1.00 equivalent), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (333 mg, 1.62 mmol, 1.70 equivalents) and potassium carbonate (632 mg, 4.57 mmol, 4.80 equivalents) 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 equivalent) was added. It was flushed with argon again, and the sealed tube was stirred at 90 °C for 3 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL) and saturated NH4Cl solution (10 mL), and then extracted with dichloromethane (2 × 40 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered off, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient 0% - 10% methanol in dichloromethane), and then triturated in tert-butyl methyl ether (5 mL) to obtain 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-octahydroindolizidin-8-yl]amino]-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol

Chemical Structure

[0349] (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) of the above (Example 26 / 27, Step A, Fraction 2) were 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. It was flushed with argon again, and the sealed tube was stirred at 90 °C for 3 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL) and saturated NH4Cl sol (10 mL), and then extracted with dichloromethane (2 × 40 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered off, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% - 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-octahydroindolizidin-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-octahydroindolizidin-8-yl]amino]-5-methyl-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol [Chemical formula]

[0351] The aforementioned title compound (Example 26) (92 mg, 0.234 mmol, 1.00 equivalent) was subjected to chiral preparative HPLC (SFC, column Chiral Lux C4, 5 μm, 250×20 mm; method: 25% iPrOH + DEA; 120 bar BPR, 90 mL / min), affording 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) in two fractions.

[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 [Chemical Structure]

[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 eq) 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 eq), then the mixture was stirred at 100 °C for 30 min, then cooled to 20 °C, and commercially available [(E)-aminocarbonohydrazonoyl]ammonium; hydron; carbonate (CAS No. 2582-30-1, 4.54 g, 33.4 mmol, 1.0 eq) was added portionwise at 20 °C and stirred at 20 °C for 3 h. NaOH (16.7 mL in water, 66.7 mmol, 2.0 eq, 4 M) was added (adjusting the pH to about 10), then the mixture was stirred at 20 °C for 36 h. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were 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 = 1:0~3:1) to obtain the title compound (500 mg, yield 9%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) 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 eq) in DMF (6 mL) was added NBS (388.1 mg, 2.19 mmol, 1.2 eq), then the mixture was 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 phases were 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 obtain the title compound (220 mg, yield 50%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 5.94 (br.s, 2H).

[0357] Process 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 eq) in 1,4-dioxane (2 mL) and water (0.500 mL), (2-Hydroxy-4-(trifluoromethyl)phenyl)boronic acid (172.9 mg, 0.84 mmol, 1.2 eq), Na2CO3 (185.4 mg, 1.75 mmol, 2.5 eq), and then Pd(dppf)Cl2 (102.4 mg, 0.14 mmol, 0.2 eq) were added. The reaction mixture was stirred at 100 °C for 2 h under a N2 atmosphere. The reaction mixture was cooled to 25 °C, diluted with water (50 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (50 mL), 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 (180 mg, 79% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (br.s, 1H), 8.08 (br.s, 2H), 7.54 (d, 1H), 7.27 (dd, 1H), 7.18 (s, 1H).

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

[0360] 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) were added to a mixture of benzyl(triethyl)azanium chloride (240.3 mg, 1.05 mmol, 3.8 equiv) in MeCN (3 mL). tert-Butyl nitrite (143.1 mg, 1.39 mmol, 5.0 equiv) was added at 25 °C, and then the mixture was stirred at 70 °C for 1 h under N2. 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

Chemical formula

[0362] Project 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 equivalent) and commercially available indolizidine-6-amine (1824202-77-8, 316.8 mg, 2.26 mmol, 1.50 equivalents) in 1,4-dioxane (4.9 mL) was added N,N-diisopropylethylamine (201 mg, 272 μL, 1.56 mmol, 1.033 equivalents). The reaction mixture was stirred at room temperature overnight. 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% - 10% methanol in dichloromethane) to give the title compound as two fractions: the first fraction (124 mg, yield 29%) as a green solid and the second fraction (80 mg, yield 19%) as a pale green powder. LCMS: m / z 268.3 [M+H] + ,ESI pos.

[0364] Project 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] A solution of the above N-(6-chloro-5-methyl-1,2,4-triazin-3-yl)-indolizidin-6-yl-amine (Process A, Fraction 1) (124 mg, 0.463 mmol, 1.00 equivalent) and [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (138.3 mg, 0.672 mmol, 1.45 equivalents) in 1,4-dioxane was added with extra-dry (1.8 mL) and water (0.45 mL) under cesium carbonate (434.6 mg, 1.33 mmol, 2.88 equivalents) of argon, followed by 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 equivalents). The reaction mixture was flushed with argon and stirred at 100 °C for 1 hour. 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 yellow powder: the first one (56 mg, 31%) and the second one (24 mg, 13%). LCMS (both fractions): m / z 394.3 [M+H] + ,ESI pos.

[0366] In a separate flask: To a solution of the above (Step A, Fraction 2) N-(6-chloro-5-methyl-1,2,4-triazin-3-yl)-indirizidine-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) in 1,4-dioxane, extra dry (0.95 mL) and water (0.24 mL) were added under argon, followed by cesium carbonate (266.3 mg, 0.817 mmol, 2.88 equiv), and then 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 as two fractions as 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 OD-H, 5 μm, 250×20 mm; 10% iPrOH + 0.2% diethylamine) to give two new enantiomeric fractions: the first as Example 31 as an off-white powder (30 mg, 51%), and the second as Example 32 as a white powder (35 mg, 60%). The relative stereochemistry was not investigated at this stage.

[0368] Furthermore, the other two left fractions (24 mg) and (18 mg) mentioned above were combined and subjected to RP separation (column: Gemini N X, 12 nm, 5 μM, 100×30 mm; CAN / water + 0.1% trimethylamine) to obtain two additional enantiomerically pure fractions as white powder 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 International Publication No. 20200234715.

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

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

[0373] Example A The compound of formula I can be used as an active ingredient in a manner known per se for producing tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

[0374] Example B The compound of formula I can be used as an active ingredient in a manner known per se for manufacturing capsules of the following composition. Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims

1. Formula Ib: 【Chemical 1】 wherein R １ and R ５ , and the atoms to which they are attached form any of a 4- to 6-membered heterocyclic ring 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- to 6-membered cycloalkyl ring optionally substituted with one or two substituents independently selected from halo or alkyl; R ２ is H; R ３ is methyl; Z is -NH-; R ４ is a piperidine ring substituted with alkyl) a compound of formula (I) and pharmaceutically acceptable salts thereof.

2. R1 and R5, and the atoms to which they are attached, together form any 4- to 6-membered heterocyclic ring containing only one heteroatom O, or R1 and R5, and the atoms to which they are attached, together form a 3- to 6-membered cycloalkyl ring; R2 is H; R3 is methyl; Z is -NH-; R4 is a piperidine ring substituted with alkyl, the compound according to claim 1.

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

4. A compound that 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-triene-2-ol, or a pharmaceutically acceptable salt thereof.

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

6. A compound according to any one of claims 1 to 5 for use as a therapeutic 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 symptom 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 symptom selected from Alzheimer's disease and Parkinson's disease.

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

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