Oxazolo[4,5-B]pyrazine and oxazolo[4,5-B]pyridine derivatives as NLRP3 inhibitors for the treatment of inflammatory diseases, etc.

Abstract

The present invention relates to a compound of formula (I) which is an NLRP3 inhibitor (NOD-like receptor pyrin domain-containing protein 3) for the treatment of inflammatory diseases and the like. TIFF2026514783000053.tif50161

Description

Technical Field

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

[0002] The present invention relates to a compound of formula I

Chemical formula

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

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

[0005] NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental, and host-derived factors. When activated, NLRP3 binds to apoptosis-related speckled proteins (ASCs) that contain caspase activation and recruitment domains. The ASCs then polymerize to form large aggregates known as ASC specks. The polymerized ASCs then interact with the cysteine ​​protease caspase-1 to form a complex called the inflammasome. This results in the activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (referred to as pro-IL-1β and pro-IL-18, respectively), thereby activating these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. ASC specks can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 to induce apoptotic cell death.

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

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

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

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

[0010] The role of NLRP3 in central nervous system disorders is becoming clearer, and lung diseases have also been shown to be affected by NLRP3. NLRP3 has been suggested to be involved in several central nervous system conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, and brain injury due to pneumococcal meningitis (Walsh et al., Nature Reviews, 15:84-97, 2014, and Dempsey et al. Brain. Behav. Immun. 2017 61:306-316). NLRP3 has also been shown to be involved in several lung diseases, including chronic obstructive pulmonary disease (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al., Am.J. Pathol., 184:42-54, 2014 and Kim et al. Am J Respir Crit Care Med. 2017 196(3):283-97). Furthermore, NLRP3 is involved in the development of liver disease, kidney disease, and aging. Many of these associations are linked to NLRP3. - / - Although defined using mice, insights into the specific activation of NLRP3 in these diseases also exist. In type 2 diabetes (T2D), the deposition of islet amyloid polypeptides in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

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

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

[0013] International Publication No. 2023 / 066825 discloses compounds useful as NLRP3 inhibitors. However, there is a need to provide compounds with improved pharmacological and / or physiological and / or physicochemical properties, as well as compounds that provide useful alternatives to known compounds. Furthermore, when developing NLRP3 inhibitors to treat peripheral indications, it is advantageous to minimize exposure of NLRP3 inhibitor compounds in the brain compared to systemic exposure in order to minimize the risk of potential side effects in the central nervous system (CNS). P-gp (P-glycoprotein) is an important transporter expressed in capillary endothelial cells that constitute the blood-brain barrier and the blood-testis barrier, returning foreign substances to the capillaries and limiting exposure to the brain. Compounds of formula I achieve peripheral preference by showing increased efflux and / or reduced passive permeability in transcellular assays expressing the active P-gp transporter without compromising systemic distribution. By slightly increasing the polar surface area, compounds of formula I surprisingly yield the desired profile and exhibit lower permeability. Furthermore, there was a need for compounds that demonstrate a reduction in the risk of phospholipidosis for chronic indications, using compounds that exhibit a combination of increased polarity and finely tuned pKa. [Overview of the Initiative]

[0014] This invention relates to formula I [ka] A novel compound of which, in the formula, R 1R is cyano, halo, or haloalkyl, 9 is H, or R 1 and R 9 Furthermore, the atoms to which they are bonded form a 5-membered cycloalkyl group or a 5-membered heterocycle containing one oxygen heteroatom; R 2 R is alkyl, hydroxyalkyl, alkoxyalkyl or cyano, 1 If R is cyano, 2 It is not cyano; A1 is -CR 10 -or -N-; R 10 is H, fluoro, or alkoxy; R x is H, alkyl, heteroarylalkyl, hydroxyalkyl, or COOH-alkyl, and the heteroaryl in heteroarylalkyl is oxazolyl, tetrazolyl, or oxadiazolyl; R y is either H or -OH; R 1 If R is a haloalkyl, x R is a hydroxyalkyl or COOH-alkyl, y is -OH, compound and its pharmaceutically acceptable salt, provided that the compound is 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-benzonitrile; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-(methoxymethyl)phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-(methoxymethyl)phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-propyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-methyl-piperidine-3-ol; 5-Chloro-2-[2-[[(3R,5S)-1-ethyl-5-fluoro-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; (3R,5R)-5-[[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-ethyl-piperidine-3-ol; formic acid; (3R,5R)-5-[[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-ethyl-piperidine-3-ol; 5-Chloro-2-[2-[[(3R)-1-(3,3-difluoropropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-3-(hydroxymethyl)-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-2-[2-[[(3R)-1-(3-hydroxypropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-(2-hydroxypropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; (3S,5R)-5-[[5-[4-chloro-2-hydroxy-6-(methoxymethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]-1-methyl-piperidine-3-ol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; 2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[[(3R)-1-[[trans-2-hydroxycyclobutyl]methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol or 5-chloro-2-[2-[[(3R)-1-[[cis-2-hydroxycyclobutyl]methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-ethyl-piperidine-3-ol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-fluoro-3-methylphenol; 5-Fluoro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; formic acid; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-4-[2-[[(3R,5S)-5-Hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-methylbenzonitrile; 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-methylbenzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-Chloro-3-methyl-2-[2-[[(3R)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; dihydrochloride; 5-Chloro-3-methyl-2-[2-[[(3R)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol The present invention provides compounds and their pharmaceutically acceptable salts, provided that they are not compounds selected from the given list. [Brief explanation of the drawing]

[0015] [Figure 1] Voltage patterns for stimulating cells

[0016] The term "alkyl" refers to a monovalent linear or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. In some embodiments, unless otherwise stated, alkyl refers to a group consisting of 1 to 6 carbon atoms (C 1-6 -alkyl) or 1 to 4 carbon atoms (C 1-4 -Contains alkyl) C 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl. Specific alkyl groups are methyl and ethyl.

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

[0018] The term "alkoxyalkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl group is replaced by an alkoxy group. Examples of alkoxyalkyls are methoxymethyl and methoxyethyl. A specific example of an alkoxyalkyl is methoxymethyl.

[0019] The term "cycloalkyl" refers to monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbons. In some embodiments, unless otherwise stated, cycloalkyls contain 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, cycloalkyls are saturated monocyclic or polycyclic hydrocarbons. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0020] The terms "halogen," "halide," and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodine.

[0021] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by a halo. Examples of haloalkyls are trifluoromethyl, difluoromethyl, and fluoromethyl. A specific example is trifluoromethyl.

[0022] The term "heteroaryl" refers to a monovalent aromatic monocyclic or bicyclic ring system of 4 to 9 ring atoms, containing 1, 2, 3, or 4 ring heteroatoms selected from N and O, with the remaining ring atoms being carbon. Examples of heteroaryls include thiazolyl, pyridyl, oxazolyl, tetrazolyl, and oxadiazolyl.

[0023] The term "heteroarylalkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl group is replaced by a heteroaryl group. Examples include oxyzolylethyl, tetrazolylethyl, and oxadiazolylethyl. A specific example is oxazolylethyl.

[0024] The term "heterocyclic" refers to a monocyclic or bicyclic ring system of 4 to 9 ring atoms, which contains 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocyclic rings include azetidinyl, diazepanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and piperazinyl. Examples of polycyclic saturated heterocyclic rings include azaspiroheptanyl, diazaspiroheptanyl, azaspirooctanyl, diazospirooctanyl, diazaspirononanyl, oxazaspirooctanyl, and oxadiazaspirononanyl.

[0025] The term "hydroxy" refers to the -OH group.

[0026] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a hydroxyl group. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylethyl, hydroxymethylpropyl, and dihydroxypropyl. An example of a hydroxyalkyl group is hydroxyethyl.

[0027] The term "cyano" represents a -C≡N group.

[0028] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid and is not biologically or otherwise undesirable. 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, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic base or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, and magnesium. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins. Compounds of formula I can also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of compounds of formula I are salts formed with formic acid, and salts formed with hydrochloric acid that yield hydrochloride, dihydrochloride, or trihydrochloride.

[0029] The abbreviation uM stands for micromoles and is equivalent to the symbol μM.

[0030] The abbreviation uL stands for microliter and is equivalent to the symbol μL.

[0031] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0032] Compounds of formula I may contain several chiral centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers, or mixtures of racemates of diastereoisomers.

[0033] According to the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can have either an "R" or "S" stereoconfiguration.

[0034] Furthermore, one embodiment of the present invention provides a compound according to formula I described herein and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula I described herein and a pharmaceutically acceptable salt thereof, more specifically a compound according to formula I described herein.

[0035] One embodiment of the present invention is given by Formula I [ka] A compound by which, in the formula, R 1 R is cyano, halo, or haloalkyl, 9 is H, or R 1 and R 9 Furthermore, the atoms to which they are bonded form a 5-membered cycloalkyl group or a 5-membered heterocycle containing one oxygen heteroatom; R 2 R is alkyl, hydroxyalkyl, alkoxyalkyl or cyano, 1 If R is cyano, 2 It is not cyano; A1 is -CR 10 -or -N-; R 10 is H, fluoro, or alkoxy; R xis H, alkyl, heteroarylalkyl, hydroxyalkyl, or COOH-alkyl, and the heteroaryl in heteroarylalkyl is oxazolyl, tetrazolyl, or oxadiazolyl; R y is either H or -OH; R 1 If R is a haloalkyl, x R is a hydroxyalkyl or COOH-alkyl, y is -OH, compound and its pharmaceutically acceptable salt, provided that the compound is 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-benzonitrile; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-(methoxymethyl)phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-(methoxymethyl)phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-propyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-methyl-piperidine-3-ol; (3R,5R)-5-[[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-ethyl-piperidine-3-ol; formic acid; (3R,5R)-5-[[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-ethyl-piperidine-3-ol; 5-Chloro-2-[2-[[(3R)-1-(3,3-difluoropropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-3-(hydroxymethyl)-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-2-[2-[[(3R)-1-(3-hydroxypropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-(2-hydroxypropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; (3S,5R)-5-[[5-[4-chloro-2-hydroxy-6-(methoxymethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]-1-methyl-piperidine-3-ol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-ethyl-piperidine-3-ol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-fluoro-3-methylphenol; 5-Fluoro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; formic acid; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-4-[2-[[(3R,5S)-5-Hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-methylbenzonitrile; 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-methylbenzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-Chloro-3-methyl-2-[2-[[(3R)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; dihydrochloride; 5-Chloro-3-methyl-2-[2-[[(3R)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol A compound that is not selected from the following: The present invention provides both the present invention and its pharmaceutically acceptable salts.

[0036] One embodiment of the present invention is R 1 However, it is cyano or haloalkyl, R9 Is H or R 1 and R 9 The present invention provides a compound according to formula I, wherein the atoms to which they are bonded form a five-membered heterocycle containing one oxygen heteroatom.

[0037] One embodiment of the present invention is R 1 is cyano, R 9 Is H or R 1 and R 9 The present invention provides a compound according to formula I, wherein the atoms to which they are bonded form a five-membered heterocycle containing one oxygen heteroatom.

[0038] One embodiment of the present invention is R 1 is cyano, R 9 This specification provides compounds according to formula I, wherein H is present.

[0039] One embodiment of the present invention is R 1 and R 9 The present invention provides a compound according to formula I, wherein the atoms to which they are bonded form a five-membered heterocycle containing one oxygen heteroatom.

[0040] One embodiment of the present invention is R 2 The present specification provides compounds according to formula I, which are alkyl or alkoxyalkyl.

[0041] One embodiment of the present invention provides a compound according to formula I described herein, wherein A1 is -N-.

[0042] One embodiment of the present invention is R 10 The present specification provides compounds according to formula I, wherein H is or an alkoxy.

[0043] One embodiment of the present invention is R 10 The present specification provides a compound according to formula I, wherein H is present.

[0044] One embodiment of the present invention is Rx The present specification provides compounds according to formula I, wherein H is alkyl, heteroarylalkyl, hydroxyalkyl, or COOH-alkyl, and the heteroaryl of the heteroarylalkyl is oxazolyl.

[0045] One embodiment of the present invention is R x The present specification provides compounds according to formula I, wherein H is alkyl, heteroarylalkyl or hydroxyalkyl, and the heteroaryl of the heteroarylalkyl is oxazolyl.

[0046] One embodiment of the present invention is R x The present specification provides compounds according to formula I, wherein the compound is an alkyl, heteroarylalkyl, or hydroxyalkyl, and the heteroaryl of the heteroarylalkyl is oxazolyl.

[0047] One embodiment of the present invention is R x The present specification provides compounds according to formula I, which are alkyl or hydroxyalkyl.

[0048] One embodiment of the present invention is R x The present specification provides a compound according to formula I, which is a hydroxyalkyl compound.

[0049] One embodiment of the present invention is R y The present specification provides a compound according to formula I, wherein H is present.

[0050] One embodiment of the present invention is a compound according to formula I described herein, wherein, R 1 However, it is cyano or haloalkyl, R 9 Is H, or R 1 and R 9 Furthermore, the atoms to which they are bonded form a five-membered heterocycle containing one oxygen heteroatom; R 2 However, it is alkyl or alkoxyalkyl; A1 is -CR 10 - or -N-; R 10 is H or alkoxy; R x is H, alkyl, heteroarylalkyl, hydroxyalkyl or COOH-alkyl, and the heteroaryl of heteroarylalkyl is oxazolyl; R y is H or -OH; R 1 When R is haloalkyl, R x is hydroxyalkyl or COOH-alkyl, and R y is -OH, a compound and its pharmaceutically acceptable salts are provided.

[0051] One embodiment of the present invention is a compound according to formula I described herein, wherein R 1 is cyano, and R 9 is H, or R 1 and R 9 and the atoms to which they are attached form a 5-membered heterocyclic ring containing one O heteroatom; R 2 is alkyl or alkoxyalkyl; A1 is -CR 10 - or -N-; R 10 is H or alkoxy; R x is alkyl or hydroxyalkyl; R y is H or -OH, a compound and its pharmaceutically acceptable salts are provided.

[0052] One embodiment of the present invention is a compound according to formula I described herein, wherein R 1 is cyano, and R 9 is H, or R 1 and R9 and the atoms to which they are attached form a 5-membered heterocycle containing one O heteroatom; R 2 is alkyl or alkoxyalkyl; A1 is -CR 10 - or -N-; R 10 is H; R x is hydroxyalkyl; R y is H, a compound and its pharmaceutically acceptable salts are provided.

[0053] One embodiment of the present invention is a compound according to formula I described herein, wherein, R 1 and R 9 and the atoms to which they are attached form a 5-membered heterocycle containing one O heteroatom; R 2 is alkyl or alkoxyalkyl; A1 is -CR 10 - or -N-; R 10 is H; R x is hydroxyalkyl; R y is H, a compound and its pharmaceutically acceptable salts are provided.

[0054] One embodiment of the present invention is a compound according to formula I described herein, wherein, R 1 and R 9 and the atoms to which they are attached form a 5-membered heterocycle containing one O heteroatom; R 2 is alkyl or alkoxyalkyl; A1 is -N-; R 10 is H; R x is hydroxyalkyl; R y However, the compound is H. The present invention provides both the present invention and its pharmaceutically acceptable salts.

[0055] One embodiment of the present invention is a compound according to formula I described herein, wherein, R 1 is cyano, R 9 H is; R 2 However, it is alkyl or alkoxyalkyl; A1, -CR 10 -or -N-; R 10 However, it is H or alkoxy; R x However, H is alkyl, heteroarylalkyl or hydroxyalkyl, and the heteroaryl in heteroarylalkyl is oxazolyl; R y However, the compound is H or -OH. The present invention provides both the present invention and its pharmaceutically acceptable salts.

[0056] One embodiment of the present invention is a compound according to formula I described herein, wherein, R 1 is cyano, R 9 H is; R 2 However, it is alkyl or alkoxyalkyl; A1 is -N-; R 10 However, it is H or alkoxy; R x However, H is alkyl, heteroarylalkyl or hydroxyalkyl, and the heteroaryl in heteroarylalkyl is oxazolyl; R y is a compound that is H or -OH. The present invention provides both the present invention and its pharmaceutically acceptable salts.

[0057] One embodiment of the present invention is a compound according to formula I described herein, wherein, R 1 is cyano, R 9 H is; R 2 However, it is alkyl or alkoxyalkyl; A1, -CR 10 -or -N-; R 10 However, H is; R x However, it is alkyl, heteroarylalkyl or hydroxyalkyl, where the heteroaryl of the heteroarylalkyl is oxazolyl; R y However, the compound is H or -OH. The present invention provides both the present invention and its pharmaceutically acceptable salts.

[0058] One embodiment of the present invention is a compound according to formula I described herein, wherein, R 1 is cyano, R 9 H is; R 2 However, it is alkyl or alkoxyalkyl; A1 is -N-; R 10 However, H is; R x However, it is alkyl, heteroarylalkyl or hydroxyalkyl, where the heteroaryl of the heteroarylalkyl is oxazolyl; R y However, the compound is H or -OH. The present invention provides both the present invention and its pharmaceutically acceptable salts.

[0059] Specific examples of compounds of formula I described herein are: 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-(2-oxazole-2-ylethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-(methoxymethyl)benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; Selected from the pharmaceutically acceptable salts thereof.

[0060] Other specific examples of compounds of formula I described herein are: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methylbenzonitrile; Selected from the pharmaceutically acceptable salts thereof.

[0061] Other specific examples of compounds of formula I described herein are: 4-[(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]-1-piperidyl]butanoic acid; (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol; 3-Hydroxy-4-[2-[[(3R,5S)-5-Hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-Hydroxy-4-[2-[[(3R,5S)-5-Hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-methylbenzonitrile; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methylbenzonitrile; Selected from the pharmaceutically acceptable salts thereof.

[0062] Other specific examples of compounds of formula I described herein are: (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol; 3-Hydroxy-4-[2-[[(3R,5S)-5-Hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methylbenzonitrile; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile; Selected from the pharmaceutically acceptable salts thereof.

[0063] Other specific examples of compounds of formula I described herein are: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; Selected from the pharmaceutically acceptable salts thereof.

[0064] Other specific examples of compounds of formula I described herein are: 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-(methoxymethyl)benzonitrile; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-indan-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-methyl-indan-4-ol; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-(methoxymethyl)benzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; (3S,5R)-1-(2-hydroxyethyl)-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazine-2-yl]amino]piperidine-3-ol; (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazine-2-yl]amino]piperidine-3-ol; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-(methoxymethyl)benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7-fluoro-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-(3-oxazol-2-ylpropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 4-[7-fluoro-2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol; Selected from the pharmaceutically acceptable salts thereof.

[0065] Preferred examples of compounds of formula I described herein are: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methylbenzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; Selected from the pharmaceutically acceptable salts thereof.

[0066] Other preferred examples of compounds of formula I described herein are: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; and 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methylbenzonitrile Selected from.

[0067] A more preferred example of a compound of formula I described herein is: 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methylbenzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; Selected from the pharmaceutically acceptable salts thereof.

[0068] The most preferred example of a compound of formula I described herein is: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; Selected from the pharmaceutically acceptable salts thereof.

[0069] The most preferred example of the compound of formula I described herein is 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol, or a pharmaceutically acceptable salt thereof.

[0070] Another embodiment of the present invention provides pharmaceutical compositions or pharmaceuticals containing the compounds of the present invention and therapeutic inert carriers, diluents or excipients, as well as methods for using the compounds of the present invention to prepare such compositions and pharmaceuticals. In one example, the compound of formula I can be formulated into a galenic dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to the recipient at the dose and concentration used, at ambient temperature, at a suitable pH, and to a desired degree of purity. The pH of the formulation depends primarily on the specific application and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula I is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula I is sterile. The compounds can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0071] The composition is formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical symptoms, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the healthcare professional.

[0072] The compounds of the present invention may be administered by any suitable means, including orally, topically (including buccal and sublingual), rectally, vaginally, percutaneously, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, intrathecally and epidurally, as well as intranasally, and, if desired for topical treatment, intrafocal administration. Parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0073] 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, and patches. Such compositions may contain common components in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and further active agents.

[0074] Typical formulations are prepared by mixing the compound of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C., Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, smoothing agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow enhancers, processing aids, colorants, sweeteners, flavorings, diluents, and other known additives for providing a drug (i.e., the compound of the present invention or its pharmaceutical composition) in an appealing manner or for assisting in the manufacture of a pharmaceutical product (i.e., a pharmaceutical).

[0075] Compounds of formula I and pharmaceutically acceptable salts thereof can be treated with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injectable solutions, or topical formulations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used as such adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules, for example.

[0076] Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0077] Suitable adjuvants for the production of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0078] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerol, and vegetable oil.

[0079] Suitable adjuvants for suppositories include, for example, natural or hydrogenated oils, waxes, fats, and semi-solid or liquid polyols.

[0080] Suitable adjuvants for topical ophthalmic formulations include, for example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0081] Furthermore, pharmaceutical preparations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts, buffers, masking agents, or antioxidants to alter osmotic pressure. They may also contain other substances of therapeutic value.

[0082] Dosage can vary widely and, of course, to suit the individual requirements of each specific case. Generally, for oral administration, a daily dose of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g., about 300 mg per person), is preferably divided into 1 to 3 individual doses, which, if appropriate, may consist of equal amounts, for example. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be between 0.1 and 25 mg, can be administered by a single dose per day or per week, by multiple doses per day (2 to 4 times), or by multiple doses per week. However, where indicated, it will be clear that the upper or lower limits given herein may be exceeded.

[0083] One embodiment of the present invention is a compound according to Formula I described herein for use as a therapeutically active substance.

[0084] One embodiment of the present invention is a compound according to Formula I described herein for use in the treatment or prevention of a disease, disorder, or symptom, wherein the disease, disorder, or symptom is responsive to NLRP3 inhibition.

[0085] One embodiment of the present invention is a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or symptom, the disorder or symptom being responsive to NLRP3 inhibition.

[0086] As used herein, the term "NLRP3 inhibition" refers to a complete or partial reduction of the activity level of NLRP3, including, for example, inhibition of active NLRP3 and / or inhibition of NLRP3 activation.

[0087] There is evidence regarding the roles of NLRP3-induced IL-1 and IL-18 in inflammatory responses associated with or resulting from numerous different disorders (Menu et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

[0088] In one embodiment, the disease, disorder, or symptom is selected from the following: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) metabolic diseases; (vi) cardiovascular disease; (vii) respiratory diseases; (viii) Liver disease; (ix) renal disease; (x) eye diseases; (xi) skin diseases; (xii) Lymphatic symptoms; (xiii) Graft-versus-host disease; (xiv) Allodynia; (xv) Symptoms associated with diabetes; and (xvi) Any disease determined that the individual has a germline or somatic non-silent mutation in NLRP3.

[0089] In another embodiment, the disease, disorder or symptom is selected from: (i) Cancer; (ii) Infectious diseases; (iii) Cardiovascular diseases; (iv) Liver diseases; (v) Eye diseases; and (vi) Skin diseases.

[0090] In a further exemplary embodiment of the present invention, the disease, disorder or symptom is 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 spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis or Reiter's disease); (iii) Muscle symptoms such as polymyositis or myasthenia gravis; (iv) Gastrointestinal tract 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, caseous rhinitis, hypertrophic rhinitis, purulent rhinitis (rhinitis pumlenta), 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) Ocular symptoms such as uveitis, allergic conjunctivitis or vernal conjunctivitis; (ix) Infectious diseases 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 of 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; (x) 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; (xi) Lymphatic symptoms such as Castleman's disease; (xii) Conditions of the immune system or related thereto, such as hyper-IgE syndrome, hepatoblastomatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (xiii) Liver conditions such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, hepatic fibrosis, or liver failure; (xiv) Cancers including the above-mentioned cancers; (xv) burns, wounds, injuries, bleeding, or stroke; (xvi) radiation exposure; (xvii) metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or (xiii) Pain such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.

[0091] One embodiment of the present invention is a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or symptom selected from the following: inflammation; autoimmune diseases; cancer; infectious diseases; metabolic diseases; cardiovascular disease; respiratory diseases; Liver disease; kidney disease; eye diseases; skin diseases; Lymphatic symptoms; Graft-versus-host disease; Allodynia; Symptoms associated with diabetes; and Any disease in which an individual is determined to have germline or somatic non-silent mutations in NLRP3.

[0092] One embodiment of the present invention is the use of a compound according to Formula I described herein in the treatment or prevention of a disease, disorder, or symptom, wherein the disease, disorder, or symptom is responsive to NLRP3 inhibition.

[0093] One embodiment of the present invention is the use of a compound according to Formula I described herein for use in the treatment or prevention of a disease, disorder, or symptom selected from asthma and COPD.

[0094] One embodiment of the present invention is the use of a compound according to Formula I described herein for the treatment or prevention of cardiovascular disease, disorder, or symptoms.

[0095] One embodiment of the present invention is the use of a compound according to Formula I described herein for the treatment or prevention of cardiovascular metabolic diseases, disorders, or symptoms.

[0096] One embodiment of the present invention is the use of a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or symptom selected from cryopyrin-associated periodic syndromes.

[0097] One embodiment of the present invention is a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or symptom selected from asthma and COPD.

[0098] One embodiment of the present invention is a compound of formula I described herein for the treatment or prevention of cardiovascular disease, disorder, or symptoms.

[0099] One embodiment of the present invention is a compound of formula I described herein for the treatment or prevention of cardiovascular metabolic diseases, disorders, or symptoms.

[0100] One embodiment of the present invention is a compound according to Formula I described herein for treating or preventing a disease, disorder, or symptom selected from cryopyrin-associated periodic syndromes.

[0101] One embodiment of the invention is the use of a compound according to formula I described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma and COPD.

[0102] One embodiment of the invention is the use of a compound according to formula I described herein for the preparation of a medicament for the treatment or prevention of a cardiovascular disease, disorder or condition.

[0103] One embodiment of the invention is the use of a compound according to formula I described herein for the preparation of a medicament for the treatment or prevention of a cardiometabolic disease, disorder or condition.

[0104] One embodiment of the invention is the use of a compound according to formula I described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from cryopyrin-associated periodic syndromes.

[0105] One embodiment of the invention is a method for the treatment or prevention of a disease, disorder or condition selected from asthma and COPD, the method comprising administering an effective amount of a compound according to formula I described herein.

[0106] One embodiment of the invention is a method for treating or preventing a cardiovascular disease, disorder or condition, the method comprising administering an effective amount of a compound of formula I described herein.

[0107] One embodiment of the invention is a method for treating or preventing a cardiometabolic disease, disorder or condition, the method comprising administering an effective amount of a compound of formula I described herein.

[0108] One embodiment of the invention is a method for treating or preventing a disease, disorder or condition selected from cryopyrin-associated periodic syndromes, the method comprising administering an effective amount of a compound of formula I described herein.

[0109] One embodiment of the present invention relates to a method for inhibiting NLRP3, comprising administering an effective amount of a compound according to Formula I described herein.

[0110] Furthermore, one embodiment of the present invention is a compound of formula I described herein, when manufactured according to any one of the processes described.

[0111] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to Formula I described herein and a therapeutically inactive carrier.

[0112] Assay procedure NLRP3 and pyroptosis It is well established that NLRP3 activation leads to cellular pyroptosis, and that this characteristic plays a crucial role in the manifestation of clinical diseases (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, inhibitors of NLRP3 are expected to block pyroptosis and the release of pro-inflammatory cytokines (e.g., IL-1β) from cells.

[0113] THP-1 cells: culture and preparation THP-1 cells (ATCC#TIB-202) were grown in RPMI containing L-glutamine (Gibco#11835) supplemented with 1 mM sodium pyruvate (Sigma#S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma#P4333) in 10% fetal bovine serum (FBS) (Sigma#F0804). The cells were periodically passaged until confluence (approximately 10) 6 Cells were grown to a concentration of 625,000 cells / ml. On the day of the experiment, THP-1 cells were collected and resuspended in RPMI medium (without FBS). The cells were then counted, and viability (>90%) was confirmed by trypan blue (Sigma#T8154). Appropriate dilution was performed to obtain a concentration of 625,000 cells / ml. LPS (Sigma#L4524) was added to this diluted cell solution to obtain a final assay concentration (FAC) of 1 μg / ml. 40 μl of the final preparation was dispensed into each well of a 96-well plate. The plates prepared in this way were used for compound screening.

[0114] THP-1 cell pyroptosis assay For compound screening, we followed the stepwise assay method described below.

[0115] THP-1 cells (25,000 cells / well) containing 1.0 μg / ml of LPS are seeded into 40 μl of RPMI medium (without FBS) in a 96-well black-walled, transparent-bottom cell culture plate (VWR#734-0317) coated with poly-D-lysine.

[0116] Add 5 μl of the compound (8-point semi-logarithmic dilution using the highest dose of 10 μM) or the vehicle (DMSO 0.1% FAC) to the appropriate well.

[0117] Incubate at 37°C with 5% CO2 for 3 hours.

[0118] Add 5 μl of nigericin (Sigma # N7143) (FAC 5 μM) to all wells.

[0119] Incubate at 37°C and 5% CO2 for 1 hour.

[0120] At the end of the incubation period, rotate the plate at 300xg for 3 minutes and remove the supernatant.

[0121] Next, add 50 μl of resazurin (Sigma #R7017) (resazurin with 100 μM FAC in RPMI medium without FBS), and incubate the plate at 37°C and 5% CO2 for a further 1-2 hours.

[0122] The plates were read using an Envision reader at Ex 560nm and Em 590nm.

[0123] I C 50 Fitting the data to a nonlinear regression equation (log-inhibitor versus response variable gradient, 4 parameters)

[0124] The results of the pyroptosis assay were obtained from THP IC. 50 This is summarized in Table 1 below.

[0125] Human whole blood IL-1β release assay For systemic delivery, the ability of a compound to inhibit NLRP3 when present in the bloodstream is crucial. Therefore, the NLRP3 inhibitory activity of numerous compounds in human whole blood was investigated according to the following protocol.

[0126] Human whole blood in Li-heparin tubules was obtained from healthy donors selected from a volunteer donor panel.

[0127] Plate out 80 μl of whole blood containing 1 μg / ml of LPS into a 96-well clear-bottom cell culture plate (Corning #3585).

[0128] Add 10 μl of the compound (8-point semi-logarithmic dilution using the highest dose of 10 μM) or the vehicle (DMSO 0.1% FAC) to the appropriate well.

[0129] Incubate at 37°C with 5% CO2 for 3 hours.

[0130] Add 10 μl of nigericin (Sigma # N7143) (10 μM FAC) to all wells.

[0131] Incubate at 37°C and 5% CO2 for 1 hour.

[0132] At the end of the incubation period, rotate the plate at 300×g for 5 minutes to pellet the cells, remove 20 μl of supernatant, and add it to a 96-well v-bottom plate for IL-1β analysis (Note: These plates, including the supernatant, can be stored at -80°C for analysis on a later date).

[0133] IL-1β was measured according to the manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000).

[0134] I C 50 Fitting the data to a nonlinear regression equation (log-inhibitor versus response variable gradient, 4 parameters)

[0135] Results of human whole blood assays, HWB IC 50 This is summarized in Table 1 below.

[0136] Microsomal stability: Microsomes (0.5 mg / mL) and 1 μM of the test compound in cofactor NADPH were incubated in a 96-well plate at 37°C using a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system. After a 10-minute pre-incubation step with the microsomes and test compound, the enzymatic reaction was initiated by adding the cofactor. Aliquots of the incubation were taken at 1, 3, 6, 9, 15, 25, 35, and 45 minutes and quenched with 1:3 (v / v) acetonitrile containing an internal standard. The samples were then cooled, centrifuged, and the supernatant was analyzed by LC-MS / MS2.

[0137] Metabolic stability in hepatocytes: Assay description: Biological materials. Obtain cryopreserved hepatocytes [mouse, rat, rabbit, monkey, and human (mixed sexes)]. The viability of reconstituted hepatocytes should be at least 80% throughout the entire experiment. Obtain ready-to-use rat / human HepatoPac® culture medium [long-term hepatocyte co-culture medium; pool (human male n=5, and female n=5)], stromal mouse fibroblasts (negative control; pool), incubation plates, application medium, and maintenance medium.

[0138] Metabolism by suspended hepatocytes. First, pooled cryopreserved hepatocytes were reconstituted in pre-warmed William's E medium containing 10% FCS, 0.05 mg / mL streptomycin and 50 U / mL penicillin, and 0.4 mM L-glutamine; as well as 0.01 mg / mL gentamicin, 0.048 mg / mL hydrocortisone, and 0.004 mg / mL insulin, to a final suspension density of 1 × 10⁶ cells / mL. Incubation was performed fully automated using a Liquid Handling System (Tecan) equipped with a CO₂ incubator with an orbital shaker. After adding, for example, 1 μM of the test compound to each well (1 × 10⁵ cells / well), the 96-well hepatocyte suspension culture plate was incubated at 5% CO₂, 37°C. The sample was quenched at specified time points up to 2 hours by adding acetonitrile (containing the internal standard) to the incubation wells.

[0139] The test substance (e.g., 1 μM, 0.1% v / v DMSO) used in the HepatoPac® metabolic suspension assay is incubated in a 96-well plate containing either adherent hepatocytes co-cultured with mouse fibroblast control cells, or control cells alone (5% CO2 atmosphere, 37°C). The incubation medium for human HepatoPac® is the same as that used in the suspended hepatocytes. At predetermined time points (2, 18, 26, 48, 72, and 96 hours), all wells are quenched with ice-cold acetonitrile containing an internal standard.

[0140] Subsequently, the sample is properly centrifuged, and the supernatant is analyzed by LC-MS / MS. Incubation is performed with n=1 or n=2.

[0141] hERG Screening Assay In the development process of small molecule drugs, arrhythmias are one of the most frequent side effects that lead to drug failure. Such failures are often related to the drug's ability to inhibit human ether-a-go-go related gene (hERG) cardiac potassium channels. Therefore, no or low inhibition of hERG cardiac potassium channels is considered beneficial.

[0142] cell A CHO clerox hERG cell line (ATCC reference Nr. PTA-6812, female Chinese hamster cells) was generated and validated using Roche. Immediately usable frozen CHO-hERG cells were cryopreserved at Evotec (Germany) and used directly in experiments.

[0143] Experimental solution The extracellular solution contains the following (in mM): NaCl 150; KCl 4; CaCl21; MgCl21; HEPES 10; pH 7.2-7.4 with NaOH, osmolality 290-330 mOsm. The internal solution contains the following (in mM): KCl 10; KF 100; NaCl 10; HEPES 10; EGTA 20; pH 7.0-7.4 with KOH, osmolality 260-300 mOsm.

[0144] Electrophysiology The effect of the compound on the hERG K+ current parameter will be evaluated at two concentrations in at least four cells.

[0145] The hERG test is performed using the SynchroPatch® 384 automated patch clamp system (Nanion Technologies GmbH, Germany). The K+ current is measured at 35-37°C in a whole cell composition using patch voltage clamp technology.

[0146] The cells were held at a quiescent voltage of -80mV and stimulated with the voltage pattern shown in Figure 1 (outward K at 35-37°C). + The pulse pattern used to extract the current activated the hERG channel with a stimulation frequency of 0.1 Hz (6 bpm), conducting an outward IKhERG current.

[0147] Data Analysis The amplitude of the IKhERG was recorded at each drug concentration and fractional blocks were defined by comparing it to the vehicle control value (set as 100%). The concentration-response data were fitted according to the following relationship: [Table 1]

[0148] The concentration-response curves were fitted using nonlinear regression analysis with the EworkBook suite (ID Business Solutions Ltd, UK). Data fitting was performed using a four-parameter logistic model (fit=(A+(B / (1+((x / C)^D)))), where A=0 and B=100).

[0149] hERG assay results, hERG IC 20 This is summarized in Table 2 below.

[0150] Transcellular P-gp assay: A typical assay uses transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human P-gp or mouse P-gp, cultured on a 96-well semipermeable filter membrane plate, where these cells form a polarized monolayer with tight junctions, acting as a barrier between the apical and basal-lateral compartments.

[0151] P-gp is expressed on the apical membrane of the cell monolayer. The adhesion of the cell monolayer and the functional activity of P-gp are confirmed by the addition of Lucifer Yellow, a cell impermeability marker, and edoxaban, a reference P-gp substrate, respectively. (J. Pharmacol. Exp Ther., 2021, 376, 322-329.)

[0152] PAMPA: PAMPA (Parallel Microwave Permeability Assay) is a first-line permeability screening method for drug candidates. The PAMPA assay uses an artificial phospholipid membrane to mimic transcellular absorption conditions. This assay determines permeability values ​​that can be used for compound optimization and ranking, as well as for input parameters in in silico models predicting intestinal absorption.

[0153] The donor concentration is measured at t-start (reference) and compared with the donor and acceptor concentrations after a certain period of time (t-end) to calculate the extent to which the compound passes through the membrane.

[0154] Bacterial reverse mutagenesis test (AMES): The compound testing is performed as outlined in these guidelines. Test No. 471: Bacterial Reverse Mutation Test | OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects | OECD iLibrary (oecd-ilibrary.org)

[0155] Bacterial culture: The bacterial strains used were TA98, TA100, TA1535, TA97a, and TA102. Batch of each strain was maintained as frozen stock. The vials were thawed and used for inoculation into cultures in nutrient broth. The cultures were placed in an incubator set to 37°C with agitation for approximately 10 hours to obtain working cultures of at least 10⁸ cells / mL.

[0156] To ensure that the cultures are at the appropriate stage of growth and culture density, samples are taken from each culture at the end of the incubation period and the culture density is evaluated by either viability plating or OD650 assessment.

[0157] treatment: Each compound and positive control concentration is included in a 3-series, and each vehicle control in a 6-series.

[0158] The formulation is prepared using DMSO and allows for exposure up to the solubility limit or a maximum exposure of 1000 μg / well for the freely soluble test substance. This concentration is equivalent to 5000 μg / plate used in a typical plate-integrated Ames assay.

[0159] Concentrations are typically separated at semi-logarithmic intervals in a single experiment. For soluble compounds, the concentrations are 0, 3.2, 10, 32, 100, 320, and 1000 μg / well.

[0160] The positive controls used are as follows: Abbreviations, names, and stocks are used for this purpose. 2NF 2-Nitrofluorene TA98-S-9 NaN3 Sodium azide TA100 and TA1535-S-9 AAC 9-aminoacridin TA97a-S-9 MMC Mitomycin C TA102-S-9 B[a]P benzo[a]pyrene TA98+S-9 AAN Aminoanthracene TA100, TA1535, TA97a and TA102+S-9

[0161] Plating is achieved by the following series of additions to 400 μL of replenished molten agar at 45 ± 1°C. 20 μL bacterial culture • 20 μL of test substance solution / vehicle control / positive control • 100 μL of 10% S-9 mix or buffer solution Then, mix quickly and pour into the mutation plate (wells).

[0162] Once solidified, invert the plate and incubate it in a dark incubator set to 37°C for 2-3 days.

[0163] toxicity: Toxicity is detected by the following parameters: • Reduction of background loans • Significant reduction in revertant mutants compared to the simultaneous vehicle control. • Reduction of mutagenic response.

[0164] Scoring: Bacterial colonies are scored manually or electronically using an automated colony counter.

[0165] In vitro mammalian cell micronucleus test: The testing of the compound is carried out as outlined in these guidelines. Test number 487: In vitro mammalian cell micronucleus test | OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects | OECD iLibrary (oecd-ilibrary.org)

[0166] Cell culture: The cultures are maintained in tissue culture flasks containing HEPES-buffered RPMI 1640 medium containing GlutaMAX-1 with 10% (v / v) heat-inactivated fetal bovine serum and 100 units / mL / 100 μg / mL penicillin / streptomycin, in a humidified incubator set to 37°C and 5% (v / v) CO2 in air. The cells are subcultured at low to medium density at least once before treatment.

[0167] The day before the procedure, the cells are subcultured at a density of approximately 7 × 10⁴ cells / mL. The cells are maintained in a humidified environment before the procedure at 37°C and 5% (v / v) CO₂ in the air.

[0168] treatment: Cultured human lymphoblastoid TK6 cells were exposed to a compound for 3 hours in the presence of S-9, followed by a 24-hour recovery period. Furthermore, a continuous 27-hour treatment in the absence of S-9 was included, as several chemicals have been reported to only exhibit a positive effect after prolonged treatment. This corresponds to approximately 1.5–2.0 times the average generation time of TK6 cells used in this laboratory (cell cycle approximately 15 hours). All cultures were sampled 27 hours after the start of treatment.

[0169] Prepare a diluent in DMSO that allows for maximum exposure up to the solubility limit, whichever is lower: 1 mM or 500 μg / mL.

[0170] Typically, at least 12 concentrations are spaced 0.7 times apart from the upper limit (for soluble compounds with MW ≥ 500, the concentrations are 9.887, 14.12, 20.18, 28.82, 41.18, 58.82, 84.04, 120.1, 171.5, 245, 350, and 500 μg / mL). The final concentration of DMSO is 1% v / v. Positive controls are noscapine in the absence of S-9 and cyclophosphamide in the presence of S-9. Each treatment is placed in a 96-well plate with two sets of compounds and multiple co-vehicles and positive controls at each concentration, and incubated at 37°C and 5% (v / v) CO2 for the treatment time. Wash the 3-hour treated culture once and re-incubate in fresh medium for 24 hours.

[0171] Collection: At the specified sampling time, aliquots of cell suspension from the designated culture will be taken for cell counting using a Coulter Counter. The designated culture for analysis will be centrifuged at approximately 200 g for 5 minutes. After resuspending the cells in 0.075 M KCl, fix them with fresh cold methanol / glacial acetic acid (7:1 v / v). The fixed cells will be stored in the fixative at 2–8°C before slide preparation. Air-dry the slides before staining, immerse them in 12.5 μg / mL acridine orange in phosphate-buffered saline (PBS), pH 6.8 for approximately 10 minutes, and then wash with PBS for several seconds (with agitation).

[0172] Cytotoxicity readout and concentration selection: Toxicity is expressed as population doubling (PD) compared to the vehicle control. PD is calculated for each concentration as follows: PD = [log(N / X0)] / log2 In the formula, N = average final cell number at each concentration / culture X0 = Start (baseline) count

[0173] The maximum concentration for micronucleus analysis should not exceed (approximately) 50% cytotoxicity, be the highest concentration tested, or be the lowest precipitate concentration observed by eye at the end of the treatment incubation period. Analyze slides from the highest selective concentration and at least two lower concentrations to cover the range of cytotoxicity from maximum to almost or none, as needed. A minimum of 1000 mononuclear cells (2000 per concentration) from each culture will be analyzed for micronuclei.

[0174] Evaluation criteria: The compound is thought to induce chromosomal abnormalities and / or aneuploidy events in the following cases: -A statistically significant increase in the frequency of MNMON cells is observed at concentrations of 1 or more. - The incidence of cells with such a concentration of micronuclei exceeds the normal range in both replicates. - A concentration-related increase in the proportion of cells with micronuclei is observed (positive trend test).

[0175] If all of the above criteria are met, the compound is considered positive in this assay.

[0176] If none of the above criteria are met, the compound is considered negative in this assay.

[0177] Results that only partially meet the above criteria are treated on a case-by-case basis, but in the context of screening studies, they are concluded as either positive, negative, or inconclusive. Evidence of concentration-related effects is considered useful, but is not essential for evaluating positive results. Biological relevance takes into account, for example, the consistency of responses within and between concentrations, and between experiments (where applicable), or effects that occur only at highly toxic concentrations.

[0178] Pharmacokinetic profiles of test substances in miniature pigs: The pharmacokinetics of the test substance were determined in miniature pigs after intravenous and oral administration. The experimental design consisted of three male miniature pigs, each receiving a single intravenous bolus and a single oral dose with the test item. The intravenous dose was administered at a nominal dose volume of 1 mL / kg. The oral dose was administered via gastric administration at a nominal dose volume of 5 mL / kg. There was a washout period of at least 7 days between the last sampling and the next administration to the same animal. The content of all formulations was within the desired range of 85–115% of the nominal content. After administration, blood samples (1 mL) were collected from the saphenous vein (via cannula) or jugular vein of each animal before administration, and at 5, 15, and 30 minutes after IV administration, and at 1, 2, 4, 8, and 24 hours after administration, and at 15, 30 minutes before, 1, 2, 4, 6, 8, 24, and 48 hours after oral administration. Hematocrit was calculated at all time points. Blood:plasma partition coefficients were determined at 2 and 4 hours, and urine was collected as a single sample over 24 hours post-dose administration. Blood samples (nominal 1 mL) were collected from the saphenous vein (via cannula) or jugular vein of each animal into polypropylene tubes containing K2EDTA anticoagulant, and centrifuged (1500 g, 10 min, 4°C) to prepare plasma for analysis. Remaining blood cells were discarded. Plasma vials were capped and stored on wet ice for 60 minutes or less, then transferred to storage at <-50°C (nominal -80°C) before analysis by specific LC-MS methods.

[0179] Toxicity evaluation of test substances in miniature pigs The maximum tolerated dose (MTD) of the test item is determined after once-daily oral (gastric) administration to miniature pigs. The toxicity of repeated daily administrations for 14 days is then evaluated. Furthermore, the toxicological profile of the test item is characterized. Sufficiently reared Gottingen miniature pigs are obtained from Ellegaard Gottingen, Dalmose, Denmark (animals: 2-3 months old and 4-6 kg body weight range). At the start of administration, the animals are 4-5 months old and weigh in the 6-9.5 kg range. A dose volume of 10 mL / kg is used. Individual dose volumes are calculated from each animal's current body weight to 30, 100, and 300 mg / kg / day or other target dose levels, depending on the non-MTD results. Blood samples are taken on days 1 and 14 to determine plasma drug concentrations and derived toxicological parameters. Animals are not fed on the scheduled necropsy days. Each animal is anesthetized by intramuscular injection of a zoletyl mixture and then killed by bleeding. All tissues are preserved in an appropriate fixative. Further analysis includes food consumption, body weight, clinical pathology, and complete histopathological examination of the target organ. [Table 2] [Table 3] [Table 4]

[0180] Herein, the present invention is illustrated by the following embodiments, which do not have limiting features.

[0181] If the prepared example is obtained as a mixture of enantiomers or diastereoisomers, the pure enantiomer or diastereoisomer can be obtained by the method described herein or by methods known to those skilled in the art, such as chiral chromatography or crystallization. Compounds without salts can be prepared in the same manner as the described examples that produce salts.

[0182] Experimental method [Table 5]

[0183] Preparation of intermediates Intermediate 1 3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile [ka]

[0184] Step A: 4-Bromo-2-methoxy-6-methylaniline 2-methoxy-6-methylaniline (CAS#50868-73-0, 50.0 g, 364.5 mmol, 1.0 equivalent) and acetic acid (50.0 mL, 874.2 mmol, 2.4 equivalents) Br2 (22.4 mL, 437.4 mmol, 1.2 equivalents) were slowly added dropwise at 0°C to a solution in methanol (150 mL). The mixture was then stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (PE / Â, 1:0~10:1) to obtain the title compound (30.3 g, yield 38%) as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ [ppm]:6.82(d,1H),6.78(d,1H),4.57(m,2H),3.77(s,3H),2.06(s,3H).

[0185] Process B: 4-amino-3-methoxy-5-methylbenzonitrile 4-Bromo-2-methoxy-6-methylaniline (30.3 g, 140.2 mmol, 1.0 equivalent) and Zn(CN)2 (16.5 g, 140.51 mmol, 1.0 equivalent) were dissolved in DMF (260 mL), to which Pd(PPh3)4 (32.4 g, 28.1 mmol, 0.2 equivalents) was added under N2. The mixture was stirred under a nitrogen atmosphere at 100 °C for 12 hours. After the reaction was complete, the mixture was cooled to 20 °C, poured into water (500 mL), and extracted with ethyl acetate (3 × 300 mL). The organic phase was washed with brine (3 × 200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / siRNA, 1:0-5:1) to obtain the title compound (22.0 g, 97% yield) as a pink solid. 1 H NMR(400 MHz,DMSO-d6)δ [ppm]:7.05(s,2H),5.48(s,2H),3.81(s,3H),2.09(s,3H).

[0186] Process C: 4-Bromo-3-methoxy-5-methylbenzonitrile To a solution of 4-amino-3-methoxy-5-methylbenzonitrile (22.0 g, 135.6 mmol, 1.0 equivalent) and CuBr (29.2 g, 203.5 mmol, 1.5 equivalent) in MeCN (220 mL), butyl nitrite (20.9 mL, 203.5 mmol, 1.5 equivalent) was added dropwise at 25°C. The mixture was then stirred at 65°C for 2 hours. After the reaction was complete, the mixture was cooled to 20°C, diluted with MeCN (150 mL), filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / Â, 1:0-5:1). The residue was then slurryed with a mixture of ethyl acetate (30 mL) and petroleum ether (3 mL), filtered, and the cake was recovered to obtain the title compound (18.0 g, 59% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ [ppm]:7.46(s,1H),7.43(s,1H),3.91(s,3H),2.39(s,3H).

[0187] Process D: 4-bromo-3-hydroxy-5-methylbenzonitrile To a solution of 4-bromo-3-methoxy-5-methylbenzonitrile (6.0 g, 26.5 mmol, 1.0 equivalent) in DCM (30 mL), BBr3 (30.0 mL, 316.1 mmol, 11.9 equivalents) was added at 0°C, and the mixture was stirred at 25°C for 1 hour. Once the reaction was complete, this was combined with another batch (10 g) and diluted with water (500 mL). The mixture was extracted with ethyl acetate (3 × 150 mL), the combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane / Â, 1:0~10:1) to obtain the title compound (13.3 g, yield 89%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ [ppm]:10.15(s,1H),6.42(d,1H),6.24(d,1H),1.51(s,3H).

[0188] Step E: 4-Bromo-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile To a solution of 4-bromo-3-hydroxy-5-methylbenzonitrile (13.3 g, 62.7 mmol, 1.0 equivalent) in DMF (60 mL), Cs2CO3 (33.3 g, 102.1 mmol, 1.6 equivalents) was added at 0°C, and the mixture was stirred at 20°C for 0.5 hours. Then, 2-(trimethylsilyl)ethoxymethyl chloride (CAS#76513-69-4, 15.5 mL, 87.8 mmol, 1.4 equivalents) was added dropwise at 0°C, and the mixture was stirred at 20°C for 1 hour. After the reaction was complete, water (200 mL) was added, and the mixture was extracted with MTBE (3 × 150 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then purified by silica gel column chromatography (hexane / siRNA, 1:0-10:1) to obtain the title compound (16.3 g, 76% yield) as a white solid. 1H NMR(400 MHz,CDCl3)δ [ppm]:7.27(d,1H),7.18(d,1H),5.30(s,2H),3.77(t,2H),2.44(s,3H),0.95(t,2H),0.00(s,9H).

[0189] Process F: 3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxy-methoxy)benzonitrile 1,4-Dioxane (100 mL) contains 4-bromo-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile (10.0 g, 29.2 mmol, 1.0 equivalent) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (14.8 g, 58.43 mmol, 2.0 equivalents) To the solution, Cs2CO3 (19.04 g, 58.43 mmol, 2.0 equivalents), tris(4-methoxy-3,5-dimethylphenyl)phosphane (CAS#121898-64-4, 1.28 g, 2.92 mmol, 0.1 equivalent), and Pd(OAc)2 (0.66 g, 2.92 mmol, 0.1 equivalent) were added, and the mixture was stirred under N2 at 95°C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (150 mL) and ethyl acetate (50 mL), filtered, and the filtrate was extracted with ethyl acetate (3 × 100 mL). 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 filtrate was purified by silica gel column chromatography (PE / siRNA, 1:0-10:1) (17 g), then polished with MeOH (51 mL), filtered, and the cake was recovered to obtain the title compound (8.38 g, yield 74%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ [ppm]:7.13(s,1H),7.07(s,1H),5.18(s,2H),3.72(t,2H),2.36(s,3H),1.38(s,12H),0.94(t,2H),0.00(s,9H).

[0190] Intermediate 2 4-(6-amino-5-benzyloxypyrazine-2-yl)-3-methyl-5-(2-trimethylsilylethoxymethoxy)-benzonitrile [ka]

[0191] Process A: 3-Benzyloxy-6-chloropyrazine-2-amine To a stirred solution of benzyl alcohol (4.49 mL, 43.2 mmol, 1.0 equivalent) in room temperature THF (90 mL), NaH (1.73 g, 43.18 mmol, 1.0 equivalent, 60% in mineral oil) was added, and stirring was continued for 10 minutes. Then, 3-bromo-6-chloropyrazine-2-amine (CAS#212779-21-0, 9.0 g, 43.2 mmol, 1.0 equivalent) was added, and the reaction mixture was heated at 70°C for 4 hours. The reaction mixture was cooled to room temperature. Ethyl acetate (60 mL) and water (80 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (80 mL x 2). The combined extract was washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1), and then purified by normal-phase flash chromatography (column: Welch Ultimate XB-CN 250*70*10μm; conditions: hexane-EtOH start B 12 end B 12; gradient time (min): 15 100% B; retention time (min): 5; flow rate (ml / min): 140) to obtain the title compound (2.3g, yield 23%) as a yellow solid. LCMS: m / z 236.0 [M+H] + ,ESI pos.

[0192] Step B: 4-(6-amino-5-benzyloxypyrazine-2-yl)-3-methyl-5-(2-trimethylsilylethoxymethoxy)-benzonitrile To a solution of the above-mentioned 3-benzyloxy-6-chloropyrazine-2-amine (2000 mg, 8.49 mmol, 1.0 equivalent), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxy-methoxy)-benzonitrile (3965.2 mg, 10.2 mmol, 1.2 equivalents), and CsF (2578.2 mg, 16.9 mmol, 2.0 equivalents) in 1,4-dioxane (30 mL) and water (3 mL), XPhos Pd G3 (719.2 mg, 0.85 mmol, 0.1 equivalent) was added under N2. The mixture was then stirred at 95°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. Ethyl acetate (150 mL) and water (150 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (150 mL x 2). The combined extracts were washed with brine (250 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to obtain the title compound (2.70 g, yield 69%) as a yellow solid. LCMS: m / z 463.2 [M+H] + ,ESI pos.

[0193] Intermediate 3 (3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidine-3-amine [ka]

[0194] Process A: Benzyl N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]carbamate A solution of benzyl N-[(3R)-3-piperidyl]carbamate (CAS#478646-32-1, 2.0 g, 8.54 mmol, 1.0 equivalent) in methanol (30 mL) was mixed with (tert-butyldimethylsilyloxy)acetaldehyde (1.64 g, 9.39 mmol, 1.1 equivalents), followed by the addition of NaBH3CN (1.35 g, 21.3 mmol, 2.5 equivalents). The mixture was stirred at 20°C for 3 hours. The mixture was quenched with water (50 mL) and then concentrated under vacuum to remove methanol. Subsequently, HCl (100 mL) was added and the layers were separated. The aqueous phase was extracted with HCl (300 mL x 2). The combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / Âce; PE = 77% to 33%) to obtain the title compound (2100.0 mg, yield 63%) as a colorless oil. LCMS m / z 393.3 [M+H] + ,ESI pos.

[0195] Step B: (3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidine-3-amine To a solution of benzyl N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]carbamate (2.1 g, 5.35 mmol, 1.0 equivalent) in methanol (30 mL), Pd / C (10%, 200 mg) and Pd(OH)2 (10%, 200 mg) were added under N2 conditions. The suspension was then degassed under vacuum, purged several times with H2, and stirred at 50°C for 16 hours under an H2 balloon. The suspension was filtered through a Celite pad, the filter cake was washed with MeOH (3 × 50 mL), and the combined filtrate was concentrated under vacuum to obtain the desired compound (1100.0 mg, yield 80%) as a yellow oily substance. 1H NMR(400 MHz,CD3OD)δ [ppm]:3.79(t,2H),2.93-2.91(m,1H),2.83-2.76(m,2H),2.54(t,2H),2.11-2.06(m,1H),1.92- 1.84(m,2H),1.73-1.68(m,1H),1.61-1.55(m,1H),1.15-1.06(m,1H),0.90(s,9H),0.83(s,6H).

[0196] Intermediate 4 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)benzonitrile [ka]

[0197] Process A: Methyl 2-amino-5-bromo-3-methoxybenzoate To a solution of methyl 2-amino-3-methoxybenzoate (10.0 g, 55.2 mmol, 1.0 equivalent CAS#5121-34-6) in methanol (40 mL), a solution of Br2 (3.4 mL, 66.2 mmol, 1.2 equivalents) in acetic acid (20 mL) was added dropwise at 0-10°C. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into an aqueous solution of NaHSO3 (20 mL) and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1-5 / 1) to obtain the title compound (10.0 g, yield 70%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ [ppm]:7.43(d,1H),7.10(d,1H),6.46(br.s,1H),3.85(s,3H),3.80(s,3H).

[0198] Step B: Methyl 2-amino-5-cyano-3-methoxybenzoate To a solution of methyl 2-amino-5-bromo-3-methoxybenzoate (10.0 g, 38.45 mmol, 1.0 equivalent) in NMP (50 mL), CuCN (4.13 g, 46.1 mmol, 1.2 equivalents) was added, and the mixture was stirred under microwave at 180°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0~5:1) to obtain the title compound (6.0 g, yield 76%) as a white solid. LCMS: m / z 207.1 [M+H] + ,ESI pos.

[0199] Step C: Methyl 2-bromo-5-cyano-3-methoxybenzoate To a solution of methyl 2-amino-5-cyano-3-methoxybenzoate (5.7 g, 27.64 mmol, 1.0 equivalent) and CuBr (5.95 g, 41.5 mmol, 1.5 equivalent) in MeCN (80 mL), butyl nitrite (4.28 g, 41.5 mmol, 1.5 equivalent) was added, and the mixture was stirred at 65°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0~5:1) to obtain the title compound (4.0 g, yield 54%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ [ppm]:7.78(d,1H),7.74(d,1H),3.96(s,3H),3.88(s,3H).

[0200] Process D: 2-Bromo-5-cyano-3-hydroxybenzoic acid To a solution of methyl 2-bromo-5-cyano-3-methoxybenzoate (3.8 g, 14.1 mmol, 1.0 equivalent) in DCM (20 mL), BBr3 (13.6 mL, 140.7 mmol, 10.0 equivalent) was added at -65°C, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0~2:1) to obtain the title compound (2.9 g, yield 85%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ [ppm]:13.76(br.s,1H),11.41(s,1H),7.52(d,1H),7.33(d,1H).

[0201] Step E: 2-Trimethylsilylethoxymethyl 2-bromo-5-cyano-3-(2-trimethylsilylethoxymethoxy)-benzoate A solution of 2-bromo-5-cyano-3-hydroxybenzoic acid (2.9 g, 11.9 mmol, 1.0 equivalent) and Cs2CO3 (7.81 g, 23.96 mmol, 2.0 equivalent) in DMF (50 mL) was stirred at 25°C for 10 minutes. Then, SEM-Cl (4.0 g, 23.96 mmol, 2.0 equivalent) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:0~2:1) to obtain the title compound (3.60 g, yield 60%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ [ppm]:7.83(d,1H),7.78(d,1H),5.49(d,4H),3.82-3.73(m,4H),0.96-0.87(m,4H),-0.01(s,9H),-0.07(s,9H).

[0202] Process F: 4-Bromo-3-(hydroxymethyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)benzonitrile To a solution of 2-trimethylsilylethoxymethyl 2-bromo-5-cyano-3-(2-trimethylsilylethoxymethoxy)benzoate (3.0 g, 5.97 mmol, 1.0 equivalent) in THF (20 mL), NaBH4 (903.31 mg, 23.9 mmol, 4.0 equivalents) was added and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:0~5:1) to obtain the title compound (1.6 g, yield 75%) as a white solid. 1 1H NMR (CD3OD , 400MHz)δ[ppm]:7.55(d,1H),7.48(d,1H),5.65(t,1H),5.43(s,2H),4.52(d,2H),3.73(t,2H),0.88(t,2H),-0.05(s,9H).

[0203] Process G: 4-Bromo-3-(methoxymethyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)benzonitrile To a solution of 4-bromo-3-(hydroxymethyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (200 mg, 0.56 mmol, 1.0 equivalent) in THF (3 mL), NaH (44.7 mg, 1.12 mmol, 2.0 equivalents, 60%) was added and the mixture was stirred at 25°C for 10 minutes. Then, MeI (0.1 mL, 1.61 mmol, 2.88 equivalents) was added and the mixture was stirred at 25°C for 2 hours. The mixture was quenched with water (30 mL) and extracted with siRNA (30 mL x 3). The organic phase was washed with brine (30 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / siRNA, 50:1 to 10:1) to obtain the title compound (130 mg, yield 63%) as a colorless oil. 1 1H NMR (DMSO-d6, 400MHz)δ[ppm]:7.60(s,1H),7.46(s,1H),5.44(s,2H),4.48(s,2H),3.74(t,2H),3.39(s,1H),0.88(t,2H),-0.04(s,9H).

[0204] Process H: 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)benzonitrile To a mixture of 1,4-dioxane (4 mL), 4-bromo-3-(methoxymethyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (130.0 mg, 0.35 mmol, 1.0 equivalent), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (441.68 mg, 1.75 mmol, 5.0 equivalents) was added, and KOAc (102.8 mg, 1.05 mmol, 3.0 equivalents) and Pd(dppf)Cl2 (25.5 mg, 0.03 mmol, 0.1 equivalents) were added. The mixture was then stirred at 95°C for 4 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAC = 1:0 to 10:1) to obtain the title compound (20.0 mg, yield 14%) as a white solid. 1 1H NMR (CD3OD , 400MHz)δ[ppm]:7.31(s,1H),7.26(s,1H),5.30(s,2H),4.49(s,2H),3.84 -3.76(m,2H),3.32(s,3H),1.40(s,12H),0.99-0.92(m,2H),0.01(s,9H).

[0205] Intermediate 5 5-Bromo-2-chloro-oxazolo[4,5-b]pyridine [ka]

[0206] Step A: 5-Bromooxazolo[4,5-b]pyridine-2-thiol To a mixture of 2-amino-6-bromopyridine-3-ol (CAS#934758-27-7, 5.0 g, 26.45 mmol, 1.0 equivalent) in DMF (50 mL), 1,1'-thiocarbonyldiimidazole (6.13 g, 34.4 mmol, 1.3 equivalents) was added and the mixture was stirred at 20°C for 16 hours. Ethyl acetate (100 mL) and water (100 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 100 mL). The combined extract was washed with 1N aqueous HCl (2 × 150 mL), followed by washing with brine (2 × 200 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the title compound (10.0 g, 96% yield) as a yellow solid. LCMS: m / z 230.9 [M+H] + ,ESI pos.

[0207] Step B: 5-Bromo-2-chlorooxazolo[4,5-b]pyridine To a mixture of 5-bromooxazolo[4,5-b]pyridine-2-thiol (9.0 g, 22.86 mmol, 1.0 equivalent) and DMF (0.1 mL), oxalyl chloride (29.02 g, 228.63 mmol, 10.0 equivalent) was added and the mixture was stirred at 50°C for 1 hour under N2. The reaction mixture was cooled to room temperature. Ethyl acetate (100 mL) and ice water (50 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 100 mL). The combined extracts were washed with brine (2 × 200 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (gradient petroleum ether / ethyl acetate = 100:1 to 10:1) to obtain the title compound (4.0 g, yield 75%) as a yellow solid. LCMS: m / z 234.9 [M+H] + ,ESI pos.

[0208] Intermediate 6 Benzyl(3R)-3-[(3-benzyloxy-6-chloropyrazine-2-yl)carbamoteoylamino]piperidine-1-carboxylate [ka]

[0209] Process A: Benzyl(3R)-3-isothiocyanatopiperidine-1-carboxylate A solution of benzyl(R)-3-aminopiperidine-1-carboxylate (CAS#1044560-96-4, 1.0 g, 4.27 mmol, 1.0 equivalent) in DCM (5 mL) was added dropwise at 0°C to a solution of thiophosgene (0.490 g, 4.27 mmol, 1.0 equivalent) in DCM (5 mL), and the mixture was then stirred at 20°C for 2 hours. The reaction mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain the title compound (0.85 g, yield 72%) as a yellow oily substance. 1 1H NMR (DMSO-d 6, 400MHz)δ[ppm]:7.45-7.27(m,5H),5.12(s,2H),4.06-3.98(m,1H),3.96-3.62(m ,2H),3.44-3.36(m,1H),3.28-2.95(m,1H),1.95-1.82(m,2H),1.69-1.45(m,2H).

[0210] Process B: Benzyl(3R)-3-[(3-benzyloxy-6-chloropyrazine-2-yl)carbamoteoylamino]piperidine-1-carboxylate To a solution of the above-mentioned 3-benzyloxy-6-chloropyrazine-2-amine (intermediate 2, step A) (0.600 g, 2.55 mmol, 1.0 equivalent) in THF (6 mL), NaH (203.67 mg, 5.09 mmol, 2.0 equivalent, 60% in mineral oil) was added and the mixture was stirred at 0°C for 0.5 hours. Then, a solution of benzyl(3R)-3-isothiocyanatopiperidine-1-carboxylate (0.703 g, 2.55 mmol, 1.0 equivalent) in THF (3 mL) was added dropwise and the mixture was stirred at 20°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain the title compound (0.500 g, yield 36%) as yellow rubber. LCMS: m / z 512.1, [M+H] + ,ESI pos.

[0211] Intermediate 7 (4-Cyano-2-Hydroxy-6-Methylphenyl)Boronic Acid [ka]

[0212] Process A: 4-amino-3-methoxy-5-methylbenzonitrile Two batches were performed in parallel. To a solution of 4-bromo-2-methoxy-6-methylaniline (25.0 g, 115 mmol, 1.0 equivalent) in DMF (250 mL), Zn(CN)2 (13.5 g, 115 mmol, 7.34 mL, 1.00 equivalent) and Pd(PPh3)4 (66.8 g, 57.8 mmol, 0.50 equivalent) were added. The reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was poured into H2O (1.50 L) and extracted with ethyl acetate (1.00 L x 3). The organic phase was washed with brine (1.00 L x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain the title compound (28.0 g, yield 75%) as a yellow solid.

[0213] Process B: 4-bromo-3-methoxy-5-methylbenzonitrile To a solution of CuBr (46.4 g, 323 mmol, 9.86 mL, 1.50 equivalents) in MeCN (180 mL), t-BuONO (33.3 g, 323 mmol, 38.5 mL, 1.50 equivalents) was added and the mixture was stirred at 65°C. Next, a solution of 4-amino-3-methoxy-5-methyl-benzonitrile (35.0 g, 215 mmol, 1.00 equivalent) in MeCN (180 mL) was added at 65°C. The mixture was stirred at 65°C for 3.5 hours. After cooling to room temperature, saturated aqueous solution Na2SO3 (400 mL) and saturated aqueous solution NH4Cl (200 mL) were added to the mixture and extracted with ethyl acetate (500 mL x 3). The organic phase was washed with brine (500 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue is analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, R f The compound was purified using a solution of 0.75 to obtain the title compound (20.7 g, 42% yield) as a white solid.

[0214] Step C: 3-Methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile To a solution of 4-bromo-3-methoxy-5-methylbenzonitrile (18.0 g, 79.6 mmol, 1.00 equivalent) in DMF (180 mL), B2Pin2 (30.3 g, 119 mmol, 1.50 equivalent) and AcOK (35.1 g, 358 mmol, 4.50 equivalent) were added. The mixture was stirred at 20°C for 0.5 hours, and Pd(dppf)Cl2·CH2Cl2 (13.0 g, 15.9 mmol, 0.20 equivalent) was added. The mixture was stirred at 100°C for 12 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth, diluted with H2O (500 mL), and extracted with ethyl acetate (800 mL x 3). The organic phase was washed with brine (800 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1, R f The compound was purified using a solution of 0.30 to obtain the title compound (18.0 g, 83% yield) as a white solid.

[0215] Process D: (4-Cyano-2-hydroxy-6-methylphenyl)boronic acid A solution of 3-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (17.0 g, 96.0 mmol, 1.00 equivalent) in DCM (170 mL) was cooled to 0°C, and BBr3 (38.9 g, 155 mmol, 2.50 equivalents) was added dropwise at 0°C. The mixture was stirred at 0°C for 0.5 hours. The mixture was poured into H2O (200 mL), filtered, and the cake was recovered. Polishing with ethyl acetate (20 mL) yielded the title compound (4.67 g, 42% yield) as a gray solid. LCMS: m / z 178.1 [M+H] + ,ESI pos.

[0216] Intermediate 8 6-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol [ka]

[0217] Process A: 2-[2,6-dibromo-4-(methoxymethyl)phenyl]ethanol To a solution of 1,3-dibromo-5-(methoxymethyl)benzene (171 g, 610 mmol, 1.00 equivalent, CAS# 1646314-10-4) in THF (750 mL), LDA (2.00 M, 366 mL, 1.20 equivalents) was added at -78 °C, and the mixture was stirred for 30 minutes. Then, a solution of 1,3,2-dioxathiolane 2,2-dioxide (98.5 g, 794 mmol, 1.30 equivalents, CAS# 1072-53-3) in THF (750 mL) was added to the mixture at -78 °C. The mixture was heated at 25 °C for 1 hour and stirred. This reaction mixture was quenched by adding aqueous HCl (12.0 M, 170 mL) at 0 °C, then diluted with water (500 mL), and extracted with siRNA (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain the title compound (60.0 g, 30% yield) as a white solid NLRP.

[0218] Step B: 4-Bromo-6-(methoxymethyl)-2,3-dihydrobenzofuran To a solution of 2-[2,6-dibromo-4-(methoxymethyl)phenyl]ethanol (60.0 g, 185 mmol, 1.00 equivalent) in dioxane (600 mL), t-BuOLi (44.4 g, 555 mmol, 50.0 mL, 3.00 equivalent) and CuI (3.53 g, 18.5 mmol, 0.10 equivalent) were added under an N2 atmosphere. The mixture was stirred at 100°C for 5 hours. The reaction mixture was quenched by adding water (1.00 L), then diluted with ethyl acetate (500 mL), and extracted with ethyl acetate (500 mL x 3). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (50.0 g, crude) was obtained as a yellow oily substance, which was used in the next step without further purification.

[0219] Process C: 6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol To a solution of 4-bromo-6-(methoxymethyl)-2,3-dihydrobenzofuran (48.0 g, 197 mmol, 1.00 equivalent) in dioxane (250 mL) and H2O (250 mL), t-BuXphos (16.7 g, 39.4 mmol, 0.20 equivalent), Pd2(dba)3 (9.04 g, 9.87 mmol, 0.05 equivalent), and KOH (33.2 g, 592 mmol, 3.00 equivalent) were added. The mixture was stirred at 80°C for 16 hours under an N2 atmosphere. The mixture was adjusted to pH=5 with aqueous HCl (12 M) and then extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain the title compound (26 g, 74% yield) as a white solid.

[0220] Process D: 5-bromo-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol To a solution of 6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol (25.0 g, 138 mmol, 1.00 equivalent) in DCM (250 mL), NBS (22.2 g, 124 mmol, 0.90 equivalent) was added at 0°C. The mixture was stirred at 0°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 10 / 1) to obtain the title compound (16.0 g, 45% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ [ppm]:6.56(s,1H),5.72(s,1H),4.63(t,2H),4.44(s,2H),3.43(s,3H),3.22(t,2H).

[0221] Step E: 4-Benzyloxy-5-bromo-6-(methoxymethyl)-2,3-dihydrobenzofuran To a solution of 5-bromo-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol (15.0 g, 57.8 mmol, 1.00 equivalent) in MeCN (150 mL), BnBr (10.8 g, 63.6 mmol, 7.56 mL, 1.10 equivalent) and K2CO3 (16.0 g, 115 mmol, 2.00 equivalent) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (100 mL) and extracted with  (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was macerated with petroleum ether (50.0 mL) at 25°C for 16 hours. The title compound (10.0 g, 74% yield) was obtained as a white solid. LCMS: m / z 350.0 [M+H] + ,ESI pos.

[0222] Process F: 2-[4-benzyloxy-6-(methoxymethyl)-2,3-dihydrobenzofuran-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A solution of 4-benzyloxy-5-bromo-6-(methoxymethyl)-2,3-dihydrobenzofuran (1.5 g, 4.08 mmol, 1.00 equivalent) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.19 g, 1.3 mL, 6.37 mmol, 1.56 equivalent) in tetrahydrofuran (15 mL) was added dropwise with a 1.6 M n-butyllithium solution in hexane (4 mL, 6.4 mmol, 1.57 equivalent) at -76°C, and the mixture was stirred at -76°C for 2.25 hours. The reaction mixture was heated to -60°C, quenched with saturated NH4Cl aqueous solution (approx. 10 mL) at -60°C, heated to room temperature, and then extracted with ethyl acetate (approx. 70 mL) and saturated NH4Cl solution (approx. 10 mL). The aqueous layer was back-extracted with ethyl acetate (approximately 70 mL). The organic layer was washed with brine (approximately 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography (silica gel, 25 g, heptane gradient from 0% to 20% ethyl acetate) to obtain the title compound (1.26 g, yield 74%) as a colorless oil. LCMS: m / z 397.3 [M+H] + ,ESI pos.

[0223] Process F: 6-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol A solution of 2-[4-benzyloxy-6-(methoxymethyl)-2,3-dihydrobenzofuran-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.24 g, 2.98 mmol, 1.00 equivalent) in ethyl acetate (15 mL) and methanol (2.5 mL) was alternately evacuated and flushed with argon three times. Activated carbon-supported palladium, 10% Pd base (136 mg, 127.8 μmol, 0.043 equivalents) was carefully added. The reaction flask was evacuated, flushed with argon, evacuated again, and flushed with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 3 hours. The reaction mixture was then filtered and rinsed with ethyl acetate / methanol. Concentration of the filtrate under vacuum yielded the title compound (929 mg, 97% yield) as a light brown solid. LCMS: m / z 307.2[M+H] + The ESI pos. compound was used without further purification.

[0224] Intermediate 9 (3S,5R)-5-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]-1-ethyl-piperidine-3-ol [ka]

[0225] Process A: 2-Benzyloxy-5-bromo-3-isothiocyanatopyrazine To a solution of 3-benzyloxy-6-bromopyrazine-2-amine (2.0 g, 7.14 mmol, 1.0 equivalent; CAS# 2767116-11-8) in DCM (20 mL), 1,1'-thiocarbonyldipyridine-2(1H)-one (1.99 g, 8.57 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at 30°C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 50:1) to obtain the title compound (1.2 g, yield 51%) as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ [ppm]:8.39(s,1H),7.52-7.50(m,2H),7.43-7.35(m,3H),5.47(s,2H).

[0226] Process B: tert-butyl(3R,5S)-3-[(3-benzyloxy-6-bromopyrazine-2-yl)carbamoteoylamino]-5-hydroxy-piperidine-1-carboxylate A mixture of tert-butyl(3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylate (671.3 mg, 3.1 mmol, 1.0 equivalent) and DIEA (0.81 mL, 4.66 mmol, 1.5 equivalents) in DCM (10 mL) was mixed dropwise with a solution of 2-benzyloxy-5-bromo-3-isothiocyanatopyrazine (1000.0 mg, 3.1 mmol, 1.0 equivalent) in DCM (10 mL). The reaction mixture was stirred under N2 at 20°C for 1 hour. After the reaction was complete, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 59%~41%) to obtain the title compound (1580.0 mg, yield 95%) as a yellow oily substance. LCMS: m / z 484.1 [M-C4H8+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6)δ [ppm]:10.47(d,1H),8.86(s,1H),7.99(s,1H),7.51-7.49(m,2H),7.43-7.34(m,3H),5.48-5.40(m,2H),5.08(br s,1H),4.36-4.26(m,1H),3.71-3.67(m,1H),3.56-3.54(m,1H),3.44-3.35(m,1H), 3.23-3.22(m,1H),3.29-3.22(m,1H),2.15-2.05(m,1H),1.68-1.58(m,1H),1.25(br s,9H).

[0227] Process C: 1-(6-bromo-3-hydroxy-pyrazine-2-yl)-3-[(3R,5S)-5-hydroxy-3-piperidyl]thiourea To a solution of tert-butyl(3R,5S)-3-[(3-benzyloxy-6-bromopyrazine-2-yl)carbamoteoylamino]-5-hydroxy-piperidine-1-carboxylate (1800.0 mg, 3.34 mmol, 1.0 equivalent) in anisole (3 mL), TFA (3 mL) was added, and the mixture was stirred under N2 at 70°C for 2 hours. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Xtimate C18, 250 mm*50 mm*10 μm; mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 5%~39%, 15 min), and the eluent was lyophilized to obtain the title compound (750.0 mg, yield 65%) as a yellow solid. LCMS: m / z 350.0[M+2+H] + ,ESI pos.

[0228] Process D: (3S,5R)-5-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]piperidine-3-ol To a solution of 1-(6-bromo-3-hydroxypyrazine-2-yl)-3-[(3R,5S)-5-hydroxy-3-piperidyl]thiourea (50.0 mg, 0.14 mmol, 1.0 equivalent) and tetrabutylammonium iodide (10.6 mg, 0.03 mmol, 0.2 equivalents) in THF (2 mL) and methanol (0.2 mL), H2O2 (240.0 mg, 2.12 mmol, 14.74 equivalents, purity: 30% in water) was added. The resulting mixture was stirred at 20°C for 1 hour. After the reaction was complete, the mixture was quenched with saturated Na2SO3 aqueous solution (0.2 mL) and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Gemini, 150 mm*30 mm*15 μm; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 22%~40%, 10 min), and the eluent was lyophilized to obtain the title compound (10.0 mg, yield 22%) as a white solid. LCMS: m / z 314.1 [M+H] + ,ESI pos.

[0229] Process E: (3S,5R)-5-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]-1-ethyl-piperidine-3-ol CH3CH2I (0.02 mL, 0.26 mmol, 1.0 equivalent) was added to a solution of (3S,5R)-5-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]piperidine-3-ol (110.0 mg, 0.26 mmol, 1.0 equivalent) and DIEA (0.09 mL, 0.51 mmol, 2.0 equivalents) in DMF (1 mL). The reaction mixture was stirred under nitrogen at 20°C for 1 hour. After the reaction was complete, the mixture was purified by preparative HPLC (column: Xtimate C18, 250 mm*50 mm*10 μm; mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 10%~45%, 8 min), and the eluent was freeze-dried to obtain the title compound (40.0 mg, yield 26%) as a yellow solid. LCMS: m / s 343.9 [M+H] + ,ESI pos.

[0230] Intermediate 10 2,5-Dichloro-7-fluoro-oxazolo[4,5-b]pyridine [ka]

[0231] Process B: 6-Chloro-4-fluoro-2-nitropyridine-3-ol To a solution of 6-chloro-4-fluoropyridine-3-ol (4.3 g, 29.15 mmol, 1.0 equivalent; CAS#1211530-63-0) in sulfuric acid (40.0 mL, 116.59 mmol, 4.0 equivalents), HNO3 (7.06 g, 100.86 mmol, 3.46 equivalents) was slowly added at 0°C, and the mixture was then stirred at 20°C for 4 hours. After the reaction was complete, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:1 to 10:1) to obtain the title compound (5.0 g) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ [ppm]:8.03(d,1H).

[0232] Process C: 2-amino-6-chloro-4-fluoropyridine-3-ol To a solution of 6-chloro-4-fluoro-2-nitropyridine-3-ol (2.1 g, 10.91 mmol, 1.0 equivalent) in ethanol (30 mL) and water (30 mL), Na2S2O4 (11.39 g, 65.44 mmol, 6.0 equivalents) was added, and the mixture was stirred at 70°C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:1~0:1) to obtain the title compound (1.27 g, yield 71%) as a yellow solid. LCMS: m / z 163.1, [M+H] + ,ESI + pos.

[0233] Process D: 5-Chloro-7-fluoro-oxazolo[4,5-b]pyridine-2-thiol To a solution of 2-amino-6-chloro-4-fluoropyridine-3-ol (500.0 mg, 3.08 mmol, 1.0 equivalent) in DMF (5 mL), 1,1'-thiocarbonyldiimidazole (603.0 mg, 3.38 mmol, 1.1 equivalent) was added, and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with 1 M HCl (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0~1:1) to obtain the title compound (320.0 mg, yield 47%) as a white solid. LCMS: m / z 205.0, [M+H] + ,ESI + pos.

[0234] Step E: 2,5-Dichloro-7-fluoro-oxazolo[4,5-b]pyridine To a solution of 5-chloro-7-fluoro-oxazolo[4,5-b]pyridine-2-thiol (320.0 mg, 1.56 mmol, 1.0 equivalent) in oxalyl dichloride (4.0 mL, 46.96 mmol, 30.0 equivalents), DMF (11.4 mg, 0.16 mmol, 0.1 equivalent) was added. The mixture was then stirred at 50°C for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0~10:1) to obtain the title compound (300.0 mg, yield 93%) as a yellow solid.

[0235] Intermediate 11 1-(6-bromo-3-hydroxypyrazine-2-yl)-3-[(3R)-1-(2-hydroxyethyl)-3-piperidyl]thiourea [ka]

[0236] Process A: 1-(3-benzyloxy-6-bromopyrazine-2-yl)-3-[(3R)-1-(2-hydroxyethyl)-3-piperidyl]-thiourea To a solution of 1-(6-bromo-3-hydroxypyrazine-2-yl)-3-[(3R)-3-piperidyl]thiourea hydrochloride (2600.0 mg, 7.03 mmol, 1.0 equivalent) in DCE (30 mL) and methanol (3 mL), CH3COONa (1730.73 mg, 21.1 mmol, 3.0 equivalent) was added, followed by CH3COOH (42.2 mg, 0.7 mmol, 0.1 equivalent) to adjust the pH to 5.0. (tert-butyldimethylsilyloxy)acetaldehyde (1838.97 mg, 10.55 mmol, 1.5 equivalent) was added, and the mixture was stirred for 10 minutes. Then, NaBH(OAc)3 (4471.67 mg, 21.1 mmol, 3.0 equivalent) was added. The mixture was stirred under N2 at 20°C for 1 hour. Next, the mixture was quenched with water (30 mL), extracted with RINKAN (60 mL x 2), the organic phase was washed with brine (60 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by C18 column chromatography (0.1% TFA-CAN = 54%~46% to 36%~64%) to obtain 1-(6-bromo-3-hydroxypyrazine-2-yl)-3-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]thiourea (100.0 mg, yield 3%) as a yellow solid (LCMS m / z: 492.2 [M+2+H]). + ESIpos and the title compound (1200.0 mg, 24% yield) were obtained as a yellow solid. LCMS m / z: 466.2 [M+H] + ,ESI pos.

[0237] Process B: 1-(6-bromo-3-hydroxypyrazine-2-yl)-3-[(3R)-1-(2-hydroxyethyl)-3-piperidyl]thiourea The solution of 1-(3-benzyloxy-6-bromopyrazine-2-yl)-3-[(3R)-1-(2-hydroxyethyl)-3-piperidyl]-thiourea (1200.0 mg, 2.57 mmol, 1.0 equivalent) was stirred in TFA (2 mL) under N2 at 70°C for 2 hours. After the reaction was complete, the mixture was concentrated under vacuum to obtain a residue, which was then purified by C18 column chromatography (0.1% NH3·H2O-CAN = 54%~46%) to obtain the title compound (300.0 mg, yield 21%) as a white solid. LCMS m / z: 376.1 [M+H] + ,ESI pos.

[0238] Preparation of Examples Example 1 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid [ka]

[0239] Process A: 1-(6-chloro-3-hydroxy-pyrazine-2-yl)-3-[(3R)-3-piperidyl]thiourea To a solution of benzyl(3R)-3-[(3-benzyloxy-6-chloropyrazine-2-yl)carbamyoylamino]piperidine-1-carboxylate (1.5 g, 2.93 mmol, 1.0 equivalent) in TFA (15.0 mL, 197.37 mmol, 67.37 equivalents), anisole (7.5 mL, 69.01 mmol, 23.56 equivalents) was added, and the reaction mixture was stirred at 75°C for 12 hours. The mixture was then concentrated under reduced pressure and purified by reverse-phase flash (CombiFlash NH3-H2O water-MeCN conditions) to obtain the title compound (320.0 mg, yield 22%) as a yellow solid. LCMS: m / z 288.2 [M+H] + ,ESI pos.

[0240] Process B: 1-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-3-(6-chloro-3-hydroxypyrazine-2-yl)thiourea To a solution of 1-(6-chloro-3-hydroxypyrazine-2-yl)-3-[(3R)-3-piperidyl]thiourea (270.0 mg, 0.94 mmol, 1.0 equivalent) in methanol (5 mL) / DCE (10 mL), (tert-butyldimethylsilyloxy)acetaldehyde (CAS#102191-92-4, 327.1 mg, 1.88 mmol, 2.0 equivalents), followed by NaBH(OAc)3 (994.3 mg, 4.69 mmol, 5.0 equivalents), was added, and the mixture was stirred at 20°C for 1.5 hours. The reaction mixture was poured onto ice (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (hexane / siRNA, 1:0-0:1) yielded the title compound (220.0 mg, 49% yield) as a yellow solid. LCMS: m / z 446.1 [M+H] + ,ESI pos.

[0241] Process C: N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-oxazolo[4,5-b]pyrazine-2-amine A mixture of 1-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-3-(6-chloro-3-hydroxypyrazine-2-yl)thiourea (220.0 mg, 0.49 mmol, 1.0 equivalent) and tetrabutylazanium iodide (200.4 mg, 0.54 mmol, 1.1 equivalents) in THF (10 mL) was mixed with H2O2 (111.8 mg, 0.99 mmol, 2.0 equivalents), and the mixture was stirred at 25°C for 2 hours. The residue was purified by silica gel column chromatography (siRNA / MeOH = 1:0~10:1) to obtain the title compound (80.0 mg, yield 40%) as a yellow solid. LCMS: m / z 412.1 [M+H] +,ESI pos.

[0242] Process D: 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile 1,4-Dioxane (4 mL) / Water (0.5 mL) contains 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile intermediate 1 (79.4 mg, 0.2 mmol, 1.2 equivalents), N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperyl A mixture of [zyl]-5-chloro-oxazolo[4,5-b]pyrazine-2-amine (step C) (70.0 mg, 0.17 mmol, 1.0 equivalent) and CsF (77.42 mg, 0.51 mmol, 3.0 equivalents) was mixed with Pd-PEPPSI-iHeptCl (CAS#905459-27-0, 14.4 mg, 0.02 mmol, 0.1 equivalent) under N2 conditions, and the mixture was stirred at 95°C for 3 hours. The reaction mixture was cooled to room temperature, poured onto ice (10 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash (CombiFlash 0.1% TFA water-MeCN conditions) to obtain the title compound (30.0 mg, yield 26%) as a yellow solid. LCMS: m / z 639.4 [M+H] + ,ESI pos.

[0243] Process E: 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid To a mixture of 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]-oxazolo[4,5-b]pyrazine-5-yl]-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile (Step D) (25.0 mg, 0.04 mmol, 1.0 equivalent) in DCM (0.1 mL), TFA (0.1 mL) was added and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase flash (CombiFlash 0.1% TFA water-MeCN conditions) to obtain the title compound (14.3 mg, yield 71%) as a yellow solid. LCMS: m / z 395.1 [M+H] + ,ESI pos.

[0244] Example 2 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid [ka]

[0245] Process A: tert-butyl(3R,5S)-3-amino-5-[tert-butyl(diphenyl)silyl]oxy-piperidine-1-carboxylate To a solution of tert-butyl(3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylate (CAS#1932513-59-1, 400 mg, 1.85 mmol, 1.0 equivalent) and 1H-imidazole (378 mg, 5.55 mmol, 3.0 equivalents) in DMF (2 mL), tert-butylchlorodiphenylsilane (1029 mg, 3.74 mmol, 2.0 equivalents) was added. The mixture was then stirred at 20°C for 48 hours. After the reaction was complete, ethyl acetate (40 mL) and water (20 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (40 mL x 2). The combined extract was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2 to 0:1) to obtain the title compound (230.0 mg, 27% yield) as a yellow oily substance. LCMS: m / z 455.4 [M+H] + ,ESI pos.

[0246] Process B: tert-butyl(3S,5R)-3-[tert-butyl(diphenyl)silyl]oxy-5-isothiocyanatopiperidine-1-carboxylate A stirred solution of TEA (102 mg, 1.01 mmol, 2.0 equivalents) and tert-butyl(3R,5S)-3-amino-5-[tert-butyl(diphenyl)silyl]oxy-piperidine-1-carboxylate (230.0 mg, 0.51 mmol, 1.0 equivalent) in DCM (2 mL) was mixed with thiophosgene (174.5 mg, 1.52 mmol, 3.0 equivalents) at 0°C, and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 4:1) to obtain the title compound (130.0 mg, yield 52%) as a yellow oil. LCMS: m / z 519.3 [M+Na] + ,ESI pos.

[0247] Process C: tert-butyl(3R,5S)-3-[[3-benzyloxy-6-[4-cyano-2-methyl-6-(2-trimethylsilylethoxy-methoxy)phenyl]pyrazine-2-yl]carbamoteoylamino]-5-[tert-butyl(diphenyl)silyl]oxy-piperidine-1-carboxylate To a solution of 4-(6-amino-5-benzyloxypyrazine-2-yl)-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile intermediate 2 (100.0 mg, 0.22 mmol, 1.0 equivalent) in THF (7 mL), NaH (60% in mineral oil, 17.3 mg, 0.43 mmol, 2.0 equivalents) was added and the mixture was stirred at 20°C for 0.5 hours. Then, a solution of tert-butyl(3S,5R)-3-[tert-butyl(diphenyl)silyl]oxy-5-isothiocyanatopiperidine-1-carboxylate (108.0 mg, 0.22 mmol, 1.01 equivalent) in THF (2 mL) was added dropwise at 0°C, and the reaction mixture was stirred at 20°C for 4 hours. Since the reaction mixture was insoluble, an additional 10.0 mL of DMF was added, and stirring was continued at 20°C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature. Ethyl acetate (50 mL) and saturated CaCl2 aqueous solution (50 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined extract was washed with saturated CaCl2 aqueous solution (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:2) to obtain the title compound (100.0 mg, yield 48%) as a yellow oil. LCMS: m / z 959.2 [M+H] + ,ESI pos.

[0248] Process D: 1-[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-3-piperidyl]-3-[6-(4-cyano-2-hydroxy-6-methylphenyl)-3-hydroxypyrazine-2-yl]thiourea tert-butyl(3R,5S)-3-[[3-benzyloxy-6-[4-cyano-2-methyl-6-(2-trimethylsilylethoxymethoxy)-phenyl]pyrazine-2-yl]carbamoteoylamino]-5-[tert-butyl-(diphenyl)silyl]oxy-piperidine-1-carboxylate (100.0 mg, 0.1 mmol, 1.0 equivalent) was dissolved in TFA (3.0 mL, 39.5 mmol, 378.7 equivalents) and stirred at 20°C for 2 hours. The mixture was then concentrated under vacuum, the residue was dissolved in methanol (2 mL), and the pH was adjusted to 7 using NH3·H2O. The crude product was then purified by reverse-phase flash (CombiFlash 0.1% NH3·H2O aqueous-ACN conditions) to obtain the title compound (40.0 mg, yield 60%) as a white solid. LCMS: m / z 639.3 [M+H] + ,ESI pos.

[0249] Process E: 1-[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-1-ethyl-3-piperidyl]-3-[6-(4-cyano-2-hydroxy-6-methylphenyl)-3-hydroxy-pyrazine-2-yl]thiourea To a solution of 1-[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-3-piperidyl]-3-[6-(4-cyano-2-hydroxy-6-methylphenyl)-3-hydroxypyrazine-2-yl]thiourea (40 mg, 0.06 mmol, 1.0 equivalent) in methanol (0.1 mL) and DCE (1 mL), acetaldehyde (0.04 mL, 0.19 mmol, 3.0 equivalents) was added. The mixture was stirred for 15 minutes, then NaBH(OAc)3 (53 mg, 0.25 mmol, 4.0 equivalents) was added, and the mixture was stirred at 20°C for 1.5 hours. The mixture was purified by reverse-phase flash (CombiFlash 0.1% NH3·H2O aqueous-MeCN conditions) to obtain the title compound (25.0 mg, yield 60%) as a white solid. LCMS: m / z 667.3 [M+H] + ,ESI pos.

[0250] Process F: 4-[2-[[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-1-ethyl-3-piperidyl]amino]oxazolo-[4,5-b]pyrazine-5-yl]-3-hydroxybenzonitrile; 2,2,2-trifluoroacetic acid A solution of 1-[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-1-ethyl-3-piperidyl]-3-[6-(4-cyano-2-hydroxy-6-methylphenyl)-3-hydroxypyrazine-2-yl]thiourea (30.0 mg, 0.04 mmol, 1.0 equivalent) and tetrabutylazanium iodide (16.6 mg, 0.04 mmol, 1.0 equivalent) in THF (1 mL) was mixed with H2O2 (70.0 mg, 0.62 mmol, 13.7 equivalents) and stirred at 25°C for 1 hour. The mixture was then concentrated under vacuum. The residue was then purified by reverse-phase flash (CombiFlash 0.1% TFA aqueous-MeCN conditions) to obtain the title compound (20.0 mg, yield 60%) as a yellow solid. LCMS: m / z 633.2 [M+H] + ,ESI pos.

[0251] Process G: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid To a solution of 4-[2-[[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-1-ethyl-3-piperidyl]amino]oxazolo-[4,5-b]pyrazine-5-yl]-3-hydroxybenzonitrile; 2,2,2-trifluoroacetic acid (15.0 mg, 0.02 mmol, 1.0 equivalent) in THF (1 mL), TBAF (0.42 mL, 0.42 mmol, 21.1 equivalents) was added. The mixture was then stirred at 20°C for 16 hours. Subsequently, the solvent was removed under vacuum, and the residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; conditions: water (TFA)-MeCN; start B: 14, end B: 44; gradient time (min): 10, 100% B; retention time (min): 3; flow rate (mL / min): 25) to obtain the title compound (3.89 mg, yield 37%) as a white solid. LCMS: m / z 395.4 [M+H] + ,ESI pos.

[0252] Example 3 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-(methoxymethyl)benzonitrile [ka]

[0253] Step A: 5-Bromo-N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5-b]pyridine-2-amine To a solution of (3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidine-3-amine intermediate 3 (200.0 mg, 0.77 mmol, 1.0 equivalent) in MeCN (2 mL), DIEA (0.26 mL, 1.55 mmol, 2.0 equivalent) was added, followed by the addition of a solution of 5-bromo-2-chloro-oxazolo[4,5-b]pyridine intermediate 5 (180.6 mg, 0.77 mmol, 1.0 equivalent) in MeCN (2 mL), and the mixture was stirred at 25°C for 2 hours. Subsequently, the reaction mixture was concentrated under vacuum, and the residue was purified by C18 column chromatography (column: Waters Xbridge 150*25mm*5um; mobile phase: A is H2O (0.1% NH3·H2O v / v), B is acetonitrile; gradient: B linear from 78% to 28% over 9 minutes; flow rate: 25 mL / mini column; temperature: rt; wavelength: 220 nm / 254 nm) to obtain the title compound (210.0 mg, yield 40%) as a colorless foam. LCMS m / z 455.1 [M+H] + ,ESI pos.

[0254] Step B: 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-(methoxymethyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile A solution of 5-bromo-N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5-b]pyridine-2-amine (100.0 mg, 0.22 mmol, 1.0 equivalent) and 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)benzonitrile intermediate 4 (110.5 mg, 0.26 mmol, 1.2 equivalents) in 1,4-dioxane (1 mL) and water (0.2 mL) is prepared by adding CsF (133.4 mg, 0.88 mmol, 4.0 equivalents) and XPhos Pd G3 (37.2 mg, 0.04 mmol, 0.2 equivalents) was added, and the reaction mixture was stirred at 95°C for 2 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature, diluted with ethyl acetate (10 mL), filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: siRNA, PE: 54% to 46%) to obtain the title compound (90.0 mg, yield 61%) as a yellow oil. LCMS m / z 668.4 [M+H] + ,ESI pos.

[0255] Step C: 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-(methoxymethyl)benzonitrile To a solution of 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-(methoxymethyl)-5-(2-trimethylsilylethoxy-methoxy)benzonitrile (45.0 mg, 0.07 mmol, 1.0 equivalent) in DCM (1 mL), TFA (1.5 mL) was added, and the mixture was stirred at 20°C for 2 hours. After the reaction was complete, the mixture was diluted with DCM (3 mL) and MeOH (1 mL), the pH was adjusted to approximately 8 using NH3·H2O, filtered, and the filtrate was concentrated under reduced pressure. Next, the crude product was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; conditions: water (0.1% NH3·H2O)-MeCN; start B 5, end B 35; gradient time (min): 10; 100% B retention time (min): 2; flow rate (mL / min) 25) to obtain the title compound as a grayish-white solid (25.9 mg, yield 89%). LCMS m / z 424.3 [M+H] + ,ESI pos.

[0256] Example 4 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-(2-oxazole-2-ylethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]benzonitrile [ka]

[0257] Step A: tert-butyl(3R)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]piperidine-1-carboxylate To a mixture of 1,4-dioxane (5.7 mL) and 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS#1783370-92-2, 600 mg, 2.84 mmol, 1.00 equivalent), tert-butyl(3R)-3-aminopiperidine-1-carboxylate (CAS#188111-79-7, 720 mg, 3.59 mmol, 1.27 equivalent), followed by triethylamine (334 mg, 0.46 mL, 3.30 mmol, 1.16 equivalent), was added. The brown solution was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated NaHCO3 aqueous solution. 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 under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, heptane gradient from 0% to 70% ethyl acetate) to obtain the title compound (991 mg, yield 94%) as a grayish-white foam. LCMS: m / z 353.1 [M+H] + ,ESI pos.

[0258] Step B: 5-Chloro-N-[(3R)-3-piperidyl]oxazolo[4,5-b]pyridine-2-amine To a solution of tert-butyl(3R)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]piperidine-1-carboxylate (Example 4, Step A) (227 mg, 0.61 mmol, 1.00 equivalent) in dichloromethane (1.8 mL) and methanol (0.90 mL), 4 M HCl (1.8 g, 1.5 mL, 6.00 mmol, 9.82 equivalents) in dioxane was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was dissolved in a small amount of dichloromethane and a few drops of methanol, then carefully added to a saturated aqueous solution of NaHCO3 and extracted three times with a mixture of dichloromethane / methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (137 mg, yield 88%) as a grayish-white solid. LCMS: m / z 253.0 [M+H] +,ESI pos.

[0259] Step C: Methyl 3-[(3R)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]-1-piperidyl]propanoate To a mixture of 5-chloro-N-[(3R)-3-piperidyl]oxazolo[4,5-b]pyridine-2-amine (Example 4, Step B) (68 mg, 0.27 mmol, 1.00 equivalent) in tetrahydrofuran (1.2 mL) and N,N-dimethylformamide (1.2 mL), N,N-diisopropylethylamine (86 mg, 0.116 mL, 0.66 mmol, 2.49 equivalents) was added, followed by the dropwise addition of methyl 3-bromopropanoate (CAS#3395-91-3, 57 mg, 0.037 mL, 0.34 mmol, 1.27 equivalents). The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and 10% LiCl aqueous solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed twice with 10% LiCl aqueous solution, once with water, and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, 0% to 10% methanol in ethyl acetate gradient) to obtain the title compound (74 mg, 78% yield) as a colorless viscous oil. LCMS: m / z 339.1 [M+H] + ,ESI pos.

[0260] Process D: 3-[(3R)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]-1-piperidyl]-N-(2,2-dimethoxyethyl)propanamide To a solution of methyl 3-[(3R)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]-1-piperidyl]propanoate (Example 4, Step C) (74 mg, 0.21 mmol, 1.00 equivalent) in tetrahydrofuran (0.80 mL) and methanol (0.80 mL), 1 M aqueous lithium hydroxide solution (0.27 mL, 0.27 mmol, 1.30 equivalent) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved twice in toluene, concentrated under vacuum, and then placed under high vacuum. The residue was suspended in N,N-dimethylformamide (1.0 mL). Aminoacetaldehyde dimethyl acetal (CAS#22483-09-6, 34 mg, 0.035 mL, 0.32 mmol, 1.55 equivalents) was added, followed by N,N-diisopropylethylamine (85 mg, 0.115 mL, 0.66 mmol, 3.17 equivalents) and HATU (100 mg, 0.26 mmol, 1.27 equivalents). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was extracted with ethyl acetate and 5% LiCl aqueous solution. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed three times with 5% LiCl aqueous solution, once with water, and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude substance was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0%-5% methanol) to obtain the title compound (56 mg, 62% yield) as a yellow viscous oil. LCMS: m / z 412.1 [M+H] + ,ESI pos.

[0261] Step E: 5-Chloro-N-[(3R)-1-(2-oxazole-2-ylethyl)-3-piperidyl]oxazolo[4,5-b]pyridine-2-amine A solution of 3-[(3R)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]-1-piperidyl]-N-(2,2-dimethoxyethyl)propanamide (Example 4, Step D) (56 mg, 0.13 mmol, 1.00 equivalent) in Eaton's reagent (CAS #39394-84-8, 1.24 g, 0.82 mL, 5.22 mmol, 40.4 equivalents) was stirred at 100°C for 16 hours. The reaction mixture was added dropwise to saturated aqueous NaHCO3 (20 mL) and then extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, 0%-10% methanol in gradient dichloromethane, followed by 10%-100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). The title compound (13 mg, yield 23%, purity 80%) was obtained as a brown viscous oil. LCMS: m / z 348.1 [M+H] + ,ESI pos.

[0262] Process F: 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-(2-oxazole-2-ylethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]benzonitrile A mixture of 5-chloro-N-[(3R)-1-(2-oxazole-2-ylethyl)-3-piperidyl]oxazolo[4,5-b]pyridine-2-amine (Example 4, Step E) (13 mg, 0.03 mmol, 1.00 equivalent, 80% purity), (4-cyano-2-hydroxy-6-methylphenyl)boronic acid, intermediate 7 (8 mg, 0.05 mmol, 1.51 equivalents), cesium carbonate (31 mg, 0.10 mmol, 3.18 equivalents), and XPhos Pd G3 (5 mg, 0.01 mmol, 0.20 equivalents) in 1,4-dioxane (0.30 mL) and water (0.075 mL) was flushed with argon and stirred at 100°C for 2.5 hours and at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and a semi-saturated aqueous NH4Cl solution. 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 under vacuum. The crude product was purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0% to 10% methanol). All fractions containing the product were combined and concentrated under vacuum to obtain the title compound (6 mg, yield 41%, purity 90%) as a pale yellow solid. LCMS: m / z 445.1 [M+H] + ,ESI pos.

[0263] Example 5: 4-[(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]-1-piperidyl]butanoic acid [ka]

[0264] Process A: Methyl 4-[(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]-1-piperidyl]butanoate To a suspension of (3S,5R)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol; dihydrochloride (Example 6, Step C) (90 mg, 0.18 mmol, 1.0 equivalent) in dichloromethane (4 mL), methyl 4-ketobutyrate ((CAS#13865-19-5), 57 mg, 0.05 mL, 0.44 mmol, 2.50 equivalents), followed by sodium acetate ((CAS#127-09-3), 36 mg, 0.44 mmol, 2.50 equivalents) and sodium triacetoxyborohydride ((CAS#56553-60-7), 68 mg, 0.32 mmol, 1.80 equivalents), were added at 0°C. The reaction mixture was stirred at 0°C for 5 minutes and at room temperature for 3 hours. A saturated NaHCO3 solution (30 ml) was added to the reaction mixture and extracted with dichloromethane (3 × 50 mL). The organic phase was separated and washed with water (20 ml) and brine (20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography (silica gel, 12 g, dichloromethane gradient 0% to 50% (dichloromethane:methanol:NH4OH 110:10:1)) to obtain the title compound (78 mg, yield 82%) as a white foam. LCMS: m / z 507.1 [MH] - ,ESI neg.

[0265] Process B: 4-[(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-oxazolo[4,5-b]pyridine-2-yl]amino]-1-piperidyl]butanoic acid To a solution of the above-mentioned methyl 4-[(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]-1-piperidyl]butanoate (76 mg, 0.14 mmol, 1.0 equivalent) in tetrahydrofuran (1.0 mL) and methanol (0.5 mL), 1 M aqueous lithium hydroxide solution (0.28 mL, 0.28 mmol, 2.0 equivalents) was added. The mixture was stirred at 23°C for 16 hours. All organic solvents were evaporated. The crude product was then purified by preparative HPLC (column: Gemini NX, 12 nm, 5 μm, 100 × 30 mm; conditions: MeCN / water + 0.1% HCOOH; gradient: 20-60 MeCN in water, run time 11 min) to obtain the title compound (34 mg, yield 46%) as a white solid. LCMS: m / z 495.2 [M+H] + ,ESI pos.

[0266] Example 6 (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol [ka]

[0267] Process A: tert-butyl(3R,5S)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]-5-hydroxy-piperidine-1-carboxylate To a mixture of 1,4-dioxane (4 mL) and 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS#1783370-92-2, 387 mg, 1.83 mmol, 1.0 equivalent), (3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (CAS#1932513-59-1, 476 mg, 2.2 mmol, 1.20 equivalents) was added, followed by the addition of triethylamine (278 mg, 0.38 mL, 2.75 mmol, 1.50 equivalents). The reaction mixture was stirred at 110°C for 48 hours. The reaction mixture was extracted with ethyl acetate (3 × 80 mL) and 1 M Na₂CO₃ (80 mL). The organic layers were washed with water (30 mL) and brine (30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum.

[0268] The crude product was purified by flash chromatography (silica gel, 12 g, dichloromethane gradient from 0% to 50% (dichloromethane:methanol:NH4OH 110:10:1)) to obtain the title compound (535 mg, yield 75%) as a colorless oil. LCMS: m / z 369.1 ([{35Cl}M+H] + ),371.1([{37Cl}M+H] + ),ESI pos.

[0269] Process B: tert-butyl-(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-1-carboxylate In a closable tube, a mixture of 1,4-dioxane (4 mL) and water (1 mL) containing the above-mentioned tert-butyl-(3R,5S)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]-5-hydroxy-piperidine-1-carboxylate (Step A) (150 mg, 0.39 mmol, 1.0 equivalent), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (163 mg, 0.54 mmol, 1.40 equivalents), and cesium carbonate (378 mg, 1.16 mmol, 3.0 equivalents) was set under argon, and finally xphos-g3-paradacycle (CAS # 1445085-55-1, 49 mg, 0.05 mmol, 0.150 equivalents) was added. The reaction mixture was stirred in a sealed tube at 90°C for 4 hours. The reaction mixture was cooled to room temperature. Quenched with water (20 mL) and saturated NH4Cl solution (20 mL), then extracted with ethyl acetate (2 × 40 mL). The organic layer was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was flash-chromatographed (silica gel, 12 g, gradient heptane with 0% to 50% ethyl acetate; then purified by ethyl acetate:methanol 9:1 (v / v) to obtain the title compound (169 mg, yield 86%) as a light brown foam. LCMS: m / z 509.1 [M+H] + ,ESI pos.

[0270] Process C: (3S,5R)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol; dihydrochloride To a solution of tert-butyl-(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-1-carboxylate (Step B) (169 mg, 0.33 mmol, 1.0 equivalent) in dichloromethane (8 mL) and methanol (2 mL), 4M HCl (997 mg, 0.83 mL, 3.32 mmol, 10.0 equivalent) in 1,4-dioxane was added dropwise at ambient temperature. The reaction mixture was stirred at 23°C for 16 hours. Upon evaporation of the reaction mixture, the title compound (158 mg, 94%) was obtained as a pale yellow foam. LCMS: m / z 409.1 [M+H] + ,ESI pos.

[0271] Process D: (3S,5R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol To a suspension of (3S,5R)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol; dihydrochloride (Step C) (68 mg, 0.13 mmol, 1.0 equivalent) in dichloromethane (3 mL), 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (CAS#102191-92-4, 65 mg, 0.07 mL, 336 mmol, 2.50 equivalents) was added at 0°C, followed by the addition of sodium acetate ((CAS#127-09-3), 28 mg, 0.34 mmol, 2.50 equivalents) and sodium triacetoxyborohydride (CAS#56553-60-7, 51 mg, 0.24 mmol, 1.80 equivalents). The reaction mixture was stirred at 0°C for 5 minutes and at 23°C for 3 hours. A saturated NaHCO3 solution (30 mL) was added to the reaction mixture and extracted with dichloromethane (3 × 50 mL). The organic phase was separated and washed with water (20 mL) and brine (20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (170 mg; 98% yield) as a light brown oily substance. LCMS: m / z 565.2 [MH] - ,ESI neg.

[0272] Process E: (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol A solution of 1M tetrabutylammonium fluoride in THF (CAS#429-41-4, 234 mg, 0.26 mL, 0.26 mmol, 2.0 equivalents) was added dropwise to a solution of (3S,5R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol (Step D) (170 mg, 0.13 mmol, 1.0 equivalent) in tetrahydrofuran (3.52 mL). The reaction mixture was stirred at 23°C for 2 hours. The reaction mixture was extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. Next, the crude product was purified by preparative HPLC (column: Gemini NX, 12 nm, 5 μm, 100 × 30 mm; conditions: MeCN / water + 0.1% TEA; gradient: 5-10-100 MeCN in water, run time 15 min) to obtain the title compound (24 mg, yield 38%) as a white solid. LCMS: m / z 453.3 [M+H] + ,ESI pos.

[0273] Example 7 3-Hydroxy-4-[2-[[(3R,5S)-5-Hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid [ka]

[0274] Process A: 4-(5-(benzyloxy)-6-isothiocyanatopyrazine-2-yl)-3-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy)benzonitrile To a solution of 1,1'-thiocarbonyldipyridine-2(1H)-one (773 mg, 3.33 mmol, 1.1 equivalents) in DCM (16 mL), 4-(6-amino-5-benzyloxypyrazine-2-yl)-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile (1400 mg, 3.03 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / ethyl acetate 20:1~10:1) to obtain the title compound as a yellow oil. LCMS: m / z 505.2 [M+H] + ,ESI pos.

[0275] Process B: tert-butyl(3R,5S)-3-(3-(3-(benzyloxy)-6-(4-cyano-2-methyl-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrazine-2-yl)thioureido)-5-hydroxypiperidine-1-carboxylate To a solution of tert-butyl(3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylate (157 mg, 0.73 mmol, 1.05 equivalents) and DIEA (0.18 mL, 1.04 mmol, 1.5 equivalents) in DCM (5 mL), a solution of 4-(5-benzyloxy-6-isothiocyanatopyrazine-2-yl)-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile (350 mg, 0.69 mmol, 1.0 equivalent) in DCM (5 mL) was added dropwise. The reaction mixture was stirred at 20°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 10:1~2:1) to obtain the title compound (450 mg, yield 90%) as a yellow oil. LCMS: m / z 721.3 [M+H] + ,ESI pos.

[0276] Process C: 1-(6-(4-cyano-2-hydroxy-6-methylphenyl)-3-hydroxypyrazine-2-yl)-3-((3R,5S)-5-hydroxypiperidine-3-yl)thiourea A solution of tert-butyl(3R,5S)-3-[[3-benzyloxy-6-[4-cyano-2-methyl-6-(2-trimethylsilylethoxymethoxy)phenyl]pyrazine-2-yl]carbamoteoylamino]-5-hydroxy-piperidine-1-carboxylate (450 mg, 0.62 mmol, 1.0 equivalent) in TFA (4.5 mL, 60.49 mmol, 97 equivalents) was stirred at 25°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum, dissolved in MeCN (1 mL), and the pH was adjusted to pH=7-8 by adding NH3·H2O. The residue was then collected in C 18 The compound was purified by column chromatography (20 g, 0.1% NH3·H2O in water / MeCN, MeCN: 30%-40%) to obtain the title compound (180 mg, yield 72%) as a white solid. 1 H NMR(400 MHz,CD3OD)δ [ppm]:7.16-7.13(m,1H),7.07(s,1H),7.04(s,1H),4.48-4.36(m,1H),3.76-3.64(m,1H),3.27(m,1H) ,3.08-2.94(m,1H),2.57-2.45(m,1H),2.44-2.36(m,1H),2.33(s,1H),2.29(s,3H),1.39-1.33(m,1H).

[0277] Process D: 1-(6-(4-cyano-2-hydroxy-6-methylphenyl)-3-hydroxypyrazine-2-yl)-3-((3R,5S)-5-hydroxy-1-methylpiperidine-3-yl)thiourea To a solution of 1-[6-(4-cyano-2-hydroxy-6-methylphenyl)-3-hydroxypyrazine-2-yl]-3-[(3R,5S)-5-hydroxy-3-piperidyl]thiourea (100 mg, 0.25 mmol, 1.0 equivalent) in methanol (1 mL) / DCE (5 mL), formaldehyde (61 mg, 0.75 mmol, 3.0 equivalents) was added and the mixture was stirred at 20°C for 0.5 hours. Then, NaBH(OAc)3 (132 mg, 0.62 mmol, 2.5 equivalents) was added. The reaction mixture was stirred at 20°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was purified by reverse-phase flash (CombiFlash 0.1% TFA aqueous-MeCN conditions) to obtain the title compound (100 mg, yield 76%) as a yellow solid. LCMS: m / z 415.2 [M+H] + ,ESI pos.

[0278] Process E: 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid A solution of 1-[6-(4-cyano-2-hydroxy-6-methylphenyl)-3-hydroxypyrazine-2-yl]-3-[(3R,5S)-5-hydroxy-1-methyl-3-piperidyl]thiourea;2,2,2-trifluoroacetic acid (100 mg, 0.19 mmol, 1.0 equivalent) and tetrabutylazanium iodide (84 mg, 0.23 mmol, 1.2 equivalents) was added dropwise to H2O2 (35 mg, 0.38 mmol, 2.00 equivalents) and stirred at 20°C for 0.5 hours. After the reaction was complete, the reaction mixture was quenched with saturated Na2SO3 aqueous solution (1 mL) and then concentrated under vacuum. The residue was purified by reverse-phase flash (CombiFlash 0.1% NH3·H2O aqueous-MeCN conditions) to obtain the crude product (60 mg). Next, this is separated by HPLC (column: Phenomenex Luna C 18The compound was purified by LCMS (150*25mm*10μm; conditions: water (TFA)-MeCN; start: B, 14, end: B: 44; gradient time (min): 10; 100% B retention time (min): 3; flow rate (ml / min): 25) to obtain the title compound (22.1 mg, yield 23%) as a white solid. LCMS: m / z 381.1 m / z 395.1 [M+H] + ,ESI pos.

[0279] Example 8 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid [ka]

[0280] Process A: 6-Chloro-4-iodo-2-nitropyridine-3-ol In a three-necked round-bottom flask, 6-chloro-4-iodopyridine-3-ol (5.0 g, 19.57 mmol, 1.0 equivalent, CAS # 877133-58-9) was added to 50 mL of acetic acid with 2.65 mL of fuming nitric acid (63.5 mmol, 3.24 equivalents) at 20°C, and the mixture was stirred at 20°C for 2 hours. Once the reaction was complete, the reaction mixture was slowly pipetted into 150 mL of ice water. 150 mL of ethyl acetate was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (3 × 150 mL). The combined extracts were washed with saturated NaHCO3 (3 × 100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. This residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1~2:1) to obtain the title compound (2.90 g, yield 49%) as a yellow solid. LCMS: m / z 298.9 [MH] - ,ESI neg.

[0281] Step B: 6-Chloro-4-methoxy-2-nitropyridine-3-ol To a solution of 6-chloro-4-iodo-2-nitropyridine-3-ol (1.3 g, 4.33 mmol, 1.0 equivalent) in methanol (13 mL), sodium methoxide (4.95 mL, 21.63 mmol, 5.0 equivalents) and CuI (0.99 g, 5.19 mmol, 1.2 equivalents) were added. The reaction mixture was stirred at 80°C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, water (30 mL) was added, and the pH was acidified to 5-6 with 1N HCl. Depositphotos (50 mL) was added, and the layers were separated. The aqueous phase was extracted with Depositphotos (3 × 50 mL). The combined extracts were washed with brine (3 × 30 mL), dried with Na₂SO₄, filtered, and concentrated under vacuum to obtain a residue. This residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 2:1) to obtain the title compound (500.0 mg, yield 56%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ [ppm]:11.43-11.14(m,1H),7.48(s,1H),4.00(s,3H).

[0282] Process C: 2-amino-6-chloro-4-methoxypyridine-3-ol To a solution of 6-chloro-4-methoxy-2-nitropyridine-3-ol (100.0 mg, 0.49 mmol, 1.0 equivalent) in methanol (1 mL), tin(II) chloride (278.06 mg, 1.47 mmol, 3.0 equivalents) was added. The reaction mixture was stirred at 70°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, water (20 mL) was added, and the pH was basicized to 7 with NaHCO3. Ether (20 mL) was added, and the layers were separated. The aqueous phase was extracted with Ether (3 × 20 mL). The combined extracts were washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. This residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:2) to obtain the title compound (45.0 mg, yield 53%) as a white solid. LCMS: m / z 175.0 [M+H] + ,ESI pos.

[0283] Step D: 5-Chloro-7-methoxyoxazolo[4,5-b]pyridine-2-thiol To a solution of 2-amino-6-chloro-4-methoxypyridine-3-ol (40.0 mg, 0.23 mmol, 1.0 equivalent) in DMF (0.5 mL), di(1H-imidazole-1-yl)methanethion (40.83 mg, 0.23 mmol, 1.0 equivalent) was added and the mixture was stirred at 20°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with water (10 mL) and acidified to pH=2-3 with 1N HCl.  (10 mL) and water (10 mL) were added, and the layers were separated. The aqueous phase was extracted with  (3 × 10 mL). The combined extracts were washed with saturated CaCl2 solution (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (30.0 mg, yield 60%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ [ppm]:7.12(s,1H),4.04(s,3H).

[0284] Step E: 2,5-Dichloro-7-methoxyoxazolo[4,5-b]pyridine To a mixture of oxalyl chloride (1.0 mL, 11.8 mmol, 85 equivalents) and 5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-thiol (30.0 mg, 0.14 mmol, 1.0 equivalent), DMF (1.01 mg, 0.01 mmol, 0.1 equivalent) was added, and the mixture was stirred at 50°C for 1 hour. After the reaction was complete, the reaction mixture was cooled to 20°C, concentrated under vacuum, and extracted with RINKAN (2 × 10 mL) after adding ice water (5 mL). The combined extract was washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain a residue. This residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1~8:1) to obtain the title compound (16.0 mg, yield 53%) as a yellow solid. LCMS: m / z 218.9 [M+H] + ,ESI pos.

[0285] Process F: (R)-N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-3-yl)-5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-amine, also known as N-[(3R)-1-[2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-3-yl)-5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-amine To a solution of (3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidine-3-amine (21.2 mg, 0.08 mmol, 1.2 equivalents) and N-ethyl-N-isopropylpropan-2-amine (17.67 mg, 0.14 mmol, 2.0 equivalents) in acetonitrile (1 mL), a solution of 2,5-dichloro-7-methoxy-oxazolo[4,5-b]pyridine (15.0 mg, 0.07 mmol, 1.0 equivalent) in acetonitrile (0.5 mL) was added dropwise at 20°C. The mixture was then stirred at 20°C for 1 hour. After the reaction was complete, the mixture was concentrated under vacuum to obtain a residue, which was purified by preparative TLC (Â:MeOH = 10:1) to obtain the title compound (15.0 mg, yield 50%) as a yellow oil. 1 H NMR(400MHz,CD3OD)δ [ppm]:6.79(s,1H),4.05(s,3H),3.96-3.88(m,1H),3.82(t,2H),3.22-3.14(m,1H),2.86-2.77(m,1H),2.66-2.58(m,2H) ,2.36-2.24(m,2H),2.05-1.96(m,1H),1.87-1.77(m,1H),1.73-1.63(m,1H),1.53-1.42(m,1H),0.87(s,9H),0.07(s,6H).

[0286] Step G: (R)-N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-3-yl)-5-chloro-7-methoxyoxazolo[4,5-b]pyridine-2-amine To a solution of N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-amine (14.0 mg, 0.03 mmol, 1.0 equivalent), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (14.8 mg, 0.04 mmol, 1.2 equivalents), and K2CO3 (10.97 mg, 0.08 mmol, 2.5 equivalents) in 1,4-dioxane (0.5 mL) and water (0.1 mL), Xphos Pd G3 (5.38 mg, 0.01 mmol, 0.2 equivalents) was added and the mixture was stirred at 90°C for 4 hours. Once the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under vacuum to obtain a residue. This residue was purified by preparative TLC (Â / MeOH = 10:1) to obtain the title compound (12.0 mg, yield 57%) as a colorless oil. 1 H NMR(400 MHz,CD3OD)δ [ppm]:7.38(s,1H),7.32(s,1H),6.66(s,1H),5.17(s,2H),4.06(s,3H),3.98-3.9 1(m,1H),3.81(t,2H),3.59(t,2H),3.24-3.17(m,1H),2.83-2.77(m,1H),2.63-2.5 6(m,2H),2.33-2.22(m,2H),2.13(s,3H),2.05-2.00(m,1H),1.85-1.78(m,1H),1. 74-1.65(m,1H),1.48(m,1H),0.87(s,8H),0.84(m,2H),0.07(d,6H),-0.05(s,9H).

[0287] Process H: 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid A solution of 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile (10.0 mg, 0.01 mmol, 1.0 equivalent) in TFA (0.83 mL, 11.2 mmol, 748 equivalents) was stirred at 40°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under vacuum to obtain the residue. This residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; conditions: water (TFA)-MeCN; start B: 14; end B: 34; gradient time (min): 7; 100% B retention time (min): 3; flow rate (ml / min): 25) to obtain the title compound (3.9 mg, yield 48%) as a white solid. LCMS: m / z 424.2 [M+H] + ,ESI pos.

[0288] Example 9 3-Hydroxy-4-[2-[[(3R,5S)-5-Hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-methylbenzonitrile [ka]

[0289] Process A: tert-butyl(3R,5S)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]-5-hydroxy-piperidine-1-carboxylate To a mixture of 1,4-dioxane (1.4 mL) and 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS#1783370-92-2, 150 mg, 0.71 mmol, 1.00 equivalent), tert-butyl(3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylate (CAS#1932513-59-1, 177 mg, 0.82 mmol, 1.15 equivalent), followed by triethylamine (83 mg, 0.115 mL, 0.83 mmol, 1.16 equivalent), was added. The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated NaHCO3 aqueous solution. 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 under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0% to 5% methanol) to obtain the title compound (251 mg, yield 86%, purity 90%) as a pale yellow oil. LCMS: m / z 369.1 [M+H] + ,ESI pos.

[0290] Process B: tert-butyl(3R,5S)-3-[[5-(4-cyano-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-5-hydroxy-piperidine-1-carboxylate A mixture of tert-butyl(3R,5S)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]-5-hydroxy-piperidine-1-carboxylate (Example 9, Step A) (251 mg, 0.61 mmol, 1.00 equivalent, 90% purity), (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid, intermediate 7 (164 mg, 0.93 mmol, 1.51 equivalents), cesium carbonate (635 mg, 1.95 mmol, 3.18 equivalents), and XPhos Pd G3 (102 mg, 0.12 mmol, 0.20 equivalents) in 1,4-dioxane (6.0 mL) and water (1.5 mL) was flushed with argon and stirred at 100°C for 3 hours. 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 under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, heptane gradient from 0% to 100% ethyl acetate) to obtain the title compound (188 mg, yield 63%) as a grayish-white solid. LCMS: m / z 466.3 [M+H] + ,ESI pos.

[0291] Step C: 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile To a solution of tert-butyl(3R,5S)-3-[[5-(4-cyano-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-5-hydroxy-piperidine-1-carboxylate (Example 9, Step B) (188 mg, 0.38 mmol, 1.00 equivalent) in dichloromethane (3 mL), trifluoroacetic acid (992 mg, 0.67 mL, 8.70 mmol, 22.7 equivalents) was added dropwise at 0°C. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane / methanol, carefully basicized with saturated NaHCO3 aqueous solution, and extracted three times with a mixture of dichloromethane / methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by SFC (column chiral IH, eluent B: 20% methanol + 0.2% diethylamine) to obtain the title compound (25 mg, yield 17%) as a white powder. LCMS: m / z 366.1 [M+H] + ,ESI pos.

[0292] Example 10 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methylbenzonitrile [ka]

[0293] Process A: tert-butyl(3R)-3-[(3-benzyloxy-6-bromopyrazine-2-yl)carbamoteoylamino]piperidine-1-carboxylate To a solution of 3-benzyloxy-6-bromopyrazine-2-amine (2700.0 mg, 9.64 mmol, 1.0 equivalent) in THF (15 mL), NaH (578.32 mg, 14.46 mmol, 1.5 equivalents) was added and the mixture was stirred for 20 minutes. Then, a solution of tert-butyl(3R)-3-isothiocyanatopiperidine-1-carboxylate (CAS#2824986-69-6, 2803.02 mg, 11.6 mmol, 1.2 equivalents) in THF (5 mL) was added dropwise, and the mixture was stirred under N2 at 20°C for 4 hours. After the reaction was complete, the mixture was quenched with NH4Cl (60 mL), extracted with siRNA (100 mL x 2), the organic phase was washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE:Â, 87%~13%) to obtain the title compound (3700.0 mg, yield 73%) as a yellow oily substance. LCMS (de-BOC) m / z: 466.1 [M+H] + ,ESI pos.

[0294] Process B: 1-(6-bromo-3-hydroxy-pyrazine-2-yl)-3-[(3R)-3-piperidyl]thiourea To a solution of tert-butyl(3R)-3-[(3-benzyloxy-6-bromo-pyrazine-2-yl)carbamoteoylamino]piperidine-1-carboxylate (3700.0 mg, 7.08 mmol, 1.0 equivalent) in anisole (20 mL), TFA (20 mL) was added and the mixture was stirred at 70°C for 2 hours under N2. After the reaction was complete, the mixture was concentrated under vacuum, diluted with MeOH (6 mL), and the pH was adjusted to 8.0. The residue was C 18 The compound was purified by column chromatography (0.1% NH3·H2O-Me CN=54%~46%), and the eluent was freeze-dried to obtain the title compound (1400.0 mg, yield 60%) as a white solid. LCMS m / z: 334.0 [M+2+H] + ,ESI pos.

[0295] Process C: 1-(6-bromo-3-hydroxypyrazine-2-yl)-3-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]thiourea To a solution of 1-(6-bromo-3-hydroxypyrazine-2-yl)-3-[(3R)-3-piperidyl]thiourea (570.0 mg, 1.72 mmol, 1.0 equivalent) in DCE (10 mL) and methanol (1 mL), CH3COOH (10.3 mg, 0.17 mmol, 0.1 equivalent) was added and the mixture was stirred for 20 minutes. Then, NaBH(OAc)3 (1.82 g, 8.58 mmol, 5.0 equivalent) was added, and the mixture was stirred at 20°C for 1 hour. After the reaction was complete, the mixture was quenched with H2O (30 mL), extracted with siRNA (30 mL x 2), the organic phase was washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate, 61% to 39%) to obtain the title compound (540.0 mg, yield 64%) as a yellow oily substance. LCMS m / z: 492.2 [M+2+H] + ,ESI pos.

[0296] Process D: 5-Bromo-N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5-b]pyrazine-2-amine To a solution of 1-(6-bromo-3-hydroxypyrazine-2-yl)-3-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]thiourea (540.0 mg, 1.1 mmol, 1.0 equivalent) in THF (20 mL), tetrabutylammonium iodide (406.6 mg, 1.1 mmol, 1.0 equivalent) was added, followed by the dropwise addition of H2O2 (390.0 mg, 3.44 mmol, 3.13 equivalents), and the mixture was stirred at 25°C for 1 hour. After the reaction was complete, the mixture was quenched with H2O (30 mL) and Na2SO3 (30 mL), extracted with siRNA (20 mL x 2), washed with Na2SO3 (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate, 65% to 35%) to obtain the title compound (169.0 mg, yield 34%) as a yellow oily substance. LCMS m / z: 456.3 [M+H] + ,ESI pos.

[0297] Step E: 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile To a solution of 5-bromo-N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5-b]pyrazine-2-amine (269.0 mg, 0.59 mmol, 1.0 equivalent) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (344.2 mg, 0.88 mmol, 1.5 equivalents) in 1,4-dioxane (4 mL) and water (0.8 mL), CsF (358.08 mg, 2.36 mmol, 4.0 equivalents) and XPhos Pd G3 (99.9 mg, 0.12 mmol, 0.2 equivalents) were added, and the mixture was stirred at 95°C for 2 hours under N2. After the reaction was complete, the reaction product was concentrated under reduced pressure, diluted with Â(3 mL), filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE:Â=1:1) to obtain the title compound (70.0 mg, yield 19%) as a yellow oil. LCMS m / z:639.5[M+H] + Furthermore, these compounds were also isolated as a yellow oily substance: 2-[(3R)-3-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]-1-piperidyl]ethanol (30.0 mg, yield 9.7%). LCMS m / z: 342.1[M+H] + ,ESI pos.; and as a yellow solid, 4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile (30.0 mg, yield 10%). LCMS m / z: 525.3 [M+H] + ,ESI pos.

[0298] Process F: 4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile To a solution of 2-[(3R)-3-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]-1-piperidyl]ethanol (30.0 mg, 0.09 mmol, 1.0 equivalent) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (51.2 mg, 0.13 mmol, 1.5 equivalents) in 1,4-dioxane (1 mL) and water (0.2 mL), CsF (53.27 mg, 0.35 mmol, 4.0 equivalents) and xphos Pd g3 (14.9 mg, 0.02 mmol, 0.2 equivalents) were added, and the mixture was then stirred at 95°C under N2 for 2 hours. Once the reaction was complete, the reaction product was concentrated under reduced pressure, diluted with siRNA (2 mL), filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (EA:MeOH = 3:1) to obtain the title compound (10.0 mg, yield 22%) as a yellow oil.

[0299] Step G: 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile To a solution of 4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile (10.0 mg, 0.02 mmol, 1.0 equivalent) in DCM (0.5 mL), TFA (0.5 mL) was added and the mixture was stirred at 40°C for 2 hours. After the reaction was complete, the mixture was diluted with DCM (2 mL) and MeOH (1 mL), the pH was adjusted to approximately 8 with NH3·H2O, then filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; conditions: water (0.1% NH3·H2O)-ACN, start B 7, end B 38; gradient time (min): 10; 100% B retention time (min): 2; flow rate (mL / min) 25) to obtain the title compound (2.12 mg, yield 27%) as a white solid. LCMS m / z: 395.2 [M+H] + ,ESI pos.

[0300] Example 11 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol [ka]

[0301] Process A: 2-[(3R)-3-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]piperidino]ethanol; 2,2,2-trifluoroacetic acid A solution of 5-bromo-N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5-b]pyrazine-2-amine (290.0 mg, 0.64 mmol, 1.0 equivalent, Example 10, Step D) in TFA (3.0 mL, 40.4 mmol, 63.6 equivalents) and DCM (3 mL) was stirred at 40°C for 1 hour. The reaction mixture was then concentrated under vacuum to obtain the residue. For purification, the two batches were combined (170 mg added), and the crude product was converted to C 18 The title compound (370.9 mg, 79% yield) was obtained as a yellow solid by purification by column chromatography (20 g, 0.1% NH3·H2O in water / MeCN, MeCN: 40%-50%). LCMS m / z: 341.9 [M+H] + ,ESI pos.

[0302] Process B: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol 1,4-Dioxane (5.6 mL) and water (2.8 mL) containing 2-[(3R)-3-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]piperidino]ethanol; 2,2,2-trifluoroacetic acid (324 mg, 710.2 μmol, 1.0 equivalent), 6-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2, A mixture of 3-dihydrobenzofuran-4-ol intermediate 8 (365 mg, 1.13 mmol, 1.6 equivalents), potassium carbonate (405 mg, 2.93 mmol, 4.126 equivalents), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (89 mg, 109 μmol, 0.15 equivalents) was flashed with argon and stirred at 90°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and semisaturated 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 under vacuum. The crude product was purified by flash chromatography (silica gel, 25 g, gradient dichloromethane with 0% to 10% methanol) to obtain the title compound (297 mg) as a brown foam. After combining with another batch (35 mg), the compound was re-purified by flash chromatography (Si-amine, 12 g, 0% to 10% methanol in ethyl acetate gradient), followed by polishing with ethyl acetate / heptane to obtain the title compound (206 mg, 63% yield) as a pale yellow powder. LCMS m / z: 442.4 [M+H] + ,ESI pos.

[0303] Example 12 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol [ka] 1,4-Dioxane (2.8 mL) and water (1.4 mL) containing 2-[(3R)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]piperidino]ethanol (124 mg, 397 μmol, 1.00 equivalent; CAS#2923540-56-9), 6-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2, A mixture of 3-dihydrobenzofuran-4-ol intermediate 8 (230 mg, 714 μmol, 1.80 equivalents), potassium carbonate (209 mg, 1.51 mmol, 3.81 equivalents), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (50 mg, 61.23 μmol, 0.15 equivalents) was flashed with argon and stirred overnight at 95°C. 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 layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0% to 10% methanol). All fractions containing the product were combined, concentrated under vacuum, and re-purified by flash chromatography (Si-amine, 12 g, 0%-10% methanol in ethyl acetate gradient). The title compound (73 mg, 40% yield) was obtained as a grayish-white foam. LCMS m / z: 441.3 [M+H] + ,ESI pos.

[0304] Example 13 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol [ka]

[0305] Process A: 5-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol To a solution of 5-bromo-N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5-b]pyrazine-2-amine (400.0 mg, 0.88 mmol, 1.0 equivalent, Example 10, Step D) in 1,4-dioxane (10 mL) and water (2 mL), 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol (290.39 mg, 1.05 mmol, 1.2 equivalents; CAS#2923540-54-7) and CsF (332.79 mg, 2.19 mmol, 2.5 equivalents) were added. Next, XphosPdG3 (74.27 mg, 0.09 mmol, 0.1 equivalent) was added to the above mixture. The reaction mixture was stirred under N2 at 80°C for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. HCl (10 mL) and brine (3 mL) were added to the mixture, and the layers were separated. The aqueous phase was extracted with HCl (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1) to obtain the title compound (300 mg, yield 63%) as a yellow solid. LCMS m / z: 526.3 [M+H] + ,ESI pos.

[0306] Process B: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol A solution of 5-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol (300.0 mg, 0.57 mmol, 1.0 equivalent) in DCM (3 mL) and TFA (3.0 mL, 40.39 mmol, 70.78 equivalents) was stirred at 40°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum, dissolved in MeOH (2 mL), and basicized to pH=7 by adding saturated NaHCO3 aqueous solution. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Method: Waters Xbridge column 150×25mm×5μm; Conditions: Water (ammonia hydroxide v / v)-MeCN; Start B: 0; End B: 30; Gradient time (min): 10; 100% B retention time (min): 4; Flow rate (mL / min): 25) to obtain the title compound (145.3 mg, yield 60%) as a white solid. LCMS m / z: 412.2 [M+H] + ,ESI pos.

[0307] Example 14 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol [ka] 1,4-Dioxane (1.5 mL) and water (750 μL) containing 2-[(3R)-3-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]piperidino]ethanol (70 mg, 224.1 μmol, 1.00 equivalent; CAS#2923540-56-9), 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)coumaran-4- A mixture of ol (129 mg, 350.4 μmol, 1.56 equivalents; CAS#2923540-54-7), potassium carbonate (146 mg, 1.06 mmol, 4.71 equivalents), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (28 mg, 34.3 μmol, 0.15 equivalents) was flashed with argon and stirred overnight at 95°C. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and semi-saturated NH4Cl aqueous solution. 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 under vacuum. The crude product was purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0% to 10% methanol). All fractions containing the product were combined and concentrated under vacuum. The residue (52 mg) was further purified by SFC (column: achiral 4-ethylpyridine, 12 nm, 5 μm, 250 × 20 mm, eluent B: 15% MeOH + 0.2% DEA) to obtain the title compound (16 mg, yield 17%) as a pale yellow solid. LCMS m / z: 411.1 [M + H] + ,ESI pos.

[0308] Example 15 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid [ka]

[0309] Process A: 2-[(3R)-3-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]-1-piperidyl]ethanol To a solution of 1-(6-bromo-3-hydroxypyrazine-2-yl)-3-[(3R)-1-(2-hydroxyethyl)-3-piperidyl]thiourea intermediate 11 (200.0 mg, 0.53 mmol, 1.0 equivalent) and tetrabutylammonium iodide (39.3 mg, 0.11 mmol, 0.2 equivalents) in THF (5 mL), H2O2 (180.8 mg, 1.59 mmol, 3.0 equivalents, purity: 30% aqueous solution) was added and the mixture was stirred at 20°C for 1 hour. After the reaction was complete, the mixture was quenched with saturated Na2SO3 aqueous solution (3 mL), and then concentrated under vacuum. The residue was separated by preparative HPLC (column: Xtimate C 18 The sample was purified using a 250mm*50mm*10μm mobile phase (water (0.1% ammonium hydroxide v / v)-MeCN); B%: 5%~35%, 10 min. The eluent was freeze-dried to obtain the title compound (80.0 mg, yield 39%) as a yellow solid. LCMS: m / z 344.0 [M+2+H] + ,ESI pos.

[0310] Step B: 4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-(methoxymethyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile Xphos Pd G3 (24.8 mg, 0.03 mmol, 0.2 equivalents) was added to a solution of the above-mentioned 2-[(3R)-3-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]-1-piperidyl]ethanol (50.0 mg, 0.15 mmol, 1.0 equivalent), 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (91.9 mg, 0.22 mmol, 1.5 equivalents; CAS#2923541-74-4), and CsF (66.6 mg, 0.44 mmol, 3.0 equivalents) in 1,4-dioxane (2 mL) and water (0.4 mL). Next, the mixture was stirred under nitrogen at 80°C for 2 hours. Once the reaction was complete, the reaction mixture was cooled to room temperature, poured onto ice (20 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 1:1) to obtain the title compound (30.0 mg, yield 37%) as a yellow solid. 1 H NMR(400 MHz,CD3OD)δ [ppm]:7.78(s,1H),7.56(s,1H),7.54(s,1H),5.22(s,2H),4.31(s,2H),4.07(s,1H),3.71-3.67(m,2H),3.60(t,2H),3.25(s,3H),3.00 -2.96(m,1H),2.61-2.59(m,1H),2.59-2.56(m,2H),2.47-2.45(m,2H),1.89-1.83(m,2H),1.70-1.66(m,2H),0.86(t,2H),-0.05(s,9H).

[0311] Process C: 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid To a solution of the above-mentioned 4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-(methoxymethyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (15.0 mg, 0.03 mmol, 1.0 equivalent) in DCM (0.5 mL), TFA (0.5 mL) was added. The mixture was then stirred at 20°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Gemini, 150 mm*30 mm*15 μm; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 22%~52%, 12 min), and the eluent was lyophilized to obtain the title compound (12.8 mg, yield 110%, TFA salt) as a yellow oil. LCMS: m / z 425.3 [M+H] + ,ESI pos.

[0312] Example 16 = Example 8 as a free salt 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile [ka]

[0313] Example 17 = Example 2 as a free salt 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile [ka]

[0314] Example 18 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-indan-4-ol [ka]

[0315] Process A: N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-[6-methyl-4-(2-trimethylsilylethoxymethoxy)indan-5-yl]oxazolo[4,5-b]pyrazine-2-amine Xphos Pd G3 (18.6 mg, 0.02 mmol, 0.2 equivalents) was added to a solution of 5-bromo-N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5-b]pyrazine-2-amine (110.0 mg, 0.11 mmol, 1.0 equivalent; Example 10, Step D), trimethyl-[2-[[6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-4-yl]oxymethoxyethyl]silane (53.2 mg, 0.13 mmol, 1.2 equivalents; Example 19, Step G), and CsF (66.6 mg, 0.44 mmol, 4.0 equivalents) in 1,4-dioxane (1 mL) and water (0.2 mL). The reaction vessel was sealed and heated in a microwave at 95°C for 3 hours. Once the reaction was complete, the reaction mixture was cooled to room temperature, then diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate) to obtain the title compound (50.0 mg, yield 42%) as yellow rubber. LCMS: m / z 654.4 [M+H] + ,ESI pos.

[0316] Process B: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-indan-4-ol A solution of N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-[6-methyl-4-(2-trimethylsilylethoxymethoxy)indan-5-yl]oxazolo[4,5-b]pyrazine-2-amine (50.0 mg, 0.08 mmol, 1.0 equivalent) in HCl / dioxane (1.0 mL, 2 M) was stirred at 25°C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Gemini, 150 mm*25 mm*10 μm; mobile phase: [water (0.1% NH4HCO3, V / V)-MeCN]; B%: 22%-55%, 10 min), and then lyophilized to obtain the title compound (5.1 mg, yield 16.0%) as a white solid. LCMS: m / z 410.3 [M+H] + ,ESI pos.

[0317] Example 19 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-methyl-indan-4-ol [ka]

[0318] Process A: 2-Vinylcyclopentene-1-carbaldehyde To a solution of 2-bromocyclopentene-1-carbaldehyde (30.0 g, 171.4 mmol, 1.0 equivalent; CAS# 89466-25-1), Cs2CO3 (167.6 g, 514.23 mmol, 3.0 equivalents), potassium vinyl trifluoroborate (29.9 g, 222.8 mmol, 1.3 equivalents), and PPh3 (4.5 g, 17.1 mmol, 0.1 equivalent) in THF (500 mL) and water (100 mL), Pd(OAc)2 (1.92 g, 8.57 mmol, 0.05 equivalents) was added, the mixture was degassed three times with N2, and stirred at 50°C for 12 hours. The reaction mixture was diluted with water (500 mL) and extracted with siRNA (300 mL x 2). The combined organic phases were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1 / 0) to obtain the title compound (15.0 g, yield 64%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ [ppm]:10.21(s,1H),7.31-7.24(m,1H),5.57(d,1H),5.54(s,1H),2.78(t,2H),2.67(t,2H),1.95-1.88(m,2H).

[0319] Process B: 3-methyl-1-(2-vinylcyclopenten-1-yl)buta-3-en-1-ol To a solution of the aforementioned 2-vinylcyclopentene-1-carbaldehyde (6.0 g, 49.1 mmol, 1.0 equivalent) in THF (20 mL), 2-methylallyl magnesium chloride (197.0 mL, 98.5 mmol, 2.01 equivalents) was added under N2 at 0°C, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with saturated NH4Cl aqueous solution (150 mL) and extracted with ELISA (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1 / 0 to 10 / 1) to obtain the title compound (2.5 g, yield 29%) as a yellow oil. 1H NMR(400 MHz,CDCl3)δ [ppm]:6.78-6.71(m,1H),5.16-5.10(m,2H),4.88(m,1H),4.85-4.82(m,2H),2.6 9-2.59(m,1H),2.57-2.43(m,4H),2.20(dd,1H),1.90-1.82(m,2H),1.79(s,3H).

[0320] Process C: 3-methyl-1-(2-vinylcyclopenten-1-yl)buta-3-en-1-one To a solution of the above-mentioned 3-methyl-1-(2-vinylcyclopenten-1-yl)buta-3-en-1-ol (2.5 g, 14.02 mmol, 1.0 equivalent) in DCM (200 mL), Dess Martin periodinane (11896.1 mg, 28.1 mmol, 2.0 equivalent) was added at 0°C. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was quenched with saturated Na2SO3 aqueous solution (150 mL) and extracted with siRNA (150 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1 / 0 to 10 / 1) to obtain the title compound (2.0 g, yield 65%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ [ppm]:7.41(dd,1H),5.49-5.41(m,2H),4.94(s,1H),4.76(d,1H),3.24(s,2H),2.80(t,2H),2.68(t,2H),1.94-1.87(m,2H),1.78(s,3H).

[0321] Process D: 6-methylindan-4-ol To a solution of the above-mentioned 3-methyl-1-(2-vinylcyclopenten-1-yl)buta-3-en-1-one (2000.0 mg, 11.4 mmol, 1.0 equivalent) in toluene (1000 mL), Hoveyda-Grubbs (567.9 mg, 0.91 mmol, 0.08 equivalent) was added, the mixture was degassed three times with N2, and the mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1~5:1) to obtain the title compound (1.2 g) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 6.67(s,1H),6.46(s,1H),4.54-4.51(m,1H),2.89(t,2H),2.82(t,2H),2.29(s,3H),2.14-2.06(m,2H).

[0322] Process E: 5-bromo-6-methyl-indan-4-ol To a solution of the above-mentioned 6-methylindan-4-ol (1.2 g, 8.1 mmol, 1.0 equivalent) and i-Pr2NH (163.6 mg, 1.62 mmol, 0.2 equivalents) in DCM (20 mL), NBS (1441.2 mg, 8.1 mmol, 1.0 equivalent) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with DCM (50 mL) and washed with brine (40 mL). The organic layer was separated, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1~10:1) to obtain the title compound (1.0 g, yield 54%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.73(s,1H),5.58(s,1H),2.93-2.83(m,4H),2.37(s,3H),2.14-2.06(m,2H).

[0323] Process F: 2-[(5-bromo-6-methyl-indan-4-yl)oxymethoxy]ethyl-trimethyl-silane To a solution of 5-bromo-6-methylindan-4-ol (300.0 mg, 1.32 mmol, 1.0 equivalent) in DMF (5 mL), Cs2CO3 (860.8 mg, 2.64 mmol, 2.0 equivalent) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Next, 2-(trimethylsilyl)ethoxymethyl chloride (0.26 mL, 1.45 mmol, 1.1 equivalent) was added dropwise to the mixture at 0°C, and the resulting mixture was stirred at 20°C for 1 hour. After the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases 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 silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain the title compound (440.0 mg, yield 84%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6):δ 6.99(s,1H),5.10(s,2H),3.89-3.77(m,2H),2.90(t,2H),2.79(t,2H),2.31(s,3H),2.02-1.97(m,2H),0.95-0.85(m,2H),0.01(s,9H).

[0324] Process G: Trimethyl-[2-[[6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-4-yl]oxymethoxy]ethyl]silane Pd(OAc)2 (55.3 mg, 0.25 mmol, 0.2 equivalents) was added to a solution of the above-mentioned 2-[(5-bromo-6-methyl-indan-4-yl)oxymethoxy]ethyl-trimethyl-silane (440.0 mg, 1.23 mmol, 1.0 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (625.5 mg, 2.46 mmol, 2.0 equivalents), Cs2CO3 (802.4 mg, 2.46 mmol, 2.0 equivalents), and tris(4-methoxy-3,5-dimethylphenyl)phosphane (107.5 mg, 0.25 mmol, 0.2 equivalents) in 1,4-dioxane (10 mL) under N2 conditions. The mixture was stirred at 95°C for 3 hours. Once the reaction was complete, the reaction mixture was cooled to room temperature, then diluted with water (30 mL) and ethyl acetate (20 mL), filtered, and the filtrate was extracted with ethyl acetate (20 mL x 3). The combined organic phase was 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 (petroleum ether:ethyl acetate = 20:1) to obtain the title compound (330.0 mg, yield 66%) as a colorless oil. 1 H NMR(400 MHz,CD3OD)δ [ppm]:6.81(s,1H),5.07(s,2H),4.60(s,2H),3.75-3.88(m,2H),2.75-3.03(m,4H),2.30( s,3H),1.92-2.11(m,2H),1.37(s,12H),1.34-1.43(m,1H),0.82-1.00(m,2H),0.00(s,9H).

[0325] Process H: 7-Methoxy-5-[6-methyl-4-(2-trimethylsilylethoxymethoxy)indan-5-yl]-N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5-b]pyridine-2-amine To a solution of N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-amine (110.0 mg, 0.13 mmol, 1.0 equivalent, Example 8, Step F) in 1,4-dioxane (2 mL) and water (0.400 mL), the above-mentioned trimethyl-[2-[[6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-4-yl]oxymethoxyethyl]silane (63.8 mg, 0.16 mmol, 1.2 equivalents), CsF (39.9 mg, 0.26 mmol, 2.0 equivalents), and Xphos Pd G3 (22.3 mg, 0.03 mmol, 0.2 equivalents) were added. The reaction vessel was sealed and heated in a microwave at 95°C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, then diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate) to obtain the title compound (70.0 mg, yield 26%) as yellow rubber. LCMS: m / z 683.6 [M+H] + ,ESI pos.

[0326] Step I: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-methyl-indan-4-ol A solution of 7-methoxy-5-[6-methyl-4-(2-trimethylsilylethoxymethoxy)indan-5-yl]-N-[rac-(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5-b]pyridine-2-amine (70.0 mg, 0.1 mmol, 1.0 equivalent) in HCl / 1,4-dioxane (1.0 mL, 2 M) was stirred at 25°C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, then adjusted to pH=7 with saturated NaHCO3 aqueous solution at 0°C, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Gemini column, 150 mm*25 mm*10 μm; mobile phase: [water (0.1% NH4HCO3, V / V)-MeCN]; B%: 22%-52%, 12 min) and then lyophilized to obtain the title compound (10.1 mg, yield 22%) as a white solid. LCMS: m / z 439.3 [M+H] + ,ESI pos.

[0327] Example 20 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-(methoxymethyl)benzonitrile [ka]

[0328] Step A: 3-(methoxymethyl)-4-[7-methoxy-2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-(2-trimethylsilylethoxymethoxy)benzonitrile Xphos Pd was added to a solution of N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-amine (60.0 mg, 0.14 mmol, 1.0 equivalent; Example 8, Step F), 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxy-methoxy)benzonitrile (68.5 mg, 0.16 mmol, 1.2 equivalents; CAS#2923541-74-4), and CsF (41.3 mg, 0.27 mmol, 2.0 equivalents) in 1,4-dioxane (2 mL) and water (0.4 mL). G3 (23.1 mg, 0.03 mmol, 0.2 equivalents) was added. The reaction vessel was sealed and heated under nitrogen in a microwave at 95°C for 1.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate) to obtain the title compound (50.0 mg, yield 35%) as yellow rubber. 1 H NMR(400 MHz,CD3OD)δ [ppm]:7.55-7.52(m,1H),7.51-7.48(m,1H),6.72(s,1H),5.20(s,2H),4.86(s,1H),4.25(s,2 H),4.06(s,3H),3.98-3.92(m,1H),3.82(t,2H),3.59(t,2H),3.34-3.32(m,1H),3.27(s,3H),3 .25-3.18(m,1H),2.86-2.74(m,1H),2.66-2.55(m,2H),2.35-2.23(m,2H),2.06-1.99(m,1H),1 .86-1.77(m,1H),1.74-1.65(m,1H),1.55-1.42(m,1H),0.87(s,9H),0.07(s,6H),0.00(s,9H).

[0329] Step B: 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-(methoxymethyl)benzonitrile The above-mentioned solution of 3-(methoxymethyl)-4-[7-methoxy-2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-(2-trimethylsilylethoxymethoxy)benzonitrile (50.0 mg, 0.07 mmol, 1.0 equivalent) in HCl / 1,4-dioxane (1.0 mL, 2 M) was stirred at 25°C for 1 hour. After the reaction was complete, the above mixture was adjusted to pH=7 with saturated NaHCO3 aqueous solution at 0°C, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini, 150 mm*25 mm*10 μm; mobile phase: [water (0.1% NH4HCO3, V / V)-MeCN]; B%: 22%-52%, 11 min), and then lyophilized to obtain the title compound (18.7 mg, yield 58%) as a white solid. LCMS: m / z 454.3 [M+H] + ,ESI pos.

[0330] Example 21 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol [ka]

[0331] Step A: 6-(methoxymethyl)-5-[7-methoxy-2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-2,3-dihydrobenzofuran-4-ol Xphos-PdG3 (13.5 mg, 0.02 mmol, 0.1 equivalent) was added to a solution of 6-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol intermediate 8 (58.3 mg, 0.19 mmol, 1.2 equivalents) and N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-amine (70.0 mg, 0.16 mmol, 1.0 equivalent; Example 8, Step F), K2CO3 (54.8 mg, 0.4 mmol, 2.5 equivalents) in 1,4-dioxane (1 mL) and water (0.200 mL). Next, the reaction mixture was stirred under N2 at 95°C for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. Ethyl acetate (10 mL) and water (5 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined extract was washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1) to obtain the title compound (70.0 mg, yield 60%) as a yellow solid. LCMS: m / z 585.3 [M+H] + ,ESI pos.

[0332] Process B: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol The above-mentioned solution of 6-(methoxymethyl)-5-[7-methoxy-2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-2,3-dihydro-benzofuran-4-ol (70.0 mg, 0.12 mmol, 1.0 equivalent) in HCl / dioxane (2 M, 1.0 mL) was stirred at 25°C for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was separated by preparative HPLC (column: Xtimate C). 18The sample was purified by LCMS (150mm*25mm*5μm; mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 10%~40%, 5 min), and then freeze-dried to obtain the title compound (43.9 mg, yield 78%) as a white solid. LCMS: m / z 471.2 [M+H] + ,ESI pos.

[0333] Example 22 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol [ka]

[0334] Step A: 5-[7-Methoxy-2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-amine (50.0 mg, 0.11 mmol, 1.0 equivalent; Example 8, Step F) and 6-methyl-5-(4,4,5, Xphos-PdG3 (9.6 mg, 0.01 mmol, 0.1 equivalent) was added to a solution of 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol (37.6 mg, 0.14 mmol, 1.2 equivalents; CAS#2923540-54-7) and K2CO3 (39.2 mg, 0.28 mmol, 2.5 equivalents). The reaction mixture was stirred under N2 at 90°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. Ethyl acetate (10 mL) and water (15 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined extract was washed with brine (5 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC(Â) to obtain the title compound (50.0 mg, 77% yield) as a yellow solid. LCMS: m / z 555.3 [M+H] + ,ESI pos.

[0335] Process B: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol A solution of the above-mentioned 5-[7-methoxy-2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol (45.0 mg, 0.08 mmol, 1.0 equivalent) in HCl / dioxane (2 M, 1.0 mL) was stirred at 25°C for 10 minutes. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was dissolved in methanol (1 mL), basicized to pH=7 with saturated NaHCO3 aqueous solution, then filtered, and the filtrate was concentrated under vacuum. The residue was separated by preparative HPLC (column: Xtimate C 18 The sample was purified by LCMS (150mm*25mm*5um; mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 15%~45%, 10 min), and then freeze-dried to obtain the title compound (16.9 mg, yield 46%) as a white solid. LCMS: m / z 441.2 [M+H] + ,ESI pos.

[0336] Example 23 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid [ka]

[0337] Process A: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-(methoxymethyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile Xphos-PdG3 (7.9 mg, 0.01 mmol, 0.2 equivalents) was added to a solution of the intermediate 9(3S,5R)-5-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]-1-ethyl-piperidine-3-ol (16.0 mg, 0.05 mmol, 1.0 equivalent), 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (21.57 mg, 0.05 mmol, 1.1 equivalents; CAS#2923541-74-4), and K2CO3 (18.1 mg, 0.13 mmol, 2.8 equivalents) in 1,4-dioxane (1 mL) and water (0.2 mL). Next, the reaction mixture was stirred under N2 at 95°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with methanol (2 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (methanol:ethyl acetate = 1:5) to obtain the title compound (16.0 mg, yield 55%) as a white solid. LCMS: m / z 555.3, [M+H] + ,ESI pos.

[0338] Process B: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid To a solution of 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-(methoxymethyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (14.0 mg, 0.03 mmol, 1.0 equivalent) in DCM (1 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at 20°C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini, 150 mm*30 mm*15 μm; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 22%-50%, 11 min), and lyophilized to obtain the title compound (10.45 mg, yield 77%) as yellow rubber. LCMS: m / z 425.3, [M+H] + ,ESI pos.

[0339] Example 24 (3S,5R)-1-(2-hydroxyethyl)-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazine-2-yl]amino]piperidine-3-ol [ka]

[0340] Process A: (3S,5R)-5-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidine-3-ol (tert-butyldimethylsilyloxy)acetaldehyde (58.6 mg, 0.34 mmol, 1.5 equivalents) was added to a solution of (3S,5R)-5-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]piperidine-3-ol (120.0 mg, 0.22 mmol, 1.0 equivalent; intermediate 9, step D), CH3COOH (33.7 mg, 0.56 mmol, 2.5 equivalents), and CH3COONa (55.2 mg, 0.67 mmol, 3.0 equivalents) in DCM (2 mL) and methanol (0.200 mL). The reaction mixture was stirred at 20°C for 5 minutes. Then, NaBH(OAc)3 (237.6 mg, 1.12 mmol, 5.0 equivalents) was added to the reaction mixture and stirred at 20°C for 30 minutes. Once the reaction was complete, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 4). The combined extract was washed with brine (10 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate:methanol = 1:0 to 10:1) to obtain the title compound (30.0 mg, yield 35%) as a white solid. 1 H NMR(400 MHz,CD3OD)δ [ppm]:7.90(s,1H),4.04-3.96(m,1H),3.81(t,2H),3.26-3.20(m,1H),3.09-3.01(m,1H),2.6 4(t,2H),2.36-2.29(m,1H),2.18-2.04(m,2H),1.46-1.27(m,2H),0.88(s,9H),0.08(s,6H)).

[0341] Process B: (3S,5R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazine-2-yl]amino]piperidine-3-ol XphosPdG3 (7.2 mg, 0.01 mmol, 0.2 equivalents) was added to a solution of the above-mentioned (3S,5R)-5-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidine-3-ol (20.0 mg, 0.04 mmol, 1.0 equivalent), 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol (14.0 mg, 0.05 mmol, 1.2 equivalents; CAS#2923540-54-7), K2CO3 (14.6 mg, 0.11 mmol, 2.5 equivalents) in 1,4-dioxane (1 mL) and water (0.2 mL). The reaction mixture was stirred under N2 at 90°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. Ethyl acetate (10 mL) and water (5 mL) were added to the mixture, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL x 4). The combined extract was washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (siRNA) to obtain the title compound (20.0 mg, 1.0 equivalent) as a yellow oil. LCMS: m / z 542.2 [M+H] + ,ESI pos.

[0342] Process C: (3S,5R)-1-(2-hydroxyethyl)-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazine-2-yl]amino]piperidine-3-ol A solution of (3S,5R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazine-2-yl]amino]piperidine-3-ol (20.0 mg, 0.04 mmol, 1.0 equivalent) and TFA (0.5 mL) in DCM (0.5 mL) was stirred at 40°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was dissolved in methanol (1 mL), basicized to pH=7 with saturated NaHCO3 aqueous solution, and then the mixture was subjected to preparative HPLC (column: Xtimate C). 18 The sample was purified by LCMS (250mm*50mm*10μm; mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 5%~45%, 12 min) and lyophilized to obtain the title compound (12.2 mg, yield 77%) as a yellow solid. LCMS: m / z 428.2 [M+H] + ,ESI pos.

[0343] Example 25 (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazine-2-yl]amino]piperidine-3-ol [ka] Intermediate 9(3S,5R)-5-[(5-bromooxazolo[4,5-b]pyrazine-2-yl)amino]-1-ethyl-piperidine-3-ol (20.0 mg, 0.06 mmol, 1.0 equivalent), 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) in 1,4-dioxane (1 mL) and water (0.2 mL). To a solution of (Lu)-2,3-dihydrobenzofuran-4-ol (19.4 mg, 0.07 mmol, 1.2 equivalents; CAS#2923540-54-7) and K2CO3 (22.7 mg, 0.16 mmol, 2.8 equivalents), Xphos-PdG3 (9.9 mg, 0.01 mmol, 0.2 equivalents) was added, and the mixture was then stirred under N2 at 90°C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with methanol (2 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini, 150 mm*25 mm*10 μm; mobile phase: [water (0.1% NH4HCO3, V / V)-MeCN]; B%: 22%-52%, 12 min), and the eluent was then lyophilized to obtain the title compound (7.28 mg, yield 30%) as a white solid. LCMS: m / z 412.2 [M+H] + ,ESI pos.

[0344] Example 26 = Example 15 as a free salt 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-(methoxymethyl)benzonitrile [ka]

[0345] Example 27 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7-fluoro-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile [ka]

[0346] Step A: tert-butyl(3R,5S)-3-[(5-chloro-7-fluoro-oxazolo[4,5-b]pyridine-2-yl)amino]-5-hydroxy-piperidine-1-carboxylate To a solution of (3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (275.8 mg, 1.28 mmol, 1.2 equivalents) and 2,5-dichloro-7-fluoro-oxazolo[4,5-b]pyridine (220.0 mg, 1.06 mmol, 1.0 equivalent) in MeCN (4 mL), DIPEA (274.2 mg, 2.13 mmol, 2.0 equivalents) was added, and the mixture was stirred at 20°C for 0.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0~0:1) to obtain the title compound (380.0 mg, yield 97%) as a yellow solid. LCMS: m / z 387.1, [M+H] + ,ESI pos.

[0347] Process B: tert-butyl(3R,5S)-3-[[5-[4-cyano-2-methyl-6-(2-trimethylsilylethoxymethoxy)phenyl]-7-fluoro-oxazolo[4,5-b]pyridine-2-yl]amino]-5-hydroxy-piperidine-1-carboxylate 1,4-Dioxane (8 mL) and water (1 mL) contain tert-butyl(3R,5S)-3-[(5-chloro-7-fluoro-oxazolo[4,5-b]pyridine-2-yl)amino]-5-hydroxy-piperidine-1-carboxylate (370.0 mg, 0.96 mmol, 1.0 equivalent), intermediate 13-methyl-4-(4,4,5,5-tetramethyl-1,3,2 To a solution of (-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (558.7 mg, 1.43 mmol, 1.5 equivalents) and K2CO3 (371.0 mg, 2.68 mmol, 2.8 equivalents), XphosPdG3 (121.6 mg, 0.14 mmol, 0.15 equivalents) was added, and the mixture was stirred under N2 at 95°C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with 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, petroleum ether:ethyl acetate = 1:0~0:1) to obtain the title compound (500.0 mg, yield 82%) as a yellow solid. LCMS: m / z 614.3, [M+H] + ,ESI pos.

[0348] Step C: 4-[7-fluoro-2-[[(3R,5S)-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile To a solution of tert-butyl(3R,5S)-3-[[5-[4-cyano-2-methyl-6-(2-trimethylsilylethoxymethoxy)phenyl]-7-fluoro-oxazolo[4,5-b]pyridine-2-yl]amino]-5-hydroxy-piperidine-1-carboxylate (100.0 mg, 0.16 mmol, 1.0 equivalent) in DCM (1 mL), TFA (1.0 mL) was added, and the mixture was stirred at 20°C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the title compound (TFA salt, 81.0 mg, 0.16 mmol, yield 99.95%) as yellow rubber. LCMS: m / z 384.1, [M+H] + ,ESI pos.

[0349] Process D: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7-fluoro-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile To a solution of 4-[7-fluoro-2-[[(3R,5S)-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methylbenzonitrile (TFA salt, 81.0 mg, 0.16 mmol, 1.0 equivalent) and DIPEA (84.1 mg, 0.65 mmol, 4.0 equivalents) in DMF (1 mL), iodoethane (24.5 mg, 0.16 mmol, 1.0 equivalent) was added, and the mixture was then stirred at 20°C for 12 hours. After the reaction mixture was complete, the reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Xtimate C18, 250 mm*50 mm*10 μm; mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 5%-35%, 10 min), followed by lyophilization to obtain the title compound (10.02 mg, 0.02 mmol, yield 14.66%) as a white solid. LCMS: m / z 412.1, [M+H] + ,ESI pos.

[0350] Example 28 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-(3-oxazol-2-ylpropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]benzonitrile [ka]

[0351] Process A: Methyl(E)-3-oxazole-2-ylpropa-2-enoate To an ice-cold solution of methyl diethyl phosphonoacetate (CAS #1067-74-9, 1.12 g, 0.97 mL, 5.15 mmol, 1.05 equivalents) in tetrahydrofuran (15.2 mL), 60% sodium hydride in mineral oil (206 mg, 5.15 mmol, 1.05 equivalents) was added, and the mixture was stirred at this temperature for 10 minutes. A solution of oxazole-2-carbaldehyde (CAS # 65373-52-6, 500 mg, 4.89 mmol, 1.00 equivalent) in tetrahydrofuran (34.2 mL) was added dropwise. Stirring was continued at 0°C for 1.5 hours. The reaction mixture was 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 under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, heptane gradient from 0% to 50% ethyl acetate) to obtain the title compound (591 mg, yield 75%) as a white solid. LCMS: m / z 153.9 [M+H] + ,ESI pos.

[0352] Step B: Methyl 3-oxazole-2-ylpropanoate A solution of methyl(E)-3-oxazole-2-ylpropa-2-enoate (Example 28, Step A) (591 mg, 3.67 mmol, 1.00 equivalent) in methanol (18 mL) and ethyl acetate (9 mL) was alternately evacuated and flushed with argon three times. Activated carbon-supported palladium (195 mg, 0.18 mmol, 0.05 equivalent, 10% purity) was carefully added. The reaction flask was evacuated, flushed with argon, evacuated again, and flushed with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 3 hours. The reaction mixture was filtered through Celite and thoroughly rinsed with ethyl acetate / methanol. Concentration of the filtrate yielded the title compound (346 mg, 58% yield) as a colorless oil, which was used without further purification. LCMS: m / z 155.9 [M+H] + ,ESI pos.

[0353] Process C: 3-Oxazole-2-ylpropane-1-ol A solution of methyl 3-oxazole-2-ylpropanoate (Example 28, Step B) (150 mg, 0.92 mmol, 1.00 equivalent) in tetrahydrofuran (5.8 mL) was cooled to 0°C, and then lithium aluminum hydride (1.0 M solution in tetrahydrofuran) (1.0 mL, 1.00 mmol, 1.09 equivalents) was added dropwise at 0°C (gas generation was observed). The reaction mixture was stirred at 0°C for 2 hours. The reaction was quenched by carefully adding sodium sulfate decahydrate. Once no more bubbling was detected, the ice bath was removed, sodium sulfate was added, and the mixture was stirred at room temperature for 1 hour. The suspension was filtered through Celite and rinsed with ethyl acetate / methanol. The filtrate was concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 4g, heptane gradient 0%-100% ethyl acetate) to obtain the title compound (45mg, yield 35%, purity 90%) as a colorless oil. LCMS: m / z 128.1 [M+H] + ,ESI pos.

[0354] Process D: 3-Oxazole-2-ylpropyl-4-methylbenzenesulfonate To a solution of 3-oxazole-2-ylpropan-1-ol (Example 28, Step C) (45 mg, 0.32 mmol, 1.00 equivalent, 90% purity) in dichloromethane (1.0 mL), triethylamine (81 mg, 0.11 mL, 0.80 mmol, 2.51 equivalents) was added, followed by p-toluenesulfonyl chloride (73 mg, 0.38 mmol, 1.20 equivalents). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 and extracted three times with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (108 mg, yield 84%, purity 70%) as a pale red oil, which was used without further purification. LCMS: m / z 282.2 [M+H] + ,ESI pos.

[0355] Step E: 5-Chloro-N-[(3R)-1-(3-oxazole-2-ylpropyl)-3-piperidyl]oxazolo[4,5-b]pyridine-2-amine N,N-diisopropylethylamine (80 mg, 0.11 mL, 0.62 mmol, 2.99 equivalents) was added to a mixture of 5-chloro-N-[(3R)-3-piperidyl]oxazolo[4,5-b]pyridine-2-amine (Example 4, Step B) (55 mg, 0.21 mmol, 1.00 equivalent) and 3-oxazole-2-ylpropyl 4-methylbenzenesulfonate (Example 28, Step D) (108 mg, 0.27 mmol, 1.30 equivalent, purity 70%) in tetrahydrofuran (1.0 mL) and N,N-dimethylformamide (1.0 mL). The reaction mixture was stirred at 50°C for 16 hours and at 70°C for 6 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and 10% LiCl aqueous solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed twice with 10% LiCl aqueous solution, once with water, and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, 0% to 10% methanol in ethyl acetate gradient) to obtain the title compound (34 mg, yield 39%, purity 85%) as a colorless oil. LCMS: m / z 362.2 [M+H] + ,ESI pos.

[0356] Process F: 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-(3-oxazol-2-ylpropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]benzonitrile A mixture of 5-chloro-N-[(3R)-1-(3-oxazole-2-ylpropyl)-3-piperidyl]oxazolo[4,5-b]pyridine-2-amine (Example 28, Step E) (34 mg, 0.09 mmol, 1.00 equivalent), (4-cyano-2-hydroxy-6-methylphenyl)boronic acid, intermediate 7 (26 mg, 0.15 mmol, 1.56 equivalent), cesium carbonate (98 mg, 0.30 mmol, 3.19 equivalent), and XPhos Pd G3 (15 mg, 0.02 mmol, 0.19 equivalent) in 1,4-dioxane (0.94 mL) and water (0.24 mL) was flushed with argon and stirred at 100°C for 5 hours. 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 layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0% to 10% methanol) to obtain the title compound (25 mg, 55% yield) as a pale yellow solid. LCMS: m / z 459.3 [M+H] + ,ESI pos.

[0357] Example 29 4-[7-fluoro-2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile [ka]

[0358] Step A: N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-fluoro-oxazolo[4,5-b]pyridine-2-amine To a solution of ((3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidine-3-amine (164.8 mg, 0.64 mmol, 1.2 equivalents) and DIPEA (137.1 mg, 1.06 mmol, 2.0 equivalents) in MeCN (2 mL), the intermediate 102,5-dichloro-7-fluoro-oxazolo[4,5-b]pyridine (110.0 mg, 0.53 mmol, 1.0 equivalent) was added, and the mixture was then stirred at 20°C for 2 hours. The mixture was mixed. Once the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was 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 chromatography (SiO2, petroleum ether:ethyl acetate = 1:1 to 0:1) to obtain the title compound (200.0 mg, yield 82%) as a yellow solid. LCMS: m / z 429.1, [M+H] + ,ESI pos.

[0359] Step B: 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]-7-fluoro-oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile XphosPdG3 (59.3 mg, 0.07 mmol, 0.15 equivalents) was added to a solution of N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-fluoro-oxazolo[4,5-b]pyridine-2-amine (200.0 mg, 0.47 mmol, 1.0 equivalent), intermediate 13-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (272.3 mg, 0.7 mmol, 1.5 equivalents), and K2CO3 (180.8 mg, 1.31 mmol, 2.8 equivalents) in 1,4-dioxane (4 mL) and water (0.5 mL). Next, the mixture was stirred under N2 at 95°C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with 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, petroleum ether:ethyl acetate = 1:1~0:1) to obtain the title compound (300.0 mg, yield 93%) as a yellow solid. LCMS: m / z 656.3, [M+H] + ,ESI pos.

[0360] Step C: 4-[7-fluoro-2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile A solution of 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]-7-fluoro-oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile (100.0 mg, 0.15 mmol, 1.0 equivalent) in trifluoroacetic acid (2.0 mL) was stirred at 45°C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in DMF (1 mL), and the pH was adjusted to 8 with NH3·H2O (25% in water). The solution was then purified by reverse-phase flushing (CombiFlash [water (0.1% ammonium hydroxide v / v)-MeCN]) to obtain 4-[7-fluoro-2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile (34.39 mg, 0.08 mmol, yield 54.17%) as a white solid. LCMS: m / z 412.1, [M+H] + ,ESI pos.

[0361] Example 30 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile [ka]

[0362] Process A: tert-butyl(3R,5S)-3-[(5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-yl)amino]-5-hydroxy-piperidine-1-carboxylate To a solution of tert-butyl(3R,5S)-3-amino-5-hydroxypiperidine-1-carboxylate (54.3 mg, 0.25 mmol, 1.1 equivalents, CAS: 1932513-59-1) and 2,5-dichloro-7-methoxy-oxazolo[4,5-b]pyridine (50.0 mg, 0.23 mmol, 1.0 equivalent, Example 8, Step E) in MeCN (0.5 mL), DIEA (58.9 mg, 0.46 mmol, 2.0 equivalents) was added. The mixture was then stirred at 20°C for 0.5 hours. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3~1:5) to obtain the title compound (75.0 mg, yield 82%) as a white solid. LCMS: m / z 399.2 [M+H] + ,ESI pos.

[0363] Process B: (3S,5R)-5-[(5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-yl)amino]piperidine-3-ol To a solution of tert-butyl(3R,5S)-3-[(5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-yl)amino]-5-hydroxy-piperidine-1-carboxylate (75.0 mg, 0.19 mmol, 1.0 equivalent) in DCM (0.5 mL), TFA (0.5 mL) was added. The mixture was stirred at 20°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was purified by reverse-phase flash (CombiFlash, mobile phase: [water (0.1% TFA v / v)-MeCN]; B%: 30%-40%) and subsequently lyophilized to obtain the title compound (TFA salt, 67.0 mg, yield 86%) as a colorless oil. LCMS: m / z 299.1 [M+H] + ,ESI pos.

[0364] Process C: (3S,5R)-5-[(5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-yl)amino]-1-ethyl-piperidine-3-ol Acetaldehyde (0.16 mL, 0.81 mmol, 5.0 equivalents) was added to a solution of (3S,5R)-5-[(5-chloro-7-methoxy-oxazolo[4,5-b]pyridine-2-yl)amino]piperidine-3-ol (TFA salt, 67.0 mg, 0.16 mmol, 1.0 equivalent), TEA (16.4 mg, 0.16 mmol, 1.0 equivalent), and AcOH (14.6 mg, 0.24 mmol, 1.5 equivalents) in DCM (1 mL) / methanol (0.2 mL). The mixture was stirred at 20°C for 0.5 hours. Then, NaBH(OAc)3 (103.2 mg, 0.49 mmol, 3.0 equivalents) was added to the reaction mixture. The mixture was then stirred under nitrogen at 20°C for 1 hour. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by reverse-phase flushing (CombiFlash, mobile phase: [water (0.1% TFA v / v)-MeCN]; B%: 35%-50%) and subsequent freeze-drying to obtain the title compound (TFA salt, 35.0 mg, yield 41%) as a yellow oily substance. LCMS: m / z 327.1 [M+H] + ,ESI,pos.

[0365] Process D: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile (3S,5R)-5-[(5-chloro-7-methoxy-oxazolo[4,5-b]pyridin-2-yl)amino]-1-ethyl-piperidin-3-ol (TFA salt, 35.0 mg, 0.07 mmol, 1.0 equivalent) and the intermediate 13-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (39.6 mg, 0.1 mmol, 1.5 equivalents) were added to a solution of (3S,5R)-5-[(5-chloro-7-methoxy-oxazolo[4,5-b]pyridin-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (39.6 mg, 0.1 mmol, 1.5 equivalents) in 1,4-dioxane (1 mL) / water (0.1 mL) under N2 conditions. The reaction mixture was stirred at 95°C for 12 hours. After the reaction was complete, the mixture was cooled to 20°C and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2 to 0:1) to obtain the title compound (25.0 mg, 63% yield) as a yellow oil. LCMS: m / z 554.3 [M+H] + ,ESI pos.

[0366] Step E: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile A mixture of 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile (23.0 mg, 0.04 mmol, 1.0 equivalent) and TFA (0.1 mL) in DCM (1.0 mL) was stirred at 40°C for 2 hours. After the reaction was complete, the mixture was cooled to 20°C and concentrated under vacuum. The residue was dissolved in MeOH (2 mL) and adjusted to pH=8 with NH3·H2O (25% in water). The mixture was then purified by preparative HPLC (Method: Column: Waters Xbridge 150*25 mm*5 μm, Mobile phase: [Water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 14%~44%, 10 min). The eluent was freeze-dried to obtain the title compound (6.1 mg, 34% yield) as a white solid. LC-MS: m / z 424.1 [M+H] + ,ESI pos.

[0367] Example 31 (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol [ka] (3S,5R)-5-[(5-chlorooxazolo[4,5-b]pyridine-2-yl)amino]-1-ethyl-piperidine-3-ol (CAS#2923539-98-2, 65 mg, 0.20 mmol, 1.00 equivalent, purity 90%) in 1,4-dioxane (1.4 mL) and water (0.70 mL), 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro A mixture of benzofuran-4-ol (CAS#2923540-54-7, 117 mg, 0.32 mmol, 1.61 equivalents, 75% purity), potassium carbonate (120 mg, 0.87 mmol, 4.40 equivalents), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (25 mg, 0.03 mmol, 0.16 equivalents) was flashed with argon and stirred at 95°C for 16 hours. 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 layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0% to 10% methanol). All fractions containing the product were combined and concentrated under vacuum. The residue was further purified by SFC (column achiral DEA; eluent B: 15% methanol) to obtain the title compound (24 mg, yield 28%) as a pale yellow solid. LCMS: m / z 411.3 [M+H] + ,ESI pos.

[0368] Example A The compound of formula I can be used as an active ingredient in a manner known to itself to produce tablets of the following composition: per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropylmethylcellulose 20mg 425mg

[0369] Example B The compound of formula I can be used as an active ingredient in a manner known to itself to produce capsules of the following composition: per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5mg 220.0 mg

Claims

1. Equation I 【Chemistry 1】 A compound of which, in the formula, R １ R is cyano, halo, or haloalkyl, ９ is H, or R １ and R ９ Furthermore, the atoms to which they are bonded form a five-membered cycloalkyl group or a five-membered heterocycle containing one oxygen heteroatom; R ２ R is alkyl, hydroxyalkyl, alkoxyalkyl or cyano, １ If R is cyano, ２ It is not cyano; A １ is -CR １０ - or -N-; R １０ is H, fluoro, or alkoxy; R ｘ is H, alkyl, heteroarylalkyl, hydroxyalkyl, or COOH-alkyl, where the heteroaryl of the heteroarylalkyl is oxazolyl, tetrazolyl, or oxadiazolyl; R ｙ is either H or -OH; R １ If R is a haloalkyl, ｘ R is a hydroxyalkyl or COOH-alkyl, ｙ is -OH, compound and a pharmaceutically acceptable salt thereof, provided that the compound is 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxybenzonitrile; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-(methoxymethyl)phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-(methoxymethyl)phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-propyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-methyl-piperidine-3-ol; (3R,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-ethyl-piperidine-3-ol; Formic acid; (3R,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-ethyl-piperidine-3-ol; 5-Chloro-2-[2-[[(3R)-1-(3,3-difluoropropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-3-(hydroxymethyl)-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-2-[2-[[(3R)-1-(3-hydroxypropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-(2-hydroxypropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; (3S,5R)-5-[[5-[4-chloro-2-hydroxy-6-(methoxymethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]-1-methyl-piperidine-3-ol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridine-2-yl]amino]-1-ethyl-piperidine-3-ol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-fluoro-3-methylphenol; 5-Fluoro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; formic acid; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile; 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-Chloro-3-methyl-2-[2-[[(3R)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol; dihydrochloride; 5-Chloro-3-methyl-2-[2-[[(3R)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]phenol A compound that is not selected from the following: and its pharmaceutically acceptable salts.

2. R １ However, it is cyano or haloalkyl, R ９ Is H or R １ and R ９ The compound according to claim 1, wherein the atoms to which they are bonded form a five-membered heterocycle containing one oxygen heteroatom.

3. R １ is cyano, R ９ Is H or R １ and R ９ The compound according to any one of claims 1 to 2, wherein the atoms to which they are bonded form a five-membered heterocycle containing one oxygen heteroatom.

4. R １ and R ９ The compound according to any one of claims 1 to 3, wherein the atoms to which they are bonded form a five-membered heterocycle containing one oxygen heteroatom.

5. R ２ The compound according to any one of claims 1 to 4, wherein the compound is alkyl or alkoxyalkyl.

6. R １０ The compound according to any one of claims 1 to 5, wherein the compound is H or an alkoxy.

7. R １０ The compound according to any one of claims 1 to 6, wherein H is present.

8. R ｘ The compound according to any one of claims 1 to 7, wherein the compound is H, alkyl, heteroarylalkyl, hydroxyalkyl, or COOH-alkyl, and the heteroaryl of the heteroarylalkyl is oxazolyl.

9. R ｘ The compound according to any one of claims 1 to 8, wherein H is alkyl, heteroarylalkyl or hydroxyalkyl, and the heteroaryl of the heteroarylalkyl is oxyzolyl.

10. R ｘ The compound according to any one of claims 1 to 9, wherein the compound is an alkyl, heteroarylalkyl, or hydroxyalkyl, and the heteroaryl of the heteroarylalkyl is oxyzolyl.

11. R ｘ The compound according to any one of claims 1 to 10, wherein the compound is alkyl or hydroxyalkyl.

12. R ｘ The compound according to any one of claims 1 to 11, wherein the compound is a hydroxyalkyl group.

13. R ｙ The compound according to any one of claims 1 to 12, wherein H is present.

14. A compound according to claim 1, wherein in the formula, R １ However, it is cyano or haloalkyl, R ９ Is H, or R １ and R ９ Furthermore, the atoms to which they are bonded form a five-membered heterocycle containing one oxygen heteroatom; R ２ However, it is alkyl or alkoxyalkyl; A １ However, -CR １０ - or -N-; R １０ However, it is H or alkoxy; R ｘ The element is H, alkyl, heteroarylalkyl, hydroxyalkyl, or COOH-alkyl, where the heteroaryl in the heteroarylalkyl is oxazolyl; R ｙ However, it is either H or -OH; R １ If R is a haloalkyl, ｘ is a hydroxyalkyl or COOH-alkyl, and R ｙ Compounds where -OH and its pharmaceutically acceptable salts.

15. A compound according to claim 1, wherein in the formula, R １ is cyano, R ９ Is H, or R １ and R ９ Furthermore, the atoms to which they are bonded form a five-membered heterocycle containing one oxygen heteroatom; R ２ However, it is alkyl or alkoxyalkyl; A １ However, -CR １０ - or -N-; R １０ However, it is H or alkoxy; R ｘ However, it is alkyl or hydroxyalkyl; R ｙ However, the compound is H or -OH. and its pharmaceutically acceptable salts.

16. A compound according to claim 1, wherein in the formula, R １ is cyano, R ９ Is H, or R １ and R ９ Furthermore, the atoms to which they are bonded form a five-membered heterocycle containing one oxygen heteroatom; R ２ However, it is alkyl or alkoxyalkyl; A １ However, -CR １０ - or -N-; R １０ However, it is H; R ｘ However, it is a hydroxyalkyl; R ｙ However, H is a compound and its pharmaceutically acceptable salts.

17. A compound according to claim 1, wherein in the formula, R １ and R ９ Furthermore, the atoms to which they are bonded form a five-membered heterocycle containing one oxygen heteroatom; R ２ However, it is alkyl or alkoxyalkyl; A １ However, it is -N-; R ｘ However, it is a hydroxyalkyl; R ｙ However, H is a compound and its pharmaceutically acceptable salts.

18. A compound according to any one of claims 1 to 17, 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-(2-oxazole-2-ylethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-(methoxymethyl)benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; A compound selected from and its pharmaceutically acceptable salts.

19. A compound according to any one of claims 1 to 17, 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; A compound selected from and its pharmaceutically acceptable salts.

20. A compound according to any one of claims 1 to 17, 4-[(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]-1-piperidyl]butanoic acid; (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol; 3-Hydroxy-4-[2-[[(3R,5S)-5-Hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; A compound selected from and its pharmaceutically acceptable salts.

21. A compound according to any one of claims 1 to 17, (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol; 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile; A compound selected from and its pharmaceutically acceptable salts.

22. A compound according to any one of claims 1 to 17, 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; A compound selected from and its pharmaceutically acceptable salts.

23. A compound according to any one of claims 1 to 17, 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-(methoxymethyl)benzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-indan-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-methyl-indan-4-ol; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-5-(methoxymethyl)benzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; (3S,5R)-1-(2-hydroxyethyl)-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazine-2-yl]amino]piperidine-3-ol; (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazine-2-yl]amino]piperidine-3-ol; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-(methoxymethyl)benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7-fluoro-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-hydroxy-5-methyl-4-[2-[[(3R)-1-(3-oxazole-2-ylpropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 4-[7-fluoro-2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyridine-2-yl]amino]piperidine-3-ol; A compound selected from and its pharmaceutically acceptable salts.

24. A compound according to any one of claims 1 to 17, 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; A compound selected from and its pharmaceutically acceptable salts.

25. A compound according to any one of claims 1 to 17, 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-5-methyl-benzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; A compound selected from and its pharmaceutically acceptable salts.

26. A compound according to any one of claims 1 to 17, 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridine-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; A compound selected from and its pharmaceutically acceptable salts.

27. A compound according to any one of claims 1 to 26 for use in the treatment or prevention of a disease, disorder or symptom, wherein the disease, disorder or symptom is responsive to NLRP3 inhibition.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26 and a therapeutically inactive carrier.

29. Use of a compound according to any one of claims 1 to 26 for the treatment or prevention of a disease, disorder or symptom, wherein the disease, disorder or symptom is responsive to NLRP3 inhibition.

30. A compound according to any one of claims 1 to 26, for the treatment or prevention of a disease, disorder or symptom selected from asthma or COPD.

31. A compound according to any one of claims 1 to 26 for the treatment or prevention of cardiovascular disease, disorder, or symptoms.

32. A compound according to any one of claims 1 to 26 for the treatment or prevention of cardiovascular metabolic diseases, disorders, or symptoms.

33. Use of the compound according to any one of claims 1 to 26 in the treatment or prevention of a disease, disorder, or symptom selected from asthma or COPD.

34. Use of the compound according to any one of claims 1 to 26 in the treatment or prevention of cardiovascular disease, disorder, or symptoms.

35. Use of the compound according to any one of claims 1 to 26 in the treatment or prevention of cardiovascular metabolic diseases, disorders, or symptoms.

36. Use of the compound according to any one of claims 1 to 26 for the preparation of a medicament for the treatment or prevention of a disease, disorder or symptom selected from asthma or COPD.

37. Use of the compound according to any one of claims 1 to 26 for the preparation of a medicament for the treatment or prevention of cardiovascular disease, disorder, or symptoms.

38. Use of the compound according to any one of claims 1 to 26 for the preparation of a medicament for the treatment or prevention of cardiovascular metabolic diseases, disorders or symptoms.

39. A method for inhibiting NLRP3, comprising administering an effective amount of a compound described in any one of claims 1 to 26 to inhibit NLRP3.

40. A method for treating or preventing a disease, disorder or symptom, comprising administering an effective amount of a compound according to any one of claims 1 to 26, wherein the disease, disorder or symptom is selected from asthma or COPD.

41. A method for treating or preventing a cardiovascular disease, disorder, or symptom, comprising administering an effective amount of the compound described in any one of claims 1 to 26.

42. A method for treating or preventing a cardiovascular metabolic disease, disorder, or symptom, comprising administering an effective amount of the compound described in any one of claims 1 to 26.

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