Fused bicyclic heteroaryl compounds useful as NLRP3 inhibitors

Abstract

The present invention relates to compounds of the general formula Ic TIFF2024539068000176.tif60169 (In the formula, R 1 , R 2 , R 3 , R 8 , R 9 , R X , A 1 , A 2 , W and n are as described herein. The present invention relates to novel compounds having the formula:

Description

[Technical Field]

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

[0002] The present invention relates to a compound of formula Ic [ka] (In the formula, A 1 -N- or -CR 10 - and A 2 is -O-, -NH-, -NCH3-, or -S-, R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl, or alkylsulfonyl; R 9 is H, alkyl, halo or cyano; or R 1 and R 9 forms a 4-6 membered cycloalkyl or heterocyclic ring containing a single O heteroatom, R 2 is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or hydroxyalkyl; R 3 is H, halo, or alkyl, and R 2 and R 3 At least one of them is not H, R 8 is H or halo, R 10are selected from H, alkyl, acetyl, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, halo, haloalkyl, alkoxy, haloalkoxy, and NR'R'', where R' and R'' are independently selected from H and alkyl, or R' and R'' and the N atom to which they are attached form either a 4-6 membered N-containing heterocycle optionally substituted with -OH, or a 5 membered lactam ring; n may be 0 or 1; R X is H, alkyl, alkoxyalkyl or hydroxyalkyl, W is a 4- to 10-membered heterocycle containing up to three heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, and which is optionally substituted by one or two substituents selected from oxo, -OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, cyano, haloalkyl, alkyl ester, alkylsulfone, cycloalkyl, a heterocycle containing a single O heteroatom, cycloalkyl substituted with -OH, cycloalkyl-CH2- substituted with -OH, 6-membered heteroaryl substituted with alkoxy, and 5-membered heteroaryl having two N heteroatoms; a 4-6 membered heterocycle -CH2- containing up to two heteroatoms independently selected from N and O, the maximum number of O heteroatoms being 1, optionally substituted with alkyl; a 3- to 6-membered cycloalkyl optionally substituted with 1 to 2 substituents independently selected from —OH, alkylamino, and dialkylamino; a 4-membered cycloalkyl-CH2- optionally substituted with one or two substituents independently selected from -OH and alkyl, and 5-membered heteroaryl containing two N heteroatoms -CH2-) The present invention provides novel compounds of the formula: and pharmaceutically acceptable salts thereof.

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

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

[0005] NLRP3 is an intracellular signaling molecule that senses many pathogen-, environmental, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like proteins containing a caspase-activating and recruitment domain (ASC). ASC then polymerizes to form large aggregates known as ASC specks. Polymerized ASC then interacts with the cysteine ​​protease caspase-1 to form a complex called the inflammasome. This leads to the activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (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, leading to apoptotic cell death.

[0006] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted from cells. Active caspase-1 also cleaves gasdermin-D, causing pyroptosis. Through its control of the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high-mobility group box 1 (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 glycolytic pathways, can contribute to caspase-1-dependent inflammation.

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

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

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

[0010] The role of NLRP3 in central nervous system diseases is becoming clear, and lung diseases have also been shown to be affected by NLRP3. NLRP3 has also been suggested to play a role in several central nervous system conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, and brain damage from pneumococcal meningitis (Walsh et al., Nature Reviews, 15:84-97, 2014, and Dempsey et al., Brain. Behav. Immun. 201761:306-316). NLRP3 has also been shown to play a role in many lung diseases, including chronic obstructive pulmonary disorder (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 plays a role in the development of liver disease, kidney disease, and aging. Many of these associations are due to the involvement of NLRP3. - / - Although defined in mice, insights into the specific activation of NLRP3 in these diseases also exist. In type 2 diabetes (T2D), deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

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

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

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

[0014] The present invention relates to a compound of formula Ic [ka] (In the formula, A 1 -N- or -CR 10 - and A 2 is -O-, -NH-, -NCH3-, or -S-, R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl, or alkylsulfonyl; R 9 is H, alkyl, halo or cyano; or R 1 and R9 forms a 4-6 membered cycloalkyl or heterocyclic ring containing a single O heteroatom, R 2 is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or hydroxyalkyl; R 3 is H, halo, or alkyl, and R 2 and R 3 At least one of them is not H, R 8 is H or halo, R 10 are selected from H, alkyl, acetyl, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, halo, haloalkyl, alkoxy, haloalkoxy, and NR'R'', where R' and R'' are independently selected from H and alkyl, or R' and R'' and the N atom to which they are attached form either a 4-6 membered N-containing heterocycle optionally substituted with -OH, or a 5 membered lactam ring; n may be 0 or 1; R X is H, alkyl, alkoxyalkyl or hydroxyalkyl, W is a 4- to 10-membered heterocycle containing up to three heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, and which is optionally substituted by one or two substituents selected from oxo, -OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, cyano, haloalkyl, alkyl ester, alkylsulfone, cycloalkyl, a heterocycle containing a single O heteroatom, cycloalkyl substituted with -OH, cycloalkyl-CH2- substituted with -OH, 6-membered heteroaryl substituted with alkoxy, and 5-membered heteroaryl having two N heteroatoms; a 4-6 membered heterocycle -CH2- containing up to two heteroatoms independently selected from N and O, the maximum number of O heteroatoms being 1, optionally substituted with alkyl; a 3- to 6-membered cycloalkyl optionally substituted with 1 to 2 substituents independently selected from —OH, alkylamino, and dialkylamino; a 4-membered cycloalkyl-CH2- optionally substituted with one or two substituents independently selected from -OH and alkyl, and 5-membered heteroaryl containing two N heteroatoms -CH2-) The present invention provides novel compounds of the formula: and pharmaceutically acceptable salts thereof.

[0015] The term "acetyl" refers to the group -C(=O)CH3.

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

[0017] The term "alkoxy" refers to a group in which R' is C 1~6 represents a group of formula -O-R', which is an alkyl group. 1~6 Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular alkoxy groups include methoxy and ethoxy.

[0018] The term "alkoxyalkyl" refers to an alkyl group in which one of the alkyl group's hydrogen atoms has been replaced by an alkoxy group. Particular examples of alkoxyalkyl are methoxymethyl and methoxyethyl.

[0019] The term "amino" refers to the group --NH.sub.2.

[0020] The term "alkylamino" refers to an amino group in which one of the hydrogen atoms of the amino group has been replaced by an alkyl group. A particular example is methylamino.

[0021] The term "alkylaminoalkyl" refers to an aminoalkyl group in which one of the hydrogen atoms of the amino group has been replaced by an alkyl group. Examples of alkylaminoalkyl groups include methylaminomethyl and methylaminoethyl.

[0022] The term "dialkylamino" refers to an amino group in which two hydrogen atoms of the amino group have been replaced by two alkyl groups. A particular example is dimethylamino.

[0023] The term "dialkylaminoalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced by a dialkylamino group. Examples of dialkylaminoalkyl include (dimethylamino)methyl and (dimethylamino)ethyl. A particular example is (dimethylamino)methyl.

[0024] The term "aminoalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced by an amino group. Examples of aminoalkyl include aminomethyl and aminoethyl.

[0025] The term "ester" refers to a carboxyl group bridging two moieties joined at a carbon atom. Examples include methoxycarbonyl.

[0026] The term "alkyl ester" refers to an ester group in which one of the ester group's hydrogen atoms has been replaced by an alkyl group. Particular examples are 2-methoxy-2-oxo-ethyl and 3-methoxy-3-oxo-propyl.

[0027] The term "sulfonyl" refers to the group -S(O)2-.

[0028] The term "alkylsulfonyl" refers to a radical of the formula -S(O)2-R', where R' is an alkyl group. Particular examples of alkylsulfonyl radicals include radicals of the formula -S(O)2-R', where R' is methyl.

[0029] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise specified, a cycloalkyl contains 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, a cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, spiro[3.3]heptanyl, and the like. Particular examples include cyclobutyl, cyclopentyl, and cyclohexyl. Other particular examples include cyclopropyl and cyclohexyl.

[0030] The term "cyano" refers to the group -C≡N.

[0031] The terms "halogen," "halide," and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo. Specific halogens include fluoro, chloro, and the like.

[0032] The term "haloalkyl" refers to C 1~6 -C in which at least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom 1~6 -represents an alkyl group. Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl. Particular examples are difluoromethyl, difluoropropyl and trifluoromethyl.

[0033] The term "haloalkoxy" refers to C1~6 -C in which at least one hydrogen atom of the alkoxy group is replaced by the same or different halogen atom 1~6 -represents an alkoxy group. Examples of haloalkoxy are difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy. Particular examples are difluoromethoxy and trifluoromethoxy.

[0034] The term "heteroaryl," alone or in combination, refers to a monovalent aromatic heterocyclic monocyclic or bicyclic ring system of 5 to 12 ring atoms containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and benzothiophenyl. A specific example of a heteroaryl group is imidazole.

[0035] The terms "heterocycle ring" or "heterocycle" refer to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 10 ring atoms or 4 to 9 ring atoms containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycles are azetidinyl, diazepanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and piperazinyl. Examples of polycyclic saturated heterocycles are azaspiroheptanyl, diazaspiroheptanyl, azaspirooctanyl, diazospirooctanyl, diazaspirononanyl, oxaazaspirooctanyl, and oxadiazaspirononanyl. Specific examples of 4-membered heterocycles are azetidinyl and oxetanyl. Specific examples of 5-membered heterocycles are pyrrolidinyl, tetrahydrofuranyl, and pyrrolidinyl. Specific examples of 6-membered heterocycles are piperidyl, morpholinyl, tetrahydropyranyl, and piperazinyl. Specific examples of 7-membered heterocycles are azepanyl. Specific examples of 8-membered heterocycles are azabicyclo[2.2.2]octan-4-yl and hexahydrofuro[3,4-c]pyrrol-5-yl. Particular examples of 9-membered heterocycles are octahydroindolizinyl, octahydropyrrolo[2,3-c]pyridin-1-yl, diazaspironan-7-yl, and hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl. Particular examples of 10-membered heterocycles are octahydro-1,7-naphthyridin-1-yl and hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl.

[0036] The term "hydroxy" refers to an --OH group.

[0037] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylethyl, hydroxymethylpropyl, and dihydroxypropyl. Particular examples are hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxymethylethyl.

[0038] The term "lactam ring" refers to a cyclic amide. A particular example is 2-oxopyrrolidin-1-yl.

[0039] The term "oxo" refers to a divalent oxygen atom =O.

[0040] The term "pyrrolidinylalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a pyrrolidinyl group. An example of a pyrrolidinylalkyl is pyrrolidinylmethyl.

[0041] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable.Salts are formed with inorganic acids, such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine.In addition, these salts can be prepared by adding inorganic or organic bases to the free acid.Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins. The compound of Formula I can also exist in the form of a zwitterion. Particularly preferred pharmaceutically acceptable salts of the compound of Formula I are salts formed with formic acid and with hydrochloric acid to produce the hydrochloride, dihydrochloride, or trihydrochloride salt.

[0042] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0043] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0044] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0045] The compounds of formula Ic may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0046] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0047] Embodiments of the present invention also provide compounds according to formula Ic as described herein, and pharmaceutically acceptable salts or esters thereof, particularly compounds according to formula Ic as described herein, and pharmaceutically acceptable salts thereof, more particularly compounds according to formula Ic as described herein.

[0048] One embodiment of the present invention is 2 is —O— or —NH—.

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

[0050] One embodiment of the present invention comprises: R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl, or alkylsulfonyl; R 9 is H, alkyl, halo or cyano; or R 1 and R 9 provides compounds according to formula Ic described herein, which form a 5-membered heterocycle containing a single O heteroatom.

[0051] One embodiment of the present invention comprises: R 1 is halo, alkyl, haloalkyl, or cyano; R 9is H or or R 1 and R 9 provides compounds according to formula Ic described herein, which form a 5-membered heterocycle containing a single O heteroatom.

[0052] An embodiment of the present invention is 1 is halo or cyano, and R 9 is H.

[0053] An embodiment of the present invention is 2 is alkyl or alkoxyalkyl, and R 3 is H.

[0054] One embodiment of the present invention is R 8 is H.

[0055] An embodiment of the present invention is 10 is selected from H, alkyl, acetyl, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, alkoxy, and NR'R''; and R' and R'' and the N atom to which they are attached form either a 4-5 membered N-containing heterocycle optionally substituted with -OH, or a 5 membered lactam ring.

[0056] One embodiment of the present invention is R 10 is selected from H, cyano, and alkoxy.

[0057] One embodiment of the present invention is R 10 is H.

[0058] An embodiment of the present invention is X is H, alkoxyalkyl, or hydroxyalkyl.

[0059] One embodiment of the present invention is R X is H.

[0060] One embodiment of the present invention is a compound in which W is a 4- to 10-membered heterocycle containing up to three heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, and which is optionally substituted by one or two substituents selected from oxo, —OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, haloalkyl, 4-membered cycloalkyl, a 4-membered heterocycle containing one O heteroatom, a 4-membered cycloalkyl substituted with —OH, and a 4-membered cycloalkyl-CH— substituted with —OH; a 4-6 membered heterocycle -CH2- containing up to two heteroatoms independently selected from N and O, the maximum number of O heteroatoms being 1, optionally substituted with alkyl; 3- to 6-membered cycloalkyl optionally substituted with —OH, alkylamino, or dialkylamino; a 4-membered cycloalkyl-CH2- optionally substituted with one or two substituents independently selected from -OH and alkyl, and Compounds according to formula Ic described herein are provided wherein the aryl is selected from 5-membered heteroaryl containing two N heteroatoms -CH2-.

[0061] One embodiment of the present invention is a compound in which W is a 6-9 membered heterocycle containing up to 3 heteroatoms independently selected from N and O, with the maximum number of O heteroatoms being 1, optionally substituted with 1 or 2 substituents selected from oxo, -OH, halo, alkyl and hydroxyalkyl; alkyl-substituted 6-membered heterocycles containing a single N heteroatom -CH2-, and Provided are compounds according to formula Ic described herein, wherein the cycloalkyl group is selected from a 5-membered cycloalkyl substituted with a dialkylamino.

[0062] An embodiment of the present invention provides a compound according to formula Ic described herein, wherein W is a 6-membered heterocycle containing a single N heteroatom, optionally substituted with either alkyl or oxo, or both alkyl and -OH.

[0063] One embodiment of the present invention comprises: A 1 -N- or -CR 10 - and A 2 is -O- or -NH-, R 1 is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl, or alkylsulfonyl; R 9 is H, alkyl, halo or cyano; or R 1 and R 9 forms a five-membered heterocycle containing a single O heteroatom, R 2 is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or hydroxyalkyl; R 3 is H, halo, or alkyl, and R 2 and R 3 At least one of them is not H, R 8 is H or halo, R 10 is selected from H, alkyl, acetylalkylamino, dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, alkoxy, and NR'R'', and R' and R'' and the N atom to which they are attached form either a 4-5 membered N-containing heterocycle optionally substituted with -OH or a 5 membered lactam ring; n may be 0 or 1; R X is H, alkoxyalkyl or hydroxyalkyl, W is a 4- to 10-membered heterocycle containing up to three heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, and which is optionally substituted by one or two substituents selected from oxo, —OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, haloalkyl, 4-membered cycloalkyl, a 4-membered heterocycle containing a single O heteroatom, a 4-membered cycloalkyl substituted with —OH, and a 4-membered cycloalkyl substituted with —OH-CH—; a 4-6 membered heterocycle -CH2- containing up to two heteroatoms independently selected from N and O, the maximum number of O heteroatoms being 1, optionally substituted with alkyl; 3- to 6-membered cycloalkyl optionally substituted with —OH, alkylamino, or dialkylamino; a 4-membered cycloalkyl-CH2- optionally substituted with one or two substituents independently selected from -OH and alkyl, and Provided are compounds according to Formula Ic as described herein and pharmaceutically acceptable salts thereof, wherein the aryl group is selected from: 5-membered heteroaryl containing two N heteroatoms -CH2-;

[0064] One embodiment of the present invention comprises: A 1 -N- or -CR 10 - and A 2 is -O-, R 1 is halo, alkyl, haloalkyl, or cyano; R 9 is H or or R 1 and R 9 forms a five-membered heterocycle containing a single O heteroatom, R 2 is alkyl or alkoxyalkyl, and R 3 is H, R 8 is H, R 10 is selected from H, cyano and alkoxy; n may be 0 or 1; R X is H, W is a 6-9 membered heterocycle containing up to 3 heteroatoms independently selected from N and O, with the maximum number of O heteroatoms being 1, optionally substituted with 1 or 2 substituents selected from oxo, -OH, halo, alkyl and hydroxyalkyl; alkyl-substituted 6-membered heterocycles containing a single N heteroatom -CH2-, and Compounds according to Formula Ic as described herein and pharmaceutically acceptable salts thereof are provided wherein the 5-membered cycloalkyl substituted with dialkylamino is selected from:

[0065] One embodiment of the present invention comprises: A 1 -N- or -CR 10 - and A 2 is -O-, R 1 is halo or cyano, R 9 is H, R 2 is alkyl or alkoxyalkyl, and R 3 is H, R 8 is H, R 10 is H, n may be 0 or 1; R X is H, Compounds and pharmaceutically acceptable salts according to Formula Ic described herein are provided wherein W is a 6-membered heterocycle containing a single N heteroatom, optionally substituted with either alkyl or oxo, or both alkyl and -OH.

[0066] One embodiment of the present invention provides a compound according to formula Ib, wherein the compound of formula Ib is a compound of formula Ic. [ka]

[0067] The compounds of formula Ib may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0068] One embodiment of the present invention also provides compounds according to formula Ib as described herein, and pharmaceutically acceptable salts or esters thereof, particularly compounds according to formula Ib as described herein, and pharmaceutically acceptable salts thereof, more particularly compounds according to formula Ib as described herein.

[0069] One embodiment of the present invention comprises: A 1 -N- or -CR 10 - and A 2 is -O-, -NH-, -NCH3-, or -S-, R 1 is H, halogen, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy or cycloalkyl; R 9 is H or a halogen, or R 1 and R 9 forms a 4-6 membered cycloalkyl or heterocycloalkyl ring containing a single O heteroatom, R 2 is H, halogen, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, or alkoxyalkyl, and R 3 is H, halogen, or alkyl, and R 2 and R 3 At least one of them is not H, R 8 is H or halo, R 10 teeth, iH, ii. alkyl, iii. hydroxyalkyl, iv. Cyano, v.Halogen v. haloalkyl, vi. Alkoxy, vii. haloalkoxy, viii. A 5- to 6-membered heterocycle containing 1 or 2 N atoms optionally substituted with either halo or methyl, or ix. NR'R'' (wherein R' and R'' are independently selected from H or alkyl, or R' and R'' and the N atom to which they are attached form either a 4-6 membered N-containing heterocycle or a 5 membered lactam ring). is selected from n may be 0 or 1; W is heterocycloalkyl optionally substituted with 1 to 2 substituents independently selected from oxo, -OH, alkyl, alkylamino, alkylaminoalkyl, amino, aminoalkyl, cyano, cycloalkyl, or cycloalkyl substituted with amino, halogen, dialkylamino, dialkylaminoalkyl, ester, haloalkyl, hydroxyalkyl, sulfonyl, or pyrrolidinylalkyl; Provided herein are compounds and pharmaceutically acceptable salts according to Formula Ib described herein, wherein W is a 3-6 membered cycloalkyl optionally substituted with 1-2 substituents independently selected from -OH, alkyl, alkylamino, amino, dialkylamino, halogen, haloalkyl, and tert-butyl N-methylcarbamate.

[0070] One embodiment of the present invention comprises: A 1 -N- or -CR 10 - and A 2 is -O- or -NH, R 1 is halogen, haloalkyl, cyano, alkoxy or cycloalkyl; R 9 is H or a halogen, or R 1 and R 9 forms a five-membered heterocycle containing a single O heteroatom, R 2 is H, alkyl, cyano, haloalkyl, alkoxy, or alkoxyalkyl, and R 3 is H or alkyl, and R 2 and R 3 At least one of them is not H, R 8 is H, R 10 is selected from H or methyl; n may be 0 or 1; W is a ring system: [ka] (In the formula, B 1 is -N- or -CH-, B 2 is -CHR 4 - or -NCH3, B 3 is -CHR 5 -, -O-, or -NR 6 - and B 4 is -O-, -CH2-, -NH-, -C(=O)-, B 5 is -CH-, B 6 is -NH-, B 7 is -CH2-, B 8 is -N-, B 9 is -CH2-, B 10 is -CHR 7 - and R 4 is H or dialkylaminoalkyl, R 5 is H, —OH, alkylamino or hydroxyalkyl, R 6 is H or alkyl, R 7 is -OH) is selected from W may only have a maximum of two heteroatoms and two non-hydrogen substituents; W is a ring system (C), a ring system (E), or B 1 When is -N-, then n is 0, and pharmaceutically acceptable salts thereof.

[0071] One embodiment of the present invention comprises: A 1 -N- or -CR 10 - and A 2 is -O- or -NH, R 1 is halogen, haloalkyl, cyano or alkoxy; R 9 is H or a halogen, or R 1 and R 9 forms a five-membered heterocycle containing a single O heteroatom, R 2 is H, alkyl, cyano, haloalkyl, or alkoxyalkyl, and R 3 is H or alkyl, and R 2 and R 3 At least one of them is not H, R 8 is H, R 10 is selected from H or methyl; n may be 0 or 1; W is a ring system: [ka] (In the formula, B 1 is -CH-, B 2 is -CHR 4 - and B 3 is -NR 6 - and B 4 is -CH2- or -C(=O)-, R 4 is H, R 6 is H or alkyl) is selected from W may only have a maximum of two heteroatoms and two non-hydrogen substituents; Compounds and pharmaceutically acceptable salts according to Formula Ib described herein are provided wherein n is 0 when W is a ring system (E).

[0072] One embodiment of the present invention comprises: A 1 -N- or -CR 10 - and A 2 is -O-, R 1 is halogen, haloalkyl, cyano or alkoxy; R 9 is H or a halogen, R 2 is alkyl, cyano, or alkoxyalkyl, and R 3 is H, R 8 is H, R 10 is H, n may be 0 or 1; W is a ring system: [ka] (In the formula, B 1 is -CH-, B 2 is -CHR 4 - and B 3 is -NR 6 - and B 4 is -CH2- or -C(=O)-, R 4 is H, R 6 is H or alkyl) is selected from W may only have a maximum of two heteroatoms and two non-hydrogen substituents; Compounds and pharmaceutically acceptable salts according to Formula Ib described herein are provided wherein n is 0 when W is a ring system (E).

[0073] One embodiment of the present invention comprises: A 1 -N- or -CR 10 - and A 2 is -O-, R 1 is halogen, haloalkyl or cyano; R 9 is H, R 2 is alkyl, and R 3 is H, R 8 is H, R 10 is H, n may be 0 or 1; W is a ring system: [ka] (In the formula, B 1 is -CH-, B 2 is -CHR 4 - and B 3 is -NR 6 - and B 4 is -CH2-, R 4 is H, R 6 is alkyl) is selected from W may only have a maximum of two heteroatoms and two non-hydrogen substituents; Compounds and pharmaceutically acceptable salts according to Formula Ib described herein are provided wherein n is 0 when W is a ring system (E).

[0074] One embodiment of the present invention comprises: A 1 -CR 10 - and A 2 is -O-, R 1 is halogen or cyano, R 9 is H, R 2 is alkyl, and R 3 is H, R 8 is H, R 10 is H, n may be 0 or 1; W is a ring system: [ka] (In the formula, B 1 is -CH-, B 2 is -CHR 4 - and B 3 is -NR 6 - and B 4 is -CH2-, R 4 is H, R 6 is alkyl) is selected from W may have only up to two heteroatoms and one non-hydrogen substituent; Compounds and pharmaceutically acceptable salts according to Formula Ib described herein are provided wherein n is 0 when W is a ring system (E).

[0075] One embodiment of the present invention provides a compound according to formula I, wherein the compound of formula I is a compound of formula Ib. [ka]

[0076] The compounds of formula I may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0077] Embodiments of the present invention also provide compounds according to formula I as described herein, and pharmaceutically acceptable salts or esters thereof, particularly compounds according to formula I as described herein, and pharmaceutically acceptable salts thereof, more particularly compounds according to formula I as described herein.

[0078] One embodiment of the present invention comprises: A 1 is -N- or -CH-, A 2 is -O-, -NH-, -NCH3-, or -S-, R 1 is halogen, alkyl, haloalkyl or haloalkoxy; R 2 is H, halogen, or alkyl, and R 3 is H, halogen, or alkyl, and R 2 and R 3 At least one of them is not H, n may be 0 or 1; W is a heterocycle optionally substituted with 1 to 2 substituents independently selected from oxo, -OH, alkyl, alkylamino, alkylaminoalkyl, amino, aminoalkyl, cycloalkyl, cycloalkyl substituted with halogen, dialkylamino, dialkylaminoalkyl, haloalkyl, hydroxyalkyl, and pyrrolidinylalkyl; or Provided herein are compounds and pharmaceutically acceptable salts according to Formula I described herein, wherein W is a 4-6 membered cycloalkyl optionally substituted with 1-2 substituents independently selected from -OH, alkyl, alkylamino, amino, dialkylamino, halogen, haloalkyl, and tert-butyl N-methylcarbamate.

[0079] One embodiment of the present invention comprises: A 1 is -N- or -CH-, A 2 is -O-, -NH-, -NCH3-, or -S-, R 1 is halogen, alkyl, haloalkyl or haloalkoxy; R 2 is H, halogen, or alkyl, and R 3 is H, halogen, or alkyl, and R 2 and R 3 At least one of them is not H, n may be 0 or 1; W is a ring system [ka] and B 1 is -N- or -CH-, B 2 is -CHR 4 - or -NCH3, B 3 is -CHR 5 -, -O-, or -NR 6 - and B 4 is -O-, -CH2-, -NH-, -C(=O)-, B 5 is -CH-, B 6 is -NH-, B 7 is -CH2-, B 8 is -N-, B 9 is -CH2-, B 10 is -CHR 7 - and R 4 is H, dialkylaminoalkyl or hydroxyalkyl; R 5 is H, —OH, alkylamino, dialkylaminoalkyl, or hydroxyalkyl; R 6 is H or alkyl, R 7 is -OH, W may only have a maximum of two heteroatoms and two non-hydrogen substituents; W is a ring system C or B 1 When is -N-, then n is 0, and pharmaceutically acceptable salts thereof.

[0080] One embodiment of the present invention comprises: A 1 is -CH-, A 2 is -O- or -NH-, R 1 is haloalkyl or halogen, R 2 is alkyl, and R 3 is H, n may be 0 or 1; W is a ring system [ka] and B 1 is -N- or -CH-, B 2 is -CHR 4 - or -NCH3, B 3 is -CHR 5 -, -O-, or -NR 6 - and B4 is -O-, -CH2-, -NH-, -C(=O)-, B 5 is -CH-, B 6 is -NH-, B 7 is -CH2-, B 8 is -N-, B 9 is -CH2-, B 10 is -CHR 7 - and R 4 is H or dialkylaminoalkyl, R 5 is H, —OH, alkylamino or hydroxyalkyl, R 6 is H or alkyl, R 7 is -OH, W may only have a maximum of two heteroatoms and two non-hydrogen substituents; W is a ring system C or B 1 When is -N-, then n is 0, and pharmaceutically acceptable salts thereof.

[0081] One embodiment of the present invention comprises: A 1 is -CH-, A 2 is -O- or -NH-, R 1 is haloalkyl or halogen, R 2 is alkyl, and R 3 is H, n may be 0 or 1; W is a ring system [ka] and B 1is -N- or -CH-, B 2 is -CHR 4 - and B 3 is -CHR 5 -or-NR 6 - and B 4 is -O-, -CH2-, -NH-, -C(=O)-, B 5 is -CH-, B 6 is -NH-, B 7 is -CH2-, B 8 is -N-, B 9 is -CH2-, B 10 is -CHR 7 - and R 4 is H or dialkylaminoalkyl, R 5 is H, —OH, alkylamino or hydroxyalkyl, R 6 is H or alkyl, R 7 is -OH, W may have only up to two heteroatoms and one non-hydrogen substituent; W is a ring system C or B 1 When is -N-, then n is 0, and pharmaceutically acceptable salts thereof.

[0082] One embodiment of the present invention comprises: A 1 is -CH-, A 2 is -O- or -NH-, R 1 is haloalkyl, R 2 is alkyl, and R 3 is H, n may be 0 or 1; W is a ring system [ka] and B 1 is -N- or -CH-, B 2 is -CHR 4 - and B 3 is -CHR 5 -or-NR 6 - and B 4 is -O-, -CH2-, -NH-, -C(=O)-, B 5 is -CH-, B 6 is -NH-, B 7 is -CH2-, B 8 is -N-, B 9 is -CH2-, B 10 is -CHR 7 - and R 4 is H or dialkylaminoalkyl, R 5 is H, —OH, alkylamino or hydroxyalkyl, R 6 is H or alkyl, R 7 is -OH, W may have only up to two heteroatoms and one non-hydrogen substituent; W is a ring system C or B 1 When is -N-, then n is 0, and pharmaceutically acceptable salts thereof.

[0083] One embodiment of the present invention comprises: A 1 is -CH-, A 2 is -O- or -NH-, R 1 is haloalkyl, R 2 is alkyl, and R 3 is H, n may be 0 or 1; W is a ring system [ka] and B 1 is -N- or -CH-, B 2 is -CHR 4 - and B 3 is -CHR 5 -or-NR 6 - and B 4 is -O-, -CH2-, -NH-, -C(=O)-, B 5 is -CH-, B 6 is -NH-, B 7 is -CH2-, R 4 is H or dialkylaminoalkyl, R 5 is H, —OH, alkylamino or hydroxyalkyl, R 6 is H or alkyl, W may have only up to two heteroatoms and one non-hydrogen substituent; B 1 When is -N-, then n is 0, and pharmaceutically acceptable salts thereof.

[0084] One embodiment of the present invention comprises: A 1 is -CH-, A 2 is -O- or -NH-, R 1 is haloalkyl, R 2 is alkyl, and R 3 is H, n may be 0 or 1; W is a ring system [ka] and B 1 is -N- or -CH-, B 2 is -CHR 4 - and B 3 is -CHR 5 -or-NR 6 - and B 4 is -O- or -CH2-, R 4 is H or dialkylaminoalkyl, R 5 is H, R 6 is alkyl, W may have only up to two heteroatoms and one non-hydrogen substituent; B 1 When is -N-, then n is 0, and pharmaceutically acceptable salts thereof.

[0085] One embodiment of the present invention comprises: A 1 is -CH-, A 2 is -O-, R 1 is haloalkyl, R 2 is alkyl, and R 3 is H, n is 1, W is a ring system [ka] and B 1 is -CH-, B 2 is -CHR 4 - and B 3 is -NR 6 - and B 4 is -CH2-, R 4 is H, R 6 is alkyl; and pharmaceutically acceptable salts thereof.

[0086] Specific examples of compounds of formula Ic described herein are: 2-[2-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol or 2-[2-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol or 2-[2-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-[2-(tetrahydrofuran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 5-chloro-3-methyl-2-[2-[[rac-(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-chloro-3-methyl-2-[2-(6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl)oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-(2-azabicyclo[2.1.1]hexan-1-ylmethylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; dihydrochloride; 5-chloro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-fluoro-3-methylphenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-propyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-chloro-2-[2-[[(3R)-1-cyclobutyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-methyl-piperidin-3-ol; 5-Fluoro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; (3S,5R)-1-ethyl-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]piperidin-3-ol; 2-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-fluoro-5-(trifluoromethyl)phenol; 5-chloro-2-[2-[[(3R,5S)-1-ethyl-5-fluoro-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 2-[2-[[(1R,2R)-2-(dimethylamino)cyclopropyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-Hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methyl-benzonitrile; cis-2-[2-[(3-hydroxy-3-methyl-cyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; trans-2-[2-[(3-hydroxy-3-methyl-cyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-chloro-2-[2-[(1-ethylazetidin-3-yl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 1-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)-2-[[rac-(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-7-yl]pyrrolidin-2-one; 2-[2-[[(3R)-1-(3-hydroxycyclobutyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-(oxetan-3-yl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 3-Methyl-2-[2-[rel-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol;2,2,2-Trifluoroacetic acid; 2-[2-[(4aS,7aS)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; N-(1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl)-5-chloro-oxazolo[4,5-b]pyridin-2-amine; 3-methyl-2-[2-[[(2S)-1-methylazetidin-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol or 3-methyl-2-[2-[[(2R)-1-methylazetidin-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[2-[[(2R)-1-methylazetidin-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol or 3-methyl-2-[2-[[(2S)-1-methylazetidin-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[2-[(1-methylazetidin-2-yl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 5-chloro-2-[2-(1H-imidazol-5-ylmethylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; (3RS,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidin-3-ol; formic acid; 3,6-dimethyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; (3R,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidin-3-ol; formic acid; 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or (5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; (5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 5-chloro-2-[2-[[(3R)-1-(3,3-difluoropropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-[(3-hydroxycyclobutyl)methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-chloro-2-[2-(1H-imidazol-2-ylmethylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 2-[2-[3-(hydroxymethyl)-1-piperidyl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[4-(hydroxymethyl)-1-piperidyl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(1-ethyl-1,7-diazaspiro[3.5]nonan-7-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-Hydroxy-5-methyl-4-[2-[rac trans -6-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]-oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 3-hydroxy-5-methyl-4-[2-(7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 2-Hydroxy-4-methyl-3-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile;2,2,2-Trifluoroacetic acid; 5-chloro-3-methyl-2-[2-[(1-methyl-3-piperidyl)methyl]oxazolo[4,5-b]pyridin-5-yl]phenol; Methyl 4-[(3R)-3-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-piperidyl]butanoate; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methyl-benzonitrile; Methyl 3-[(3R)-3-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-piperidyl]propanoate; 5-chloro-2-[2-[[6-(hydroxymethyl)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol;2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[(4-isopropylmorpholin-2-yl)methyl]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; Formic acid; 3-Methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methylsulfonylphenol;2,2,2-Trifluoroacetic acid; 5-chloro-2-[2-[2-methoxyethyl-[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; Formic acid; 2-[2-[[(3R)-1-ethylazepan-3-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-chloro-2-[2-[(3-hydroxycyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-3-(hydroxymethyl)-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-chloro-2-[2-[[(3R)-1-(3-hydroxypropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-3-methyl-2-[2-[[rac-(3R)-1-(2-hydroxypropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-chloro-2-[2-[2-hydroxyethyl-[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-2-[2-[[(3S,4R)-1-ethyl-4-fluoro-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-chloro-2-[2-[[(3R,4S)-1-ethyl-4-fluoro-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; (3S,5R)-5-[[5-[4-chloro-2-hydroxy-6-(methoxymethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]-1-methyl-piperidin-3-ol; 1-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-7-yl]azetidin-3-ol; 1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-7-yl]ethanone;2,2,2-trifluoroacetic acid; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-(methylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl))phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[7-(1-hydroxy-1-methyl-ethyl)-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;2,2,2-trifluoroacetic acid; 2-[7-(1-hydroxyethyl)-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-chloro-4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-hydroxy-benzonitrile;2,2,2-trifluoroacetic acid; 4-[2-[[(1R,2R)-2-(dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl-benzonitrile;2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile;2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile;2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[[(1R,2R)-2-(dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methylphenol;2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(trifluoromethoxy)phenol; 2,2,2-trifluoroacetic acid; 3-Hydroxy-5-methyl-4-[2-[[(2S)-2-hydroxy-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile;2,2,2-Trifluoroacetic acid; 2-[7-(dimethylamino)-2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl))phenol; 2-[[(3R)-1-ethyl-3-piperidyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-7-carbonitrile; 5-chloro-2-[2-[[(3R)-1-[[rac trans -2-hydroxycyclobutyl]methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol or 5-chloro-2-[2-[[(3R)-1-[[rac cis -2-hydroxycyclobutyl]methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-[[rac trans -2-hydroxycyclobutyl]methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol or 5-chloro-2-[2-[[(3R)-1-[[rac cis -2-hydroxycyclobutyl]methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-benzonitrile; 3-methyl-2-[2-[(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl))phenol; 5-(Difluoromethyl)-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-(Difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol;2,2,2-Trifluoroacetic acid; 5-(Difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3,5-dimethylphenol; 3-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidin-4-ol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-Fluoro-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(trifluoromethyl)phenol; 2,2,2-Trifluoroacetic acid; 5-chloro-2-[6-chloro-2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 3,5-Dimethyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol;2,2,2-Trifluoroacetic acid; 3-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-fluorophenol;2,2,2-trifluoroacetic acid; 5-(Difluoromethoxy)-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol;2,2,2-Trifluoroacetic acid; 2-[2-[(1-ethylpyrrolidin-3-yl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3,5-Dichloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol;2,2,2-Trifluoroacetic acid; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-6-fluoro-1H-imidazo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidin-3-ol; 3-Methyl-2-[2-[4-(methylamino)tetrahydropyran-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol;2,2,2-Trifluoroacetic acid; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-3H-imidazo[4,5-b]pyridin-5-yl]-3-methylphenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethoxy)phenol;2,2,2-trifluoroacetic acid; 2-[2-(1-ethyl-3-piperidyl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-Octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-Octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile and pharmaceutically acceptable salts thereof.

[0087] Also specific examples of compounds of formula Ic described herein are: (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; (rac)-2-[2-[3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(3R or 3S)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(3S or 3R)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; (rac)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol; (3R or 3S)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol; (3S or 3R)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol; 3-methyl-2-(2-morpholinoxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-[2-[2-(hydroxymethyl)morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[[3-(methylamino)cyclohexyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-(2-piperazin-1-yl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidin-2-one; (rac)-3-methyl-2-[2-[3-(methylamino)-1-piperidyl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-[2-(tetrahydropyran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]azetidin-3-ol; 2-[2-[(3-hydroxycyclohexyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-(2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-(2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R or 3S)-1-ethyl-3-piperidyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3S or 3R)-1-ethyl-3-piperidyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol and pharmaceutically acceptable salts thereof.

[0088] Also specific examples of compounds of formula Ic described herein are: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aS,7aR or 3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methylphenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-benzonitrile; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 4-[2-[(3aS,7aR or 3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-(Difluoromethyl)-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5-(trifluoromethyl)phenol; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 5-Methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-6-methyl-oxazolo[4,5-b]pyridin-5-yl]-2,3-dihydrobenzofuran-4-ol; 5-Cyclopropyl-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol and pharmaceutically acceptable salts thereof.

[0089] Preferred examples of compounds of formula Ic described herein are: 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-methyl-piperidin-3-ol; 3-Hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methyl-benzonitrile; 3-Methyl-2-[2-[rel-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol;2,2,2-Trifluoroacetic acid; (3R,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidin-3-ol; formic acid; 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; (5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 5-chloro-3-methyl-2-[2-[(1-methyl-3-piperidyl)methyl]oxazolo[4,5-b]pyridin-5-yl]phenol; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methyl-benzonitrile; 5-chloro-2-[2-[[(3S,4R)-1-ethyl-4-fluoro-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; (3S,5R)-5-[[5-[4-chloro-2-hydroxy-6-(methoxymethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]-1-methyl-piperidin-3-ol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 4-[2-[[(1R,2R)-2-(dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl-benzonitrile;2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile;2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile;2,2,2-trifluoroacetic acid; 2-[[(3R)-1-ethyl-3-piperidyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-7-carbonitrile; 5-(Difluoromethyl)-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-(Difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3,5-dimethylphenol; 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-Octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-Octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile and pharmaceutically acceptable salts thereof.

[0090] More preferred examples of compounds of formula Ic described herein are: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol and pharmaceutically acceptable salts thereof.

[0091] The most preferred examples of compounds of formula Ic described herein are 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-Ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; formate salt; (5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl-benzonitrile;2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile;2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-Ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid and pharmaceutically acceptable salts thereof.

[0092] Also, the most preferred examples of compounds of formula Ic described herein are 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; (5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl-benzonitrile;2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile;2,2,2-trifluoroacetic acid; and pharmaceutically acceptable salts thereof.

[0093] Preferred examples of compounds of formula Ib described herein are: (rac)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidin-2-one; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-benzonitrile; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol 5-Methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; and pharmaceutically acceptable salts thereof.

[0094] The most preferred examples of compounds of formula Ib described herein are: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile and pharmaceutically acceptable salts thereof.

[0095] Specific examples of compounds of formula I described herein are: (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; (rac)-2-[2-[3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(3R or 3S)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(3S or 3R)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; (rac)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol; (3R or 3S)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol; (3S or 3R)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol; 3-methyl-2-(2-morpholinoxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-[2-[2-(hydroxymethyl)morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol formate; 3-Methyl-2-[2-[[3-(methylamino)cyclohexyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-(2-piperazin-1-yl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(2-piperazin-1-yl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 2,2,2-Trifluoroacetic acid; (rac)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidin-2-one; (rac)-3-methyl-2-[2-[3-(methylamino)-1-piperidyl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-[2-(tetrahydropyran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]azetidin-3-ol; 2-[2-[(3-hydroxycyclohexyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-(2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-(2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R or 3S)-1-ethyl-3-piperidyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3S or 3R)-1-ethyl-3-piperidyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol and pharmaceutically acceptable salts thereof.

[0096] Preferred examples of compounds of formula I described herein are: (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(3S or 3R)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; (3S or 3R)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol; 3-methyl-2-(2-morpholinoxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-[2-[2-(hydroxymethyl)morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol formate; 3-Methyl-2-[2-[[3-(methylamino)cyclohexyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; (rac)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidin-2-one; (rac)-3-methyl-2-[2-[3-(methylamino)-1-piperidyl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-(2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 2-[2-[[(3S or 3R)-1-ethyl-3-piperidyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol and pharmaceutically acceptable salts thereof.

[0097] More preferred examples of compounds of formula I described herein are: 2-[2-[(3S or 3R)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-(2-morpholinoxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; and pharmaceutically acceptable salts thereof.

[0098] The most preferred examples of compounds of formula I described herein are: 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; and pharmaceutically acceptable salts thereof.

[0099] The processes for preparing compounds of formula Ic described herein are an object of the present invention.

[0100] The present compounds of formula Ic and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example by the methods described below, Scheme 1 below involves reacting a compound of formula II with a compound of formula Ic, wherein R 1 , R 2 , R 3 , R 8 , R 9 , R X , A 1 , W and n are as described herein; A 2 =O or NH and R=H. [ka] Scheme 1:A 2 General procedure for the synthesis of compounds Ic containing =O or NH

[0101] Another scheme for preparing compounds of formula Ic and their pharmaceutically acceptable salts is shown by the following Scheme 2, which involves reacting a compound of formula II with a compound of formula Ic, wherein R 1 , R 2 , R 3 , R 8 , R 9 , R X , A 1 , A 2 and W is as described herein and n is 0. [ka] General synthetic procedure for compounds outlined in Scheme 2: Ic; n=0

[0102] Another scheme for preparing compounds of formula Ic and their pharmaceutically acceptable salts is shown by the following Scheme 3, which involves reacting a compound of formula X with a compound of formula Ic, wherein R 1 , R 2 , R 3 , R 8 , R 9 , R X, n and W are as described herein; A 1 is N and A 2 is O. [ka] Scheme 3:A 1 =N;A 2 General procedure for the synthesis of compounds outlined in Ic containing =O

[0103] General synthetic scheme The compound of formula Ic of the present invention can be prepared according to the process variants described below, as well as the following schemes 1, 1a, 1b, 2, 3, 3a, 3b, and 4. In addition, it will be apparent to those skilled in the art that the order of the described transformations can be changed in various orders. These transformations can include, for example, protection / cleavage of protecting groups, Pd-catalyzed coupling, reductive amination, and / or nucleophilic substitution. The starting materials are commercially available or can be prepared according to known methods.

[0104] As shown in Scheme 1a, commercially available building blocks of formula II, where X is a halogen atom such as bromine, chlorine, or iodine, more preferably chlorine or bromine, can be cyclized using reagents such as 1,1'-carbonyldiimidazole (CDI) or 1,1'-thiocarbonyldiimidazole or carbon disulfide, followed by the addition of methyl iodide in the presence of a conventional inorganic base (such as potassium carbonate) or reaction with a chlorinating agent such as POCl3, to prepare compounds of general formula III or IV, respectively. These can then be subjected to aromatic nucleophilic substitution to prepare compounds of formula V. The aromatic nucleophilic substitution can be carried out by cyclizing a suitable amine, e.g., NR x -W, but is not limited to W and R xhas the meaning indicated in the claims of the present invention, where n is 1 or 0, and is carried out in the presence of an organic base such as N,N-diisopropylethylamine (DIEA) or trimethylamine, which are common, known to those skilled in the art, and / or commercially available. Heating was typically performed, and 1,4-dioxane was used as the solvent; however, if higher temperatures were required, solvents such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), or N-methyl-2-pyrrolidine (NMP) were used. Alternatively, the reaction can be carried out under microwave irradiation. The left side is added to a compound of general formula V to form a compound of formula VI using a palladium-catalyzed reaction, e.g., Suzuki cross-coupling, in the presence of a palladium catalyst and a boronic acid or boronic acid pinacol ester according to standard conditions well known to those skilled in the art, to give the final compound of general formula Ic (depending on the substitution of the boronic acid or ester). In the case of a methyl ether protecting group, this is typically cleaved in the final step with boron tribromide (BBr) in dichloromethane to deliver compounds of general formula Ic. Specific examples of each of the exemplified compounds are described in more detail below. [ka] Scheme 1:A 2 General procedure for the synthesis of compounds Ic containing =O or NH

[0105] The synthesis of compounds of formula Ic of the present invention can be synthesized according to the general synthesis shown in Scheme 1, where R' can be OH or -C(CH3)2, and R is a protecting group known to those skilled in the art, such as Me, SEM, benzyl, or any other suitable protecting group for phenols (e.g., Protective Groups in organic Synthesis, T.W. Greene and PGM). [ka] Scheme 1a: Modification of "NW" or "W", e.g., A 2 In the case of a Boc protecting group with ═O or NH

[0106] Furthermore, amine NR x When W or W contains, for example, a tert-butyloxycarbonyl (BOC) protecting group Va, a further deprotection step can be carried out at an early stage using TFA (trifluoroacetic acid) or HCl in dioxane, as described in Scheme 1a, or at a later stage after the introduction of the left aryl (Scheme 1a or 1b, VII). The respective amine is then subjected to a reductive amination, well known to those skilled in the art, using an aldehyde or ketone in the presence of an acid (e.g., acetic acid) or a buffer such as sodium acetate, in the presence of a reducing agent such as a borohydride, more specifically, for example, sodium triacetoxyborohydride or sodium cyanoborohydride, to give the wilted derivative of general formula V or the final compound Ic. [ka] Scheme 1b.NR x -W and W derivatization.

[0107] When n=0, commercially available building blocks of formula II, where X is a halogen atom such as bromine, chlorine, or iodine, more preferably chlorine or bromine, can be first acylated under standard amide coupling conditions such as EDCI and HOBt, or HATU, or acyl chloride, followed by cyclization using, for example, acidic conditions with polyphosphoric acid, Eaton's Reagent, or via a Mitsunobu reaction using DIAD and triphenylphosphine in THF or diethyl ether to give intermediates of general formula IX. Finally, the Suzuki reaction as described above gives compounds of general formula Ic. [ka] General synthetic procedure for compounds outlined in Scheme 2: Ic; n=0 [ka] Scheme 3:A 1 =N;A 2 General procedure for the synthesis of compounds outlined in Ic containing =O

[0108] A 1 In the case of =N, chlorine and bromine can also be exchanged. Commercially available building blocks of formula X can be reacted with benzyl alcohol in the presence of a strong base, such as sodium hydride, to give compounds of general formula XI. A suitable solvent is, for example, THF. In the next step, reaction with the corresponding isothiocyanate and a base, such as sodium hydride, gives compounds of general formula XII. Cyclization to intermediate XIII can be achieved by the addition of reagents such as tetrabutylazanium; iodide, and hydrogen peroxide. In the final step, Suzuki cross-coupling in the presence of a palladium catalyst and a boronic acid or pinacol boronic acid ester under standard conditions well known to those skilled in the art gives final compounds of general formula Ic. [ka] Scheme 3a.A 1 General synthesis scheme of Ic at =N

[0109] The general formula is A1=N Ic Compounds of formula (I) can also be obtained by following the sequence outlined above. Starting from the same precursor XI, Suzuki cross-coupling in the presence of a palladium catalyst and a boronic acid or pinacol boronic acid ester according to standard conditions gives intermediate XIV. Using standard procedures known to those skilled in the art, for example, after protecting the phenol with SEM, compound XV is reacted with an isothiocyanate in the presence of a base, for example, sodium hydride, to give intermediate XVI. Subsequent cleavage of the protecting group (SEM) under standard acidic conditions (e.g., TFA) afforded access to XVII. In the final step, cyclization was achieved as outlined above. [ka] Scheme 3b. Synthesis of isothiocyanates

[0110] The described isocyanates can be prepared by reacting primary amines of the general formula shown in Scheme 3b with thiophosgene under ice cooling. Suitable solvents for the reaction are, for example, DCM or DCE. [ka] Scheme 4:A 1 =CR 10 , R 10 General procedure for compounds outlined in Ic where ≠H.

[0111] Starting from commercially available building block XVIII, nitration was carried out, for example, in the presence of a strong acid. Fuming nitric acid, known to those skilled in the art, X is iodine or bromine, preferably iodine. Reduction, for example, using tin(II) chloride or iron(III) chloride in methanol, gave aniline XX. Subsequent cyclization was achieved by adding TCDI and heating. Key intermediate XXII was obtained after reaction with a chlorinating agent, such as oxalyl chloride or POCl3, at elevated temperatures, for example, in DMF. The compound was then converted into a secondary amine or NR x The amines were subjected to aromatic nucleophilic substitution using the appropriate amines containing -W, NH-W or W, where W and R x has the meaning given for general formula Ic, in the presence of an organic base such as N,N-diisopropylethylamine (DIEA) or trimethylamine, which are common, known to those skilled in the art, and / or commercially available). Typically, 1,4-dioxane was used as the solvent, but solvents such as dimethyl sulfoxide (DMSO) or N-methyl-2-pyrrolidine (NMP) are also suitable. R 10The different substituents outlined in the claims and exemplified below were introduced in different ways using palladium-catalyzed coupling reactions, such as the Buchwald reaction in the presence of amides, carbonates or amines with the respective ligands known to those skilled in the art, or the Stille coupling using organotin reagents and other suitable cross-coupling reactions. In the final step, a Suzuki reaction was carried out to install the left hand side as shown in general formula Ic. [ka] Scheme 4a:A 1 =CR 10 , R 10 Alternative general route to compounds outlined in Ic where ≠H.

[0112] R 10 An alternative approach to the modification as described for is outlined in Scheme 4a, starting from intermediate VI. Oxidation of the pyridine nitrogen was achieved in the presence of methyltrioxorhenium(vii) in the presence of hydrogen peroxide. Subsequent introduction of X = Cl or Br was obtained by adding an appropriate halogenating reagent, such as oxalyl chloride, for example in DMF. R 10 The introduction of Ic was achieved using Pd-catalyzed cross-coupling or aromatic nucleophilic substitution as outlined above. Finally, cleavage of the Boc protecting group under acidic conditions and reductive amination as outlined above afforded the final compound Ic. [ka] Scheme 4b:A 1 =CR 10 , R 10 An alternative route to the compound outlined in Ic where ≠H.

[0113] Starting from commercially available building block XXVIII, halogenation is carried out in the presence of N-bromosuccinimide (NBS) or bromine in a solvent such as DMF, known to those skilled in the art (XXIX). Subsequent Suzuki reaction with the corresponding boronic acid or boronic ester and reduction of the nitro group using palladium on activated carbon or iron chloride or iron(III) chloride in a suitable solvent, such as methanol, gives intermediate XXXI. Finally, cyclization using TCDI, followed by methylation with, for example, methyl iodide as described above and subsequent nucleophilic aromatic substitution, gives intermediate XXXI. 10 Compounds of general formula IC with ≠H are obtained.

[0114] Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, a compound of Formula Ib can be formulated into a galenic dosage form by mixing it at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosage and concentration employed. The pH of the formulation will depend primarily on the particular use and the concentration of the compound, but is preferably somewhere in the range of about 3 to about 8. In one example, a compound of Formula Ib is formulated in acetate buffer at pH 5. In another embodiment, the compound of Formula Ib is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0115] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to physicians.

[0116] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural, and intranasal, and, if local treatment is desired, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0117] The compounds of the present invention can be administered in any convenient dosage form, such as, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain conventional components of pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0118] Typical preparation is prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide proper presentation of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0119] The compound of formula Ic and its pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injection solutions or topical preparations.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

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

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

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

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

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

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

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

[0127] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. They may also contain still other therapeutically valuable substances.

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

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

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

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

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

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

[0134] One embodiment of the present invention is a compound according to Formula Ib as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

[0135] One embodiment of the present invention is a compound according to Formula I, as described herein, for use as a therapeutically active substance.

[0136] One embodiment of the present invention is a compound according to Formula I as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0137] One embodiment of the present invention is a compound according to Formula I as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

[0138] As used herein, the term "NLRP3 inhibition" refers to a complete or partial reduction in the activity level of NLRP3, including, for example, inhibition of active NLRP3 and / or inhibition of NLRP3 activation.

[0139] There is evidence for a role for NLRP3-induced IL-1 and IL-18 in the inflammatory responses associated with or resulting from a number of different disorders (Menuet et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowiget et al., Nature, 481:278-286, 2012).

[0140] In one embodiment, the disease, disorder or condition is selected from the following: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) lymphatic symptoms; (xiv) psychological disorders; (xv) graft-versus-host disease; (xvi) allodynia; (xvii) symptoms related to diabetes; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0141] In another embodiment, the disease, disorder or condition is selected from the following: (i) Cancer; (ii) infectious diseases; (iii) central nervous system disorders; (iv) cardiovascular disease; (v) liver disease; (vi) eye disease; or (vii) Skin diseases.

[0142] In a further exemplary embodiment of the invention, the disease, disorder or condition is inflammation. Examples of inflammation that may be treated or prevented include inflammatory responses associated with or resulting from: (i) Skin conditions such as contact sensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (ii) joint conditions such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, or Reiter's disease); (iii) muscle conditions such as polymyositis or myasthenia gravis; (iv) gastrointestinal conditions such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), colitis, gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may have effects remote from the gut (e.g., migraine, rhinitis, or eczema); (v) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust-induced asthma, especially chronic or refractory asthma, e.g., late-stage asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, panlentic rhinitis, rhinitis sicca, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis, e.g., hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, volcanic ash-induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (vi) vascular conditions such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (vii) autoimmune conditions such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease; (viii) ocular conditions such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (ix) neurological conditions such as multiple sclerosis or encephalomyelitis; (x) an infection or infection-related condition such as acquired immune deficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B, or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, hemorrhagic dengue fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis (including Mycobacterium tuberculosis and HIV co-infection), Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis / epidimitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (xi) renal conditions such as mesangial proliferative glomerulonephritis, renal syndrome, nephritis, glomerulonephritis, obesity-related glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritic syndrome, renal fibrosis including chronic crystalline nephropathy, or renal hypertension; (xii) lymphatic conditions such as Castleman's disease; (xiii) conditions of or involving the immune system, such as hyper-IgE syndrome, hepatoblastomatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (xiv) hepatic conditions such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcohol-induced hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, hepatic fibrosis, or liver failure; (xv) cancer, including those listed above; (xvi) burns, wounds, trauma, hemorrhage, or stroke; (xvii) radiation exposure; (xviii) metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, or pseudogout; and / or (xix) Pain such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.

[0143] One embodiment of the present invention is a compound according to formula Ic as described herein for the treatment or prevention of a disease, disorder or condition selected from the following: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) lymphatic symptoms; (xiv) psychological disorders; (xv) graft-versus-host disease; (xvi) allodynia; (xvii) symptoms related to diabetes; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0144] One embodiment of the present invention is the use of a compound according to formula Ic described herein in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0145] One embodiment of the present invention is the use of a compound according to Formula Ic as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0146] One embodiment of the present invention is the use of a compound according to formula Ic as described herein for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0147] One embodiment of the present invention is the use of a compound according to formula Ic as described herein for use in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0148] One embodiment of the present invention is a compound according to Formula Ic as described herein for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0149] One embodiment of the present invention is a compound according to Formula Ic as described herein for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0150] One embodiment of the present invention is a compound according to Formula Ic as described herein for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0151] One embodiment of the present invention is the use of a compound according to formula Ic as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0152] One embodiment of the present invention is the use of a compound according to formula Ic as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0153] One embodiment of the present invention is the use of a compound according to formula Ic as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0154] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder, or condition selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to formula Ic described herein.

[0155] One embodiment of the present invention is a method for treating or preventing a disease, disorder, or condition selected from asthma or COPD, comprising administering an effective amount of a compound according to formula Ic described herein.

[0156] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder, or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), comprising administering an effective amount of a compound according to formula Ic, as described herein.

[0157] One embodiment of the present invention relates to a method of inhibiting NLRP3, comprising administering an effective amount of a compound according to Formula Ic described herein.

[0158] A compound of formula Ic described herein when prepared according to any one of the methods described is also an embodiment of the present invention.

[0159] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to Formula Ic described herein and a therapeutically inert carrier.

[0160] One embodiment of the present invention is the use of a compound according to formula Ib as described herein in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0161] One embodiment of the present invention is the use of a compound according to formula Ib as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0162] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0163] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0164] One embodiment of the present invention is a compound according to Formula Ib, as described herein, for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0165] One embodiment of the present invention is a compound according to Formula Ib, as described herein, for the treatment or prevention of a disease, disorder, or condition selected from asthma or COPD.

[0166] One embodiment of the present invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0167] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0168] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0169] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0170] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder, or condition selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to formula Ib as described herein.

[0171] One embodiment of the present invention is a method of treating or preventing a disease, disorder, or condition selected from asthma or COPD, comprising administering an effective amount of a compound according to formula Ib as described herein.

[0172] One embodiment of the present invention is a method of treating or preventing a disease, disorder, or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), comprising administering an effective amount of a compound according to formula Ib as described herein.

[0173] One embodiment of the present invention relates to a method of inhibiting NLRP3, comprising administering an effective amount of a compound according to Formula Ib as described herein.

[0174] Also, one embodiment of the present invention is a compound of formula Ib, as described herein, when prepared according to any one of the processes described.

[0175] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to Formula Ib described herein and a therapeutically inert carrier.

[0176] One embodiment of the present invention is the use of a compound according to formula I as described herein in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0177] One embodiment of the present invention is the use of a compound according to Formula I as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0178] One embodiment of the present invention is the use of a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0179] One embodiment of the present invention is the use of a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0180] One embodiment of the present invention is a compound according to Formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0181] One embodiment of the present invention is a compound according to Formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0182] One embodiment of the present invention is a compound according to Formula I, as described herein, for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0183] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0184] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0185] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0186] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder, or condition selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to formula I described herein.

[0187] One embodiment of the present invention is a method for treating or preventing a disease, disorder, or condition selected from asthma or COPD, comprising administering an effective amount of a compound according to formula I described herein.

[0188] One embodiment of the present invention is a method of treating or preventing a disease, disorder, or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), comprising administering an effective amount of a compound according to Formula I as described herein.

[0189] One embodiment of the present invention relates to a method of inhibiting NLRP3, comprising administering an effective amount of a compound according to Formula I described herein.

[0190] Also, one embodiment of the present invention is a compound of formula I, as described herein, when prepared according to any one of the processes described.

[0191] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to Formula I, as described herein, and a therapeutically inert carrier.

[0192] Assay procedure NLRP3 and pyroptosis It is well established that activation of NLRP3 leads to cell pyroptosis, a hallmark that plays a key role in the development of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, inhibitors of NLRP3 are expected to block pyroptosis and the release of pro-inflammatory cytokines (e.g., IL-1β) from cells.

[0193] THP-1 cells: culture and preparation THP-1 cells (ATCC No. TIB-202) were grown in RPMI containing L-glutamine (Gibco No. 11835) supplemented with 1 mM sodium pyruvate (Sigma No. S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma No. P4333) in 10% fetal bovine serum (FBS) (Sigma No. F0804). Cells were passaged periodically until confluent (approximately 10 6The cells were grown to a concentration of 625,000 cells / ml. On the day of the experiment, THP-1 cells were harvested and resuspended in RPMI medium (without FBS). Cells were then counted, and viability (>90%) was confirmed using trypan blue (Sigma #T8154). Appropriate dilutions were made to obtain a concentration of 625,000 cells / ml. LPS (Sigma #L4524) was added to this diluted cell solution to obtain a final assay concentration (FAC) of 1 μg / ml. 40 μl of the final preparation was dispensed into each well of a 96-well plate. The plate thus prepared was used for compound screening.

[0194] THP-1 cell pyroptosis assay For compound screening, the following method stepwise assay was followed. 1. Seed THP-1 cells (25,000 cells / well) in 40 μl of RPMI medium (without FBS) containing 1.0 μg / ml LPS in 96-well poly-D-lysine (VWR #734-0317) coated black-walled, clear-bottom cell culture plates. 2.5 μl of compound (8-point half-log dilutions with a top dose of 10 μM) or vehicle (DMSO 0.1% FAC) is added to the appropriate wells. 3. Incubate at 37°C, 5% CO2 for 3 hours. Add 4.5 μl of nigericin (Sigma No. N7143) (FAC 5 μM) to all wells 5. Incubate at 37°C, 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plate at 300 x g for 3 minutes and remove the supernatant. 7. 50 μl of resazurin (Sigma #R7017) (FAC 100 μM resazurin in RPMI medium without FBS) is then added and the plate is incubated at 37° C. and 5% CO2 for a further 1-2 hours. 8. The plate was read on an Envision reader at Ex 560nm and Em 590nm. 9.IC 50Fit the data to a nonlinear regression equation (log inhibitor vs. response variable slope, 4 parameters)

[0195] The results of the pyroptosis assay were compared with those of THP IC 50 These are summarized in Table 1 below.

[0196] 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, we investigated the NLRP3 inhibitory activity of a number of compounds in human whole blood according to the following protocol.

[0197] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor pool. 1. Plate out 80 μl of whole blood containing 1 μg / ml LPS into a 96-well flat-bottom cell culture plate (Corning #3585). 2. Add 10 μl of compound (8-point half log dilutions at the top dose of 10 μM) or vehicle (DMSO 0.1% FAC) to appropriate wells. 3. Incubate at 37°C, 5% CO2 for 3 hours. 4. Add 10 μl of nigericin (Sigma #N7143) (10 μM FAC) to all wells. 5. Incubate at 37°C, 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plate at 300 x g for 5 minutes to pellet the cells and remove 20 μl of the supernatant and add to a 96-well v-bottom plate for IL-1β analysis (Note: These plates containing supernatant can be stored at -80°C for analysis at a later date). 7. IL-1β was measured according to the manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000). 8. IC 50 Fit the data to a nonlinear regression equation (log inhibitor vs. response variable slope, 4 parameters) [Table 1] JPEG2024539068000032.jpg237169 JPEG2024539068000033.jpg236169 JPEG2024539068000034.jpg76169

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

[0199] Where preparations are obtained as mixtures of enantiomers, pure enantiomers or diastereomers can be obtained by methods described herein or known to those skilled in the art, for example, chiral chromatography or crystallization. For some examples, such as 99a and 99b, the absolute configuration was not determined but was assigned based on biological activity (as determined, for example, by THP assay).

[0200] Experimental Method Abbreviation: [Table 2]

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

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

[0203] system Waters Acquity UPLC -Binary Pump -Autosampler Waters 2777C (also known as CTC Pal HT) Column Manager (4 columns) Photodiode Array Detector (PDA) Single quadrupole mass spectrometers (SQD1 and SQD2)

[0204] Eluent Channel A: Water 0.1% formic acid Channel B: Acetonitrile 0.07% formic acid

[0205] Built-in column (50℃): Column 1: Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2.1 x 30 mm, 1.8 μm, Part No. 959731-902 Column 2: (MS1+5+7 only): Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 μm, Part No. 186002350 Column 3: None Column 4: None (flow injection)

[0206] method: Fast Gradient (2 min, column 1, mass range m / z 150-900) [Table 3]

[0207] Purification method (Step B) Automated reverse-phase column chromatography was performed using a Gilson GX-281 system driven by a Gilson-322 pump module, a Gilson-156 UV photometer detection unit and a Gilson-281 fraction collector. Waters Xbridge: 150*25mm* 5um pH(Water(10mM NH3H2O)-ACN)7~8 Average particle size: 5μm Prior to use, the column was conditioned with 100% MeCN (2 min) followed by 1% MeCN (0.8 min). Flow rate = 25 mL / min.

[0208] Separation operation: [Table 4]

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

[0210] General steps: GP1: Aromatic nucleophilic substitution To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 1.00 equiv.) in 1,4-dioxane (0.5 mmol / mL) was added the corresponding amine (1.16 equiv.), followed by triethylamine (1.14 equiv.). The solution was stirred at 90 °C for 16 h. After cooling to room temperature, the mixture was extracted with a suitable organic solvent, such as ethyl acetate, and the organic phase was washed with, for example, saturated aqueous NaHCO3. The combined organic layers were dried, for example, over sodium sulfate, filtered, concentrated in vacuo, and finally purified by either column chromatography or HPLC.

[0211] GP2: Suzuki 2a:with dppf A mixture of 5-chloro-N-[(3R)-1-ethyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (1.0 equiv.) and the corresponding boronic acid or boronic ester (1.4–1.7 equiv.), potassium carbonate (4.8 equiv.), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.15 equiv.) was dissolved in 1,4-dioxane (0.1067 mmol / mL) and water (0.1067 mmol / mL, v / v 2 / 1). The mixture was flushed with argon and stirred at 95 °C for 8–16 h until the starting material was consumed. After cooling to room temperature, the mixture was extracted with a suitable organic solvent, such as ethyl acetate, and the organic phase was washed with, for example, half-saturated aqueous NH4Cl. The combined organic layers were dried, for example, over sodium sulfate, filtered, concentrated in vacuo, and finally purified by either column chromatography or HPLC.

[0212] 2b.Using Xphos A mixture of 5-chloro-N-[(3R)-1-ethyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (1.00 equiv.) and the corresponding boronic acid or boronic ester (1.4–1.7 equiv.), cesium carbonate (3.0 equiv.), and XPhos Pd G3 (0.1 equiv.) was dissolved in 1,4-dioxane and water (v / v 4 / 1). The mixture was flushed with argon and stirred at 90 °C until the starting material was consumed. After cooling to room temperature, the mixture was extracted with a suitable organic solvent, such as ethyl acetate, and the organic phase was washed with, for example, brine. The combined organic layers were dried, for example, over sodium sulfate, filtered, concentrated in vacuo, and finally purified by either column chromatography or HPLC.

[0213] GP3: boc deprotection with TFA The corresponding carboxylic acid tert-butyl ester (1.0 equiv.) was treated with TFA (9.0 equiv.) in dichloromethane and the reaction was stirred at room temperature until the starting material was consumed, then the solvent was removed under reduced pressure.

[0214] GP4: Reductive amination To a suspension of the corresponding primary or secondary amine (free base; HCl or TFA salt) (1.0 equiv.) in dry DCM (0.0702 mmol / mL) was added acetaldehyde (2.5 equiv.) followed by sodium acetate (2.5 equiv.) under ice-bath cooling. Sodium triacetoxyborohydride (1.8 equiv.) was then added at 0°C. The reaction mixture was stirred at 0°C for 5 min, then the ice bath was removed and the mixture was stirred at 23°C for 3–5 h. The reaction mixture was then carefully basified with, for example, aqueous NaHCO3 solution under ice-cooling, followed by extraction with a suitable organic solvent such as dichloromethane. The combined organic layers were dried, for example, over sodium sulfate, filtered, concentrated in vacuo, and finally purified via either column chromatography or HPLC.

[0215] In certain cases, a mixture of DCM / MeOH was used as the solvent. [Example]

[0216] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen atmosphere.

[0217] Example 1: (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol [ka]

[0218] Step 1: (rac)-5-chloro-N-(1-ethyl-3-piperidyl)oxazolo[4,5-b]pyridin-2-amine

[0219] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 80 mg, 0.379 mmol, 1 equiv.) in 1,4-dioxane (0.80 mL) was added (rac)-(1-ethyl-3-piperidyl)amine (CAS No. 6789-94-2, 0.061 mL, 0.427 mmol, 1.13 equiv.), followed by triethylamine (0.060 mL, 0.430 mmol, 1.14 equiv.). The brown solution was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (96 mg, 86% yield) as a pale yellow oil. LCMS: m / z 281.3 [M+H]+, ESI pos.

[0220] Step 2: (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol

[0221] A mixture containing (rac)-5-chloro-N-(1-ethyl-3-piperidyl)oxazolo[4,5-b]pyridin-2-amine (Example 1, Step 1) (92 mg, 0.311 mmol, 1.0 equiv), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS number 2557358-38-8, 136 mg, 0.450 mmol, 1.45 equiv), XPhos Pd G3 (27 mg, 0.032 mmol, 0.102 equiv) and cesium carbonate (305 mg, 0.936 mmol, 3.01 equiv) in 1,4-dioxane (1.2 mL) and water (0.30 mL) was flushed with argon and stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). All product-containing fractions were combined to give the title compound (82 mg, 60% yield) as a pale yellow solid. LCMS: m / z 421.3 [M+H]+, ESI pos.

[0222] Examples 2, 2A and 2B: (rac)-2-[2-[3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol and its respective enantiomers 2A and 2B [ka]

[0223] Step 1: (rac)-1-[4-(5-chlorooxazolo[4,5-b]pyridin-2-yl)morpholin-3-yl]-N,N-dimethyl-methanamine

[0224] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 80 mg, 0.379 mmol, 1.0 equiv.) in (rac)-N-methyl-2-pyrrolidinone (0.720 mL), dimethyl(morpholin-3-ylmethyl)amine (CAS No. 128454-20-6, 61 mg, 0.423 mmol, 1.12 equiv.) was added, followed by triethylamine (0.060 mL, 0.430 mmol, 1.14 equiv.). The brown solution was stirred at 150 °C for 16 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed four times with water and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 12 g, gradient 0% to 5% methanol in dichloromethane) to give the title compound (85 mg, 72% yield) as a pale brown oil. LCMS: m / z 297.2 [M+H]+, ESI pos.

[0225] Step 2: (rac)-2-[2-[3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;

[0226] (rac)-1-[4-(5-chlorooxazolo[4,5-b]pyridin-2-yl)morpholin-3-yl]-N,N-dimethyl-methanamine (Example 2, Step 1) (79 mg, 0.253 mmol, 1 equiv.), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS number 2557358-38-8, 111 mg, 0.367 mmol, 1.45 equiv.), cesium carbonate (237 mg, 0.727 mmol, 2.88 equiv.) and XPhos Pd in ​​1,4-dioxane (1.0 mL) and water (0.250 mL). A mixture of G3 (21 mg, 0.025 mmol, 0.098 equiv) was flushed with argon and stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 5% methanol in dichloromethane). All product-containing fractions were combined to give the title compound (93 mg, 80% yield) as a pale yellow foam. LCMS: m / z 437.4 [M+H] + ,ESI pos.

[0227] Step 3: 2-[2-[(3R or 3S)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol and 2-[2-[(3S or 3R)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol

[0228] Racemic (rac)-2-[2-[3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol (Example 2, Step 2) (60 mg, 0.131 mmol, 1 equiv.) was separated by chiral SFC (column: Chiralpak IC, eluent B: 15% methanol + 0.2% diethylamine) to give the two enantiomers Example 2A (first elution, Rt = 1.51 min) (23 mg, 38% yield) as a light brown foam; m / z 437.3 [M+H] +, ESI pos. and Example 2B (second elution, Rt = 1.74 min) (27 mg, 45% yield) as a light brown foam. LCMS: m / z 437.3 [M+H] +, ESI pos.

[0229] Examples 3, 3A and 3B: (rac)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol and its respective enantiomers 3A and 3B [ka]

[0230] Step 1: (rac)-1-(5-chlorooxazolo[4,5-b]pyridin-2-yl)piperidin-3-ol

[0231] A mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 100 mg, 0.473 mmol, 1.0 equiv.), piperidin-3-ol (CAS No. 6859-99-0, 53 mg, 0.524 mmol, 1.11 equiv.), and triethylamine (0.073 mL, 0.524 mmol, 1.1 equiv.) in 1,4-dioxane (1.0 mL) was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 70% ethyl acetate in heptane) to give the title compound (117 mg, 93% yield) as a white solid. LCMS: m / z 254.1 [M+H] + ,ESI pos.

[0232] Step 2: (rac)-1-[5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol

[0233] (rac)-1-(5-chlorooxazolo[4,5-b]pyridin-2-yl)piperidin-3-ol (Example 3, Step 1) (117 mg, 0.438 mmol, 1.0 equiv.), 2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS No. A mixture of 2557358-25-3 (194 mg, 0.614 mmol, 1.4 equiv.), potassium carbonate (305 mg, 2.21 mmol, 5.04 equiv.), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (44 mg, 0.054 mmol, 0.123 equiv.) was flushed with argon and stirred at 110 °C for 4 h and at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 5% methanol in dichloromethane) to afford the title compound (194 mg, 98% yield, 90% purity) as a pale brown waxy solid. LCMS: m / z 408.3 [M+H]+, ESI pos.

[0234] Step 3: (rac)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol

[0235] To a solution of (rac)-1-[5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol (Example 3, Step 2) (194 mg, 0.429 mmol, 1.0 equiv., 90% purity) in dichloromethane (0.800 mL) was added boron tribromide (1 M solution in dichloromethane) (3.98 g, 1.5 mL, 1.5 mmol, 3.5 equiv.) dropwise at 0° C. Stir for 15 minutes at 0° C. and at room temperature for 3 hours. The reaction mixture was cooled to 0° C., and methanol (approximately 3 mL) was added dropwise. Stir for approximately 15 minutes at 0° C. The mixture was then added to saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 5% methanol in dichloromethane) to give the title compound 3 (134 mg, 76% yield) as an off-white foam. LCMS: m / z 394.3 [M+H]+, ESI pos.

[0236] Step 4: (3R or 3S)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol and (3S or 3R)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol

[0237] Racemic (rac)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol (Example 3, Step 3) (100 mg, 0.254 mmol) was separated by chiral SFC (column: OJ-H, 5 μm, 250 × 20 mm), eluent B: 15% methanol) to give the two enantiomers Example 3A (first elution, Rt = 3.65 min) (44 mg, 42% yield) as a white solid; m / z 394.3 [M+H] +, ESI pos, and Example 3B (second elution, Rt = 3.96 min) as an off-white solid after trituration with a mixture of ethyl acetate / heptane = 1:1 (23 mg, 21% yield, 90% purity). LCMS: m / z 394.3 [M+H] + ,ESI pos.

[0238] Example 4: 3-Methyl-2-(2-morpholinoxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol [ka]

[0239] Step 1: 5-chloro-2-morpholino-oxazolo[4,5-b]pyridine

[0240] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 100 mg, 0.473 mmol, 1.0 equiv.) in 1,4-dioxane (1.0 mL), morpholine (CAS No. 110-91-8, 0.046 mL, 0.528 mmol, 1.12 equiv.) was added, followed by triethylamine (0.074 mL, 0.531 mmol, 1.12 equiv.). The brown solution was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 80% ethyl acetate in heptane) to afford the title compound (97 mg, 81% yield) as an off-white solid. LCMS: m / z 240.1 [M+H] + ,ESI pos.

[0241] Step 2: 5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2-morpholino-oxazolo[4,5-b]pyridine

[0242] 5-Chloro-2-morpholino-oxazolo[4,5-b]pyridine (Example 4, Step 1) (94 mg, 0.373 mmol, 1.0 equiv.), 2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS no. 2557358-2) in 1,4-dioxane (2.4 mL) and water (1.2 mL). A mixture of 5-3 (165 mg, 0.522 mmol, 1.4 equiv.), potassium carbonate (260 mg, 1.88 mmol, 5.05 equiv.), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (37 mg, 0.045 mmol, 0.122 equiv.) was flushed with argon and stirred at 110 °C for 3 h and at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 70% ethyl acetate in heptane) to afford the title compound (112 mg, 65% yield, 85% purity) as a pale yellow foam. LCMS: m / z 394.3 [M+H]+, ESI pos.

[0243] Step 3: 3-methyl-2-(2-morpholinoxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol

[0244] To a solution of 5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2-morpholino-oxazolo[4,5-b]pyridine (Example 4, Step 2) (112 mg, 0.242 mmol, 1.0 equiv., 85% purity) in dichloromethane (0.460 mL) was added boron tribromide (1 M dichloromethane solution) (2.28 g, 0.860 mL, 0.860 mmol, 3.55 equiv.) dropwise at 0° C. Stir for 15 minutes at 0° C. and at room temperature for 3 hours. The reaction mixture was cooled to 0° C., and methanol (approximately 3 mL) was added dropwise. Stir for approximately 15 minutes at 0° C. The mixture was then added to saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 50% ethyl acetate in heptane) to give the title compound (48 mg, 50% yield) as an off-white solid. LCMS: m / z 380.2 [M+H]+, ESI pos.

[0245] Example 5: (rac)-[2-[2-(hydroxymethyl)morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol [ka]

[0246] Step 1: (rac)-[4-(5-chlorooxazolo[4,5-b]pyridin-2-yl)morpholin-2-yl]methanol

[0247] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 80 mg, 0.379 mmol, 1.0 equiv.) in 1,4-dioxane (0.80 mL) was added (rac)-morpholin-2-ylmethanol (CAS No. 103003-01-6, 50 mg, 0.427 mmol, 1.13 equiv.), followed by triethylamine (0.060 mL, 0.430 mmol, 1.14 equiv.). The brown solution was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% ethyl acetate in heptane) to give the title compound (90 mg, 84% yield) as a colorless oil. LCMS: m / z 270.1 [M+H]+, ESI pos.

[0248] Step 2: (rac)-[2-[2-(hydroxymethyl)morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol

[0249] A mixture of (rac)-[4-(5-chlorooxazolo[4,5-b]pyridin-2-yl)morpholin-2-yl]methanol (Example 5, Step 1) (87 mg, 0.306 mmol, 1 equiv.), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS number 2557358-38-8, 134 mg, 0.444 mmol, 1.45 equiv.), XPhos Pd G3 (26 mg, 0.031 mmol, 0.100 equiv.) and cesium carbonate (300 mg, 0.921 mmol, 3.0 equiv.) in 1,4-dioxane (1.2 mL) and water (0.30 mL) was flushed with argon and stirred at 100° C. for 2 hours and at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 5% methanol in dichloromethane). All product-containing fractions were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and repurified by flash chromatography (silica gel, 12 g, gradient 0% to 50% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)) to afford the title compound (99 mg, 75% yield) as an off-white foam. LCMS: m / z 410.3 [M+H]+, ESI pos.

[0250] Example 6: 3-Methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol formate [ka]

[0251] Step 1: 5-[2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2-piperazin-1-yl-oxazolo[4,5-b]pyridine

[0252] 5-Chloro-2-piperazin-1-yl-oxazolo[4,5-b]pyridine (CAS number 2504954-78-1, WO 2020207941) (119.4 mg, 0.500 mmol, 1 equiv.), 2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxa A mixture of borolane (CAS number 2557358-25-3, 268 mg, 0.848 mmol, 1.7 equiv.), potassium carbonate (330 mg, 2.39 mmol, 4.78 equiv.), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (42.7 mg, 0.058 mmol, 0.116 equiv.) was flushed with argon and stirred at 110 °C for 5 h. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product (dark brown solid, 304.5 mg) was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 15% MeOH in dichloromethane) to give the title compound (158.1 mg, 77% yield) as a brown solid. LCMS: m / z 393.3 [M+H]+, ESI pos.

[0253] Step 2: 3-Methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; formate salt

[0254] To a solution of the above 5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2-piperazin-1-yl-oxazolo[4,5-b]pyridine (Example 6, Step 1) (123.1 mg, 0.314 mmol, 1.0 equiv., 95% purity) in dichloromethane (1.6 mL) was added boron tribromide (1 M dichloromethane solution) (1.1 mL, 1.10 mmol, 3.5 equiv.) dropwise at −75° C. (bath with dry ice and acetone). Stir at that temperature for 1 hour and warm to room temperature overnight. The reaction mixture was cooled to −75° C., and methanol (approximately 20 mL) was added dropwise. The red solution was stirred for approximately 5 minutes. The mixture was then added to saturated aqueous NaHCO3 solution (until the pH was adjusted to 7) and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reversed-phase HPLC (column: YMC-Triart C 18 , 12 nm, 5 μm, 100 × 30 mm; eluent acetonitrile / water + 0.1% HCOOH) to give the title compound as a colorless solid as the formate salt (50.6 mg, 50% yield, 93% purity). LCMS: m / z 377.3 [M+H] +, ESI pos.

[0255] Example 7: 3-Methyl-2-[2-[[3-(methylamino)cyclohexyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol [ka]

[0256] Step 1: tert-butyl tert-butyl N-[3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]cyclohexyl]-N-methyl-carbamate

[0257] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 88 mg, 0.439 mmol, 1.0 equiv.) in 1,4-dioxane (0.90 mL), tert-butyl N-(3-aminocyclohexyl)-N-methyl-carbamate (CAS No. 1783996-31-5, 100 mg, 0.438 mmol, 0.99 equiv.) was added, followed by triethylamine (67.3 μL, 0.438 mmol, 1.1 equiv.). The clear yellow solution was stirred at 90 °C for 24 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (115 mg, 55% yield, 80% purity) as a pale yellow oil. LCMS: m / z 381.3 [M+H] + ,ESI pos.

[0258] Step 2: tert-butyl N-[3-[[5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]cyclohexyl]-N-methyl-carbamate

[0259] The above tert-butyl N-[3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]cyclohexyl]-N-methyl-carbamate (Example 7, Step 1) (115 mg, 0.242 mmol, 1 equiv.), 2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS number 2557358-25-3, 129.8 mg, 0.411 mmol, 1.7 equiv.), potassium carbonate (15 A mixture of 1,4-dioxane (1.4 mL) and water (0.7 mL) containing 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (9.5 mg, 1.15 mmol, 4.78 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (22.8 mg, 0.028 mmol, 0.116 equiv.) was flushed with argon and stirred at 110 °C for 24 h. (0.5 equiv. of catalyst and base were added for reaction completion. The reaction mixture was also stored in the refrigerator for 3 days prior to completion.) The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product (dark brown oil) was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 15% MeOH in dichloromethane) to give the title compound (78.9 mg, 52% yield, 85% purity) as a green solid. LCMS: m / z 535.5 [M+H]+, ESI pos.

[0260] Step 3: 3-methyl-2-[2-[[3-(methylamino)cyclohexyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol

[0261] To a solution of the above tert-butyl N-[3-[[5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]cyclohexyl]-N-methyl-carbamate (Example 7, Step 2) (78.9 mg, 0.148 mmol, 1.0 equiv.) in dichloromethane (2 mL), boron tribromide (1 M solution in dichloromethane) (664.2 μL, 0.664 mmol, 4.5 equiv.) was added dropwise at 0° C. (bath with dry ice and acetone). Stir at that temperature for 1 hour, then allow it to warm to room temperature over a day. The reaction mixture was cooled to 0° C., and a few drops of methanol were added. The clear yellow solution was stirred for about 5 minutes. The mixture was then added to saturated aqueous NaHCO3 solution (until the pH was basic) and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: YMC-Triart C 18 , 12 nm, 5 μm, 100 × 30 mm; eluent acetonitrile / water + 0.1% triethylamine) to give the title compound as an off-white solid, most likely as a 2:1 cis / trans diastereomeric mixture (30 mg, 30% yield, 85% purity). LCMS: m / z 421.1853 [M+H] + ,ESI pos.

[0262] Example 8: 3-Methyl-2-(2-piperazin-1-yl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 2,2,2-Trifluoroacetic acid; [ka]

[0263] Step 1: 5-Bromo-1H-imidazo[4,5-b]pyridin-2-ol

[0264] To a mixture of 6-bromopyridine-2,3-diamine (1.0 g, 5.32 mmol, 1 equiv.) in 1,4-dioxane (30 mL) was added carbonyldiimidazole (974.36 mg, 6.91 mmol, 1.3 equiv.) under N at 25 °C. The mixture was then heated at 90 °C and stirred for 4 h. The mixture was concentrated in vacuo. The crude product was triturated with MTBE (10 mL × 3). The solid was collected to give the title compound (770 mg, 68% yield) as a black solid. 1 H NMR(400MHz,DMSO-d6)δ 11.57(br.s,1H),11.01(s,1H),7.18(d,1H),7.12(d,1H).

[0265] Step 2: 5-Bromo-2-chloro-1H-imidazo[4,5-b]pyridine

[0266] A mixture of the above 5-bromo-1H-imidazo[4,5-b]pyridin-2-ol (Example 8, Step 1) (300.0 mg, 1.4 mmol, 1 equiv.) and POCl3 (4298.3 mg, 28.03 mmol, 20 equiv.) in toluene (2 mL) was stirred at 110 °C for 5 h. The mixture was concentrated under reduced pressure to give the title compound (400 mg, 18% yield, HCl salt) as a brown solid. LCMS: m / z 233.8 [M+H]+, ESI pos.

[0267] Step 3: tert-butyl 4-(5-bromo-1H-imidazo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate

[0268] To a mixture of the above 5-bromo-2-chloro-1H-imidazo[4,5-b]pyridine hydrochloride (Example 8, Step 2) (400.0 mg, 0.250 mmol, 1.0 equiv.), tert-butyl piperazine-1-carboxylate (231.59 mg, 1.24 mmol, 5 equiv.) in N-methylpyrrolidone (10 mL) was added KCO (274.6 mg, 1.99 mmol, 8.0 equiv.) under N at 25 °C. The mixture was then stirred at 90 °C for 4 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse-phase flash (0.1% TFA condition) to give the title compound (40 mg, 38% yield) as a brown solid. LCMS: m / z 384.0 [M+2H] + ,ESI pos.

[0269] Step 4: tert-butyl 4-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate

[0270] The above tert-butyl 4-(5-bromo-1H-imidazo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate (Example 8, Step 3) (40.0 mg, 0.100 mmol, 1.0 equiv.), (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid (34.5 mg, 0.160 mmol, 1.5 equiv.), NaCO in 1,4-dioxane (2 mL) / water (1 mL). 3( To a mixture of Pd(dppf)Cl (33.3 mg, 0.310 mmol, 3 equiv.) was added Pd(dppf)Cl (7.66 mg, 0.010 mmol, 0.100 equiv.) under N at 25 °C. The mixture was then stirred at 95 °C for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column silica gel using petroleum ether / ethyl acetate = 1 / 1 to give the title compound (20 mg, 33% yield) as a pale yellow solid. LCMS: m / z 478.0 [M+H], ESI pos.

[0271] Step 5: 3-methyl-2-(2-piperazin-1-yl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid

[0272] A mixture of the above tert-butyl 4-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate (Example 8, Step 4) (20.0 mg, 0.030 mmol, 1 eq.) and TFA (94.2 mg, 1.02 mmol, 30 eq.) in dichloromethane (1 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C 18 The product was purified by HPLC (75*30 mm*3 μm, water (TFA)-acetonitrile, 12% to 42%, 7 min) to give the title compound (4.69 mg, 27% yield) as a pale yellow solid. m / z 378.0 [M+H]+, ESI pos.

[0273] Example 9: (rac)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidin-2-one [ka]

[0274] Step 1: (rac)-5-(5-bromooxazolo[4,5-b]pyridin-2-yl)piperidin-2-one

[0275] A solution of 2-amino-6-bromopyridin-3-ol (CAS No. 934758-27-7, 150.0 mg, 0.790 mmol, 1.0 equiv.) and (rac)-6-oxopiperidine-3-carboxylic acid (CAS No. 22540-50-7, 113.6 mg, 0.790 mmol, 1.0 equiv.) in polyphosphoric acid (1.0 mL) was stirred at 135° C. for 12 hours. The reaction mixture was diluted with cold water (50 mL), treated with saturated sodium carbonate to adjust the pH to approximately 10, and then extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase flash (0.1% TFA condition) to give the title compound (50 mg, 11% yield) as a yellow solid. LCMS: m / z 296.0 [M+2H] + ,ESI pos.

[0276] Step 2: (rac)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidin-2-one

[0277] To a solution of (rac)-5-(5-bromooxazolo[4,5-b]pyridin-2-yl)piperidin-2-one (Example 9, Step 1) (40.0 mg, 0.140 mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) and water (0.40 mL) was added (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid (59.4 mg, 0.270 mmol, 2.0 equiv.), NaCO (42.9 mg, 0.410 mmol, 3.0 equiv.), and Pd(dppf)Cl (19.8 mg, 0.030 mmol, 0.20 equiv.). The reaction mixture was stirred at 100° C. under a N atmosphere for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5μm; condition: water (ammonia hydroxide v / v)-acetonitrile; start B18 end B48; gradient time (min): 9; 100% B retention time (min): 2; flow rate (mL / min): 25) to give the title compound (2.04 mg, 4% yield) as a white solid. LCMS: m / z 392.0 [M+H] + ESI pos.

[0278] Example 10: (rac)-3-Methyl-2-[2-[3-(methylamino)-1-piperidyl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol [ka]

[0279] Step 1: (rac)-tert-butyl N-[1-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-3-piperidyl]-N-methyl-carbamate

[0280] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 90 mg, 0.449 mmol, 1 equiv.) in 1,4-dioxane (0.90 mL) was added (rac)-N-methyl-N-(3-piperidyl)carbamic acid tert-butyl ester (CAS No. 172478-01-2, 95 μL, 0.449 mmol, 1 equiv.), followed by triethylamine (69 μL, 0.493 mmol, 1.1 equiv.). The clear brown solution was stirred at 90 °C for 2 days. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 12 g, gradient 0% to 5% methanol in dichloromethane) to give the title compound (139.2 mg, 81% yield) as an off-white solid. LCMS: m / z 367.3 [M+H] + ,ESI pos.

[0281] Step 2: (rac)-tert-butyl N-[1-[5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3-piperidyl]-N-methylcarbamate

[0282] To a mixture of the above (rac)-tert-butyl N-[1-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-3-piperidyl]-N-methyl-carbamate (Example 10, Step 10) (139.2 mg, 0.379 mmol, 1.0 equiv), 2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (179.9 mg, 0.569 mmol, 1.5 equiv), NaCO (250.7 mg, 1.81 mmol, 4.78 equiv) in 1,4-dioxane (2.3 mL) / water (1.1 mL) was added Pd(dppf)Cl (35.9 mg, 0.044 mmol, 0.116 equiv) under N at 25 °C. The mixture was then stirred at 110° C. for 2 days. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (122.8 mg, 48% yield, 77% purity) as a dark brown solid. LCMS: m / z 521.5 [M+H] + ESI pos.

[0283] Step 3: (rac)-3-methyl-2-[2-[3-(methylamino)-1-piperidyl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol

[0284] The above (rac)-tert-butyl N-[1-[5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3-piperidyl]-N-methyl-carbamate (Example 10, Step 2) (78.9 mg, 0.152 mmol, 1.0 equiv.), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8, 682 μL, 0.682 mmol, 4.5 equiv.), and XPhos Pd A mixture of G3 (11.3 mg, 0.013 mmol, 0.098 equiv) and cesium carbonate (12.2 mg, 0.373 mmol, 2.88 equiv) in 1,4-dioxane (0.5 mL) and water (0.2 mL) was flushed with argon and stirred at 100° C. for 5 h. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product (yellow oil, 114 mg) was purified by HPLC (column: Phenomenex Gemini NX C 18 -5 μm-110 Å-100x30 mm; mobile phase HO+0.1% triethylamine / acetonitrile (gradient over 15 min) to give the title compound (32.4 mg, 53% yield, 90% purity) as an off-white solid. LCMS: m / z 419.5 [M−H] - ,ESI neg.

[0285] Example 11: (rac)-3-Methyl-2-[2-(tetrahydropyran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol [ka]

[0286] Step 1: (rac)-5-chloro-N-tetrahydropyran-3-yl-oxazolo[4,5-b]pyridin-2-amine

[0287] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 100 mg, 0.498 mmol, 1 equiv.) in 1,4-dioxane (2.8 mL) was added (rac)-tetrahydropyran-3-ylamine (55.5 mg, 57.6 μL, 0.548 mmol, 1.1 equiv.), followed by triethylamine (56.5 mg, 77.8 μL, 0.558 mmol, 1.12 equiv.). The brown solution was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature and extracted with approximately 40 mL of ethyl acetate and approximately 5 mL of saturated NaHCO3 solution. The aqueous layer was back-extracted with approximately 40 mL of ethyl acetate. The organic layer was washed with approximately 5 mL of water and approximately 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 4 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (63 mg, 59%) as a white solid. LCMS: m / z=254.1 [M+H] + ,ESI pos.

[0288] Step 2: (rac)-3-methyl-2-[2-(tetrahydropyran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol

[0289] To a solution of the above (rac)-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-tetrahydropyran-3-yl-amine (Example 11, Step 1) (50 mg, 0.197 mmol, 1.0 equiv.) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8, 86.5 mg, 71.5 μL, 0.286 mmol, 1.45 equiv.) in 1,4-dioxane, extra dry (0.8 mL) and water (0.2 mL) were added under cesium carbonate (184.7 mg, 0.567 mmol, 2.88 equiv.), followed by XPhos Pd G3 (17.2 mg, 0.019 mmol, 0.098 equiv.). The reaction mixture was flushed with argon and stirred at 100°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and extracted with approximately 5 mL of ethyl acetate and approximately 5 mL of water. The aqueous layer was back-extracted with approximately 5 mL of ethyl acetate. The organic layer was washed with approximately 5 mL of water and approximately 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 4 g, gradient 0% to 10% methanol in dichloromethane). All product-containing fractions were combined to give the title compound (44 mg, 57%) as a white solid. LCMS: m / z 394.3 [M+H] + ,ESI pos.

[0290] Example 12 1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]azetidin-3-ol [ka]

[0291] Step 1: 1-(5-chlorooxazolo[4,5-b]pyridin-2-yl)azetidin-3-ol

[0292] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 0.100 g, 0.473 mmol, 1.0 equiv.) in 1,4-dioxane (1 mL), azetidin-3-ol (CAS No. 45347-82-83, 8.3 mg, 0.524 mmol, 1.11 equiv.) was added, followed by triethylamine (53.7 mg, 74 μL, 0.531 mmol, 1.12 equiv.). The brown solution was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature and extracted with approximately 20 mL of ethyl acetate, 20 mL of dichloromethane (solubility issues), and approximately 5 mL of saturated NaHCO3 solution. The aqueous layer was back-extracted with approximately 40 mL of dichloromethane. The organic layer was washed with approximately 5 mL of water and approximately 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 4 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (63 mg, 59%) as a white solid. LCMS: m / z=226.1 [M+H] + ,ESI pos.

[0293] Step 2: 1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]azetidin-3-ol

[0294] To a solution of 1-(5-chlorooxazolo[4,5-b]pyridin-2-yl)azetidin-3-ol (50 mg, 0.222 mmol, 1.0 equiv.) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (97.3 mg, 80.4 μL, 0.322 mmol, 1.45 equiv.) in 1,4-dioxane, extra dry (0.9 mL) and water (0.2 mL) were added under argon and cesium carbonate (207.7 mg, 0.637 mmol, 2.88 equiv.), followed by the addition of XPhos Pd G3 (19.4 mg, 0.022 mmol, 0.098 equiv.). The reaction mixture was flushed with argon and stirred at 100 °C for 1 h. After the reaction was complete, the mixture was cooled to room temperature and extracted with approximately 5 mL of ethyl acetate and approximately 5 mL of water. The aqueous layer was back-extracted with approximately 5 mL of ethyl acetate. The organic layer was washed with approximately 5 mL of water and approximately 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 4 g, gradient 0% to 10% methanol in dichloromethane). All fractions containing the product were combined. The reaction mixture was subjected to preparative HPLC. After lyophilization, the title compound (10.3 mg, 12%) was obtained as a white solid. LCMS: m / z=366.2 [M+H] + ,ESI pos.

[0295] Example 13: 2-[2-[(3-hydroxycyclohexyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; [ka]

[0296] Step 1: 3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]cyclohexanol

[0297] To a solution of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (0.080 g, 0.379 mmol, 1 equiv.) in 1,4-dioxane (0.8 mL), 3-aminocyclohexanol (CAS No. 6850-39-1, 48.2 mg, 0.419 mmol, 1.11 equiv.) was added, followed by triethylamine (42.98 mg, 59.2 µL, 0.425 mmol, 1.12 equiv.). The brown solution was stirred at 90 °C for 2 days. LC-MS showed 43% starting material and 51% product. 3-Aminocyclohexanol (23.9 mg, 0.208 mmol, 0.550 equiv.) was added to the reaction mixture and stirred for 5 h. LC-MS showed a small educt peak. 3-Aminocyclohexanol (23.9 mg, 0.208 mmol, 0.550 equiv) was added to the reaction mixture, which was stirred at 90 °C overnight. After completion of the reaction, the mixture was cooled to room temperature and extracted with approximately 40 mL of ethyl acetate and approximately 5 mL of saturated NaHCO3 solution. The aqueous layer was back-extracted with approximately 40 mL of ethyl acetate. The organic layer was washed with approximately 5 mL of water and approximately 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 4 g, gradient 0% to 10% methanol in dichloromethane) to afford the title compound (79.6 mg, 79%) as a pale yellow solid. LCMS: m / z = 268.1 [M+H] + ,ESI pos.

[0298] Step 2: 2-[2-[(3-hydroxycyclohexyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol

[0299] To a solution of the above 3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]cyclohexanol (Example 13, Step 1) (75 mg, 0.280 mmol, 1.0 equiv.) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (122.9 mg, 101.6 μL, 0.407 mmol, 1.45 equiv.) in 1,4-dioxane (1 mL) and water (0.3 mL) was added cesium carbonate (262.5 mg, 0.806 mmol, 2.88 equiv.), followed by XPhos Pd G3 (24.5 mg, 0.027 mmol, 0.098 equiv.). The reaction mixture was flushed with argon and stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and extracted with approximately 5 mL of ethyl acetate and approximately 5 mL of water. The aqueous layer was back-extracted with approximately 5 mL of ethyl acetate. The organic layer was washed with approximately 5 mL of water and approximately 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 4 g, gradient 0% to 70% ethyl acetate in heptane) to afford the title compound (80 mg, 67%) as a yellow solid. LCMS: m / z=408.3 [M+H] + ,ESI pos.

[0300] Example 14: 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol [ka]

[0301] Step 1: 5-chloro-N-[(3R)-1-ethyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine

[0302] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 320 mg, 1.52 mmol, 1 equiv.) in 1,4-dioxane (3.2 mL) was added (3R)-1-ethylpiperidin-3-amine (CAS No. 1020396-26-2, 240 mg, 1.76 mmol, 1.16 equiv.), followed by triethylamine (0.240 mL, 1.72 mmol, 1.14 equiv.). The brown solution was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (405 mg, 90% yield) as an off-white solid. LCMS: m / z 281.2 [M+H] + ,ESI pos.

[0303] Step 2: 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol

[0304] A mixture of 5-chloro-N-[(3R)-1-ethyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (Example 14, Step 1) (300 mg, 1.02 mmol, 1 equiv.), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS number 2557358-38-8, 430 mg, 1.42 mmol, 1.4 equiv.), cesium carbonate (995 mg, 3.05 mmol, 3.01 equiv.) and XPhos Pd G3 (89 mg, 0.105 mmol, 0.10 equiv.) in 1,4-dioxane (4.0 mL) and water (1.0 mL) was flushed with argon and stirred at 90° C. for 16 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). All fractions containing the product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate / heptane to give the title compound (328 mg, 73% yield) as an off-white solid. LCMS: m / z 421.3 [M+H] + ,ESI pos.

[0305] Example 15: 3-Methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol [ka]

[0306] Step 1: 5-chloro-N-[(3R)-1-methyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine

[0307] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 80 mg, 0.379 mmol, 1 equiv.) in 1,4-dioxane (0.800 mL) was added (3R)-1-methylpiperidin-3-amine (CAS No. 1001353-92-9, 51 mg, 0.447 mmol, 1.18 equiv.), followed by triethylamine (0.061 mL, 0.438 mmol, 1.16 equiv.). The brown solution was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (101 mg, 95% yield) as an off-white solid. LCMS: m / z 267.1 [M+H] + ,ESI pos.

[0308] Step 2: 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol

[0309] A mixture of 5-chloro-N-[(3R)-1-methyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (Example 15, Step 1) (98 mg, 0.349 mmol, 1.0 equiv), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS number 2557358-38-8, 140 mg, 0.463 mmol, 1.33 equiv), cesium carbonate (325 mg, 0.997 mmol, 2.86 equiv) and XPhos Pd G3 (29 mg, 0.034 mmol, 0.098 equiv) in 1,4-dioxane (1.2 mL) and water (0.3 mL) was flushed with argon and stirred at 100° C. for 2 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined aqueous layers were back-extracted with a mixture of dichloromethane / methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). All fractions containing the product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate / heptane to give the title compound (88 mg, 59%) as an off-white powder. LCMS: m / z 407.3 [M+H] + ,ESI pos.

[0310] Example 16: (rac)-3-Methyl-2-(2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol [ka]

[0311] Step 1: (rac)-N-(2-amino-6-bromopyridin-3-yl)-1-methylpiperidine-2-carboxamide

[0312] To a solution of (rac)-1-methylpiperidine-2-carboxylic acid (456.88 mg, 3.19 mmol, 1 equiv.), 6-bromopyridine-2,3-diamine (0.60 g, 3.2 mmol, 1.0 equiv.), and DIPEA (1.99 mL, 11.2 mmol, 3.5 equiv.) in DMF (10 mL) was added T3P (3.05 g, 4.79 mmol, 1.5 equiv., 50% purity in ethyl acetate) dropwise at 0° C. The reaction mixture was stirred under a nitrogen atmosphere at 25° C. for 2 h. LCMS showed that starting material still remained, so another batch of DIPEA (1.99 mL, 11.2 mmol, 3.5 equiv.) and T3P (3045.92 mg in ethyl acetate, 4.79 mmol, 1.5 equiv., 50% purity) was added to the mixture at 25° C. and stirred at 50° C. under nitrogen atmosphere for another 2 h. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (100 mL×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 reverse-phase flash (CombiFlash 0.1% NH4OH aqueous-acetonitrile condition) to give the title compound (400 mg, 35% yield) as a yellow solid after lyophilization. LCMS: m / z 313.0 [M+H] + ,ESI pos.

[0313] Step 2: (rac)-5-bromo-2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridine

[0314] To a solution of the above (rac)-N-(2-amino-6-bromopyridin-3-yl)-1-methylpiperidine-2-carboxamide (Example 16, Step 1) (220 mg, 0.700 mmol, 1.0 equiv.) in ethanol (3 mL) and water (0.5 mL) was added NaOH (290.0 mg, 7.25 mmol, 10.3 equiv.) at 25° C. The reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 20 hours. LCMS showed that most of the starting material still remained, so another batch of NaOH (100 mg) was added. The reaction mixture was stirred at 100° C. for an additional 18 hours. The reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (100 mL×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 preparative HPLC (Method: Column: Phenomenex Luna C 18 150*40mm*15μm; Conditions: water (0.1% TFA)-acetonitrile: start B23 end B53; Gradient time (min): 11; 100% B retention time (min): 2; Flow rate (mL / min): 60) and subsequent purification by lyophilization to give the title compound (100 mg, 48% yield) as a yellow solid. 1 H NMR(400MHz,CHLOROFORM-d)δ=7.88(d,1H),7.47(d,1H),4.71(d,1H),3.76(d,1H),3.19-3.12(m ,1H),2.69(s,3H),2.54-2.44(m,1H),2.31-2.27(m,1H),2.21-2.01(m,3H),1.79-1.721(m,1H).

[0315] Step 3: (rac)-5-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridine

[0316] A mixture of the above (rac)-2-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example 16, Step 2) (85.68 mg, 0.270 mmol, 1 equiv.), 5-bromo-2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridine (80.0 mg, 0.270 mmol, 1 equiv.), and KCO (201.08 mg, 1.9 mmol, 7 equiv.) in 1,4-dioxane (4 mL) and water (0.800 mL) was degassed and purged with N three times, and then Pd(dppf)Cl (66.4 mg, 0.080 mmol, 0.300 equiv.) was added to the mixture. The mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase flash (CombiFlash 0.1% TFA aqueous / acetonitrile) and preparative HPLC (column: 3_Phenomenex Luna C 18 Purification by 75*30mm*3um; Conditions: water (0.1% TFA)-acetonitrile; Start B: 36, End B: 56; Gradient; Time (min): 8; 100% B; Retention time (min): 2; Flow rate (mL / min): 25) gave the title compound (30 mg, 27% yield) as a black solid after lyophilization. LCMS: m / z 405.1 [M+H] + ,ESI pos.

[0317] Step 4: (rac)-3-methyl-2-(2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol

[0318] To a solution of the above (rac)-5-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridine (Example 16, Step 3) (20.0 mg, 0.050 mmol, 1.0 equiv) in DCM (12 mL) was added BBr3 (2.0 mL, 20.76 mmol, 419.7 equiv) dropwise at −60° C. The reaction mixture was stirred at −60° C. for 2.5 h and then stirred at 25° C. under a nitrogen atmosphere for an additional 0.5 h. LCMS indicated that starting material still remained, so another batch of BBr3 (2.0 mL, 20.76 mmol, 419.7 equiv) was added to the mixture. The reaction mixture was stirred at 25° C. under a nitrogen atmosphere for an additional 1 h. The reaction mixture was quenched with cold water (5 mL), adjusted to pH 8 with aqueous ammonia, and then concentrated under reduced pressure. The residue was triturated twice with methanol (10 mL), and the filtrate was purified by CombiFlash 0.1% TFA-aqueous / acetonitrile chromatography (CombiFlash 0.1% TFA-aqueous / acetonitrile) and preparative HPLC (column: 3_Phenomenex Luna C 18 Purification by HPLC (75*30mm×3μm); Conditions: water (0.1% TFA in water)-acetonitrile; Start: B21, End: B51; Gradient time (min): 7, 100% B; Retention time (min): 2; Flow rate (mL / min): 25) followed by lyophilization gave the title compound (5.89 mg, 30% yield) as a white solid. LCMS: m / z 391.1 [M+H] + ,ESI pos.

[0319] Example 17: (rac)-3-Methyl-2-(2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol [ka]

[0320] Step 1: (rac)-tert-butyl 2-((2-amino-6-bromopyridin-3-yl)carbamoyl)pyrrolidine-1-carboxylate

[0321] To a solution of (rac)-(tert-butoxycarbonyl)proline (1.0 g, 4.65 mmol, 1 equiv.) in DMF (10 mL) was added DIPEA (1.22 g, 9.29 mmol, 2 equiv.) and 6-bromopyridine-2,3-diamine (874 mg, 4.65 mmol, 1.0 equiv.), followed by T3P (3.25 g, 5.11 mmol, 1.1 equiv., 50% purity in ethyl acetate) at 0° C. The mixture was stirred at 20° C. for 2 hours. The reaction mixture was quenched with ice water (20 mL) and then extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with brine (40 mL×2), 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% NH3.H2O aqueous acetonitrile) followed by lyophilization to give the title compound (1.0 g, 56% yield) as a brown solid. LCMS: m / z 387.1 [M+2+H] + ,ESI pos.

[0322] Step 2: (rac)-tert-butyl 2-(5-bromo-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate

[0323] To a solution of (rac)-tert-butyl 2-((2-amino-6-bromopyridin-3-yl)carbamoyl)pyrrolidine-1-carboxylate (500.0 mg, 1.3 mmol, 1.0 equiv) in ethanol (5 mL) was added a solution of NaOH (779 mg, 19.5 mmol, 15 equiv) in water (1 mL). The reaction was stirred at 100° C. for 4 hours. The reaction mixture was quenched with ice water (20 mL), extracted with ethyl acetate (20 mL×3), then washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash (CombiFlash 0.1% TFA aqueous-acetonitrile condition), followed by lyophilization to afford the title compound (50 mg, 10% yield) as a pale yellow solid. LCMS: m / z 367.0 [M+H] + ,ESI pos.

[0324] Step 3: (rac)-tert-butyl 2-(5-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate

[0325] A mixture of (rac)-tert-butyl 2-(5-bromo-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate; 2,2,2-trifluoroacetic acid (80.0 mg, 0.170 mmol, 1.0 equiv.), KCO (68.82 mg, 0.500 mmol, 3 equiv.) and 2-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105.1 mg, 0.330 mmol, 2 equiv.) in 1,4-dioxane (2 mL) and water (0.4 mL) was added to a round-bottom flask and purged with nitrogen three times, then Pd(dppf)Cl (36.45 mg, 0.050 mmol, 0.300 equiv.) was added to the mixture. The reaction mixture was stirred at 90° C. for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (PE:ethyl acetate=1:1, Rf=0.4) to give the title compound (79 mg, yield 99.7%) as a brown solid. LCMS: m / z 477.2 [M+H] + ,ESI pos.

[0326] Step 4: (rac)-3-methyl-2-(2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol

[0327] To a mixture of (rac)-tert-butyl 2-(5-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate (50.0 mg, 0.10 mmol, 1.0 equiv.) in dichloromethane (1 mL) was added BBr3 (66.6 mg, 0.270 mmol, 2.53 equiv.) under N2. The mixture was stirred at 25 °C for 10 min and then at 25 °C for an additional 50 min. The reaction mixture was quenched with ice water (2 mL) and neutralized to pH 7 with NH3.HO. The residue was purified by reverse-phase flash (CombiFlash 0.1% TFA aqueous-acetonitrile condition) followed by lyophilization to afford the title compound (15.1 mg, 39% yield) as a white solid. LCMS: m / z 363.1 [M+H] + ,ESI pos.

[0328] Examples 18, 18A and 18B: (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol and its respective enantiomers 18A and 18B [ka]

[0329] Step 1: 5-Bromo-2-methylsulfanyl-1H-imidazo[4,5-b]pyridine

[0330] Under an argon atmosphere, 1,1'-thiocarbonyldiimidazole (CAS No. 6160-65-2, 917.84 mg, 4.89 mmol, 1.15 equiv.) was added portionwise to a solution of (2-amino-6-bromo-3-pyridyl)amine (CAS No. 129012-04-0, 800 mg, 4.25 mmol, 1.0 equiv.) in DMF (40 mL). The yellow solution turned black after the addition. The reaction mixture was stirred overnight at room temperature. LC-MS indicated the detection of an intermediate product, as potassium carbonate (1.18 g, 514 μL, 8.51 mmol, 2.0 equiv.) was added, followed by methyl iodide (307.25 μL, 4.94 mmol, 1.16 equiv.). The reaction mixture was stirred at room temperature for 2 hours and 30 minutes. After complete conversion (TLC reaction control using 1:1 ethyl acetate / hexanes), the product was eluted. The reaction mixture was cooled to 0°C and approximately 25 mL of water was added dropwise. The reaction mixture was further diluted with water (25 mL) and extracted three times with ethyl acetate (20 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was triturated with ether to give the title compound (618 mg, 60% yield) as a pale brown powder. LCMS: m / z 244.0 [M+H] + (Br),ESI pos.

[0331] Step 2: (rac)-(5-bromo-N-(1-ethyl-3-piperidyl)-1H-imidazo[4,5-b]pyridin-2-amine

[0332] To a mixture of the above 5-bromo-2-methylsulfanyl-1H-imidazo[4,5-b]pyridine (Example 18, Step 1) (200 mg, 0.819 mmol, 1.0 equiv.) in a sealed tube was added (rac)-(1-ethyl-3-piperidyl)amine (CAS No. 6789-94-2, 552.9 mg, 615.7 μL, 4.1 mmol, 5.0 equiv.). The pale yellow suspension was stirred at 150°C for 4 days and at 130°C for an additional day. After completion of the reaction, the reaction mixture was cooled to room temperature. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 15 g, gradient 0% to 10% methanol in dichloromethane) to afford the title compound (187 mg, 56%, 80% pure) as a viscous oil. LCMS: m / z 324.2 [M+H] + ,ESI pos.

[0333] Step 3: (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol

[0334] To a solution of the above (rac)-(5-bromo-1H-imidazo[4,5-b]pyridin-2-yl)-(1-ethyl-3-piperidyl)amine (Example 18, Step 2) (196.8 mg, 0.577 mmol, 1.0 equiv.) in 1,4-dioxane (3.3 mL) and water (1.65 mL) was added (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid (314.8 mg, 1.43 mmol, 2.48 equiv.), potassium carbonate (559 mg, 4.04 mmol, 7.0 equiv.), and Pd(dppf)Cl (79.1 mg, 0.097 mmol, 0.17 equiv.). The reaction mixture was stirred at 85° C. under a N atmosphere for 6 hours. The reaction mixture was cooled to room temperature and extracted with approximately 30 mL of ethyl acetate and approximately 4 mL of semi-saturated NH Cl solution. The aqueous layer was back-extracted with approximately 30 mL of ethyl acetate. The organic layer was washed with approximately 4 mL of water and approximately 4 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane) to afford the title compound (110 mg, 46%) as a light brown powder. LCMS: m / z 418.4 [M+H] + ,ESI pos.

[0335] Step 4: 2-[2-[[(3R or 3S)-1-ethyl-3-piperidyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol and 2-[2-[[(3S or 3R)-1-ethyl-3-piperidyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol

[0336] The above (Example 18, Step 3) (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol was separated by chiral SFC (column: chiral cellulose C4, 5 μm, 250 × 20 mm), eluent: 35% methanol + 0.2% diethylamine) to give the two enantiomers Example 18A (eluting first, Rt = 2.90 min, optical rotation (in MeOH, 20 °C): + 19.44°) (33.0 mg, 27% yield, 90% purity, containing diethylamine) as a white powder; m / z 418.4 [M+H]. + , ESI pos and Example 18B (2nd elution, Rt = 4.12 min) (28.0 mg, 25% yield) was obtained as a white powder. LCMS: m / z 418.4 [M+H] + ,ESI pos.

[0337] Example 19: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol [ka]

[0338] A mixture of 5-chloro-N-[(3R)-1-ethyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (Example 14, Step 1) (450 mg, 1.52 mmol, 1.00 equiv), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS number 1207961-50-9, 480 mg, 2.58 mmol, 1.69 equiv), potassium carbonate (1.01 g, 7.31 mmol, 4.80 equiv), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (189 mg, 0.23 mmol, 0.15 equiv) in 1,4-dioxane (9.0 mL) and water (4.5 mL) was flushed with argon and stirred at 95° C. for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and half-saturated aqueous NH4Cl. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient 0% to 10% methanol in dichloromethane). All product-containing fractions were combined and concentrated in vacuo to give the title compound (414 mg, 67% yield) as a dark brown solid. LC-MS: m / z 387.2 [M+H] + ,ESI pos.

[0339] Examples 20, 20A and 20B: (rac)-5-chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]phenol and enantiomers 20A and 20B. [ka]

[0340] Step 1: (rac)-5-chloro-2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridine

[0341] In a sealed tube, triethylamine (374 mg, 515 μL, 3.69 mmol, 3.0 equiv.) was added to a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 260 mg, 1.23 mmol, 1.0 equiv.) and 6-methyloctahydro-1H-pyrrolo[2,3-c]pyridine (CAS No. 1443980-22-0, 224 mg, 1.6 mmol, 1.3 equiv.) in 1,4-dioxane (4 mL) and N-methyl-2-pyrrolidinone (2 mL) with stirring at room temperature. The reaction mixture was heated at 120 °C for 2 h. The dark brown reaction mixture was then heated at 150 °C for 20 h. The black reaction mixture was cooled to room temperature and extracted twice with ethyl acetate:tBME (v / v) 1:1 (2 × 50 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The aqueous layer was back-extracted with ethyl acetate:tBME (v / v) 1:1 (50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed onto ISOLUTE HM-N and purified by flash chromatography (12 g SiO2; gradient 0% to 10% methanol in dichloromethane) to afford the title compound (313 mg, 86% yield) as a yellow solid. LC-MS: m / z 293.1 [M+H] + ,ESI pos.

[0342] Step 2: (rac)-5-chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]phenol

[0343] 5-Chloro-2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridine (112 mg, 0.379 mmol, 1.0 equiv.) and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (141.2 mg, 0.757 mmol, 2.00 equiv.) were dissolved in 1,4-dioxane (3 mL) and water (1.5 mL). Potassium carbonate (235.6 mg, 1.7 mmol, 4.5 equiv.) was then added at room temperature. The orange reaction mixture was purged with argon, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (61.9 mg, 0.076 mmol, 0.2 equiv.) was added. The tube was sealed and stirred at 100 °C for 20 h. The reaction was then cooled to room temperature, and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (70.6 mg, 0.379 mmol, 1.0 equiv.) in 1,4-dioxane (1.5 mL) and water (0.750 mL) was added, followed by potassium carbonate (235.6 mg, 1.7 mmol, 4.5 equiv.). The dark red reaction mixture was purged with argon, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (30.9 mg, 0.038 mmol, 0.1 equiv.) was added with stirring. The tube was sealed and stirred at 110 °C for 6 h. The reaction mixture was then extracted twice with DCM (2 × 100 mL) and aqueous ammonium chloride (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was absorbed onto ISOLUTE HM-N and purified by flash chromatography (SiO; 0% to 30% dichloromethane:methanol:NHOH (v / v) 110:10:1 in dichloromethane), followed by further purification by preparative HPLC to afford the title compound (30.2 mg, 18% yield) as a white powder. -MS: m / z 397.1 [M−H] - ,ESI neg.

[0344] Step 3: 2-[2-[(3aR, 7aS or 3aS, 7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol and 2-[2-[(3aS, 7aR or 3aR, 7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol

[0345] The (rac)-5-chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo-[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]phenol (Example 20, Step 2) was separated by chiral SFC (column: Column Chiral IJ, 5 μm, 250 × 20 mm), eluent: 25% methanol + 0.2% diethylamine) to give the two enantiomers Example 20A (8 mg, 41% yield, first elution, Rt = 1.46 min) as a light brown foam; m / z 399.2 [M+H] + , ESI pos and Example 20B (8 mg, 41% yield, 2nd elution, Rt = 2.26 min) m / z 399.2 [M+H] + ,ESI pos. was obtained as a light brown foam.

[0346] Example 21: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 2,2,2-trifluoroacetic acid salt [ka]

[0347] Step A: 2-(3-chloro-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0348] To a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4391.3 mg, 17.3 mmol, 1.0 equiv.) in THF (50 mL) was added 4,4'-di-tert-butyl-2,2'-bipyridine (139.2 mg, 0.52 mmol, 0.03 equiv.) and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (229.25 mg, 0.35 mmol, 0.02 equiv.), followed by 2-chloro-1-fluoro-4-methylbenzene (2500.0 mg, 17.29 mmol, 1.0 equiv.). The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was then cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (100 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 using a silica gel column (petroleum ether:ethyl acetate = 1:0 to 20:1) to give the title compound (4.5 g, 96% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.50(dd,1H),7.36(dd,1H),2.27(s,3H),1.29(s,12H).

[0349] Step B: 3-chloro-2-fluoro-5-methylphenol

[0350] To a solution of 2-(3-chloro-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.50 g, 16.6 mmol, 1.0 equiv.) in THF (50 mL) was slowly added dropwise HO (9.43 g, 83.17 mmol, 5.0 equiv.) at 0 °C, followed by stirring at 20 °C for 2 h. The reaction solution was diluted with water (50 mL), followed by addition of NaSO (16 g, 83 mmol), stirred at 20 °C for 20 min, and extracted with ethyl acetate (100 mL × 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 crude product was purified by silica gel column (petroleum ether:ethyl acetate=1:0 to 20:1) to give the title compound (2500 mg, yield 84%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 10.19(br.s,1H),6.77-6.68(m,2H),2.18(s,3H).

[0351] Step C: 3-chloro-2-fluoro-6-iodo-5-methylphenol

[0352] To a solution of 3-chloro-2-fluoro-5-methylphenol (1.50 g, 9.34 mmol, 1.0 equiv.) in toluene (30 mL), NaH (934.2 mg, 23.35 mmol, 60% purity in mineral oil, 2.5 equiv.) was added portionwise at 0° C. and stirred at 20° C. for 0.5 h. Then, iodine (2.13 g, 8.41 mmol, 0.9 equiv.) was added slowly portionwise at 0° C. The reaction mixture was stirred at 20° C. for 0.5 h. The reaction mixture was quenched with dilute hydrochloric acid (100 mL, 1 M solution in water) at 0° C. and extracted with ethyl acetate (50 mL×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 crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to give the title compound (1.10 g, 41% yield) as a yellow oil. LC-MS: m / z 284.8 [M−H] - ,ESI neg.

[0353] Step D: 1-chloro-2-fluoro-4-iodo-3-methoxy-5-methylbenzene

[0354] To a solution of 3-chloro-2-fluoro-6-iodo-5-methylphenol (1.0 g, 3.49 mmol, 1.0 equiv.) in DMF (5 mL) was added KCO (1206.06 mg, 8.73 mmol, 2.5 equiv.), followed by dropwise addition of MeI (0.43 mL, 6.98 mmol, 2.0 equiv.) at 0°C, followed by stirring at 20°C for 2 h. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:0 to 10:1) to afford the title compound (700.0 mg, 67% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.08(dd,1H),3.95(d,3H),2.42(s,3H).

[0355] Step E: 2-(4-chloro-3-fluoro-2-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0356] To a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (557.3 mg, 3.0 mmol, 1.5 equiv.) in THF (12 mL) was added 1-chloro-2-fluoro-4-iodo-3-methoxy-5-methylbenzene (600.0 mg, 2.0 mmol, 1.0 equiv.), followed by the dropwise addition of n-BuLi (1.5 mL, 3.75 mmol, 2.5 M in hexanes, 1.88 equiv.) at −70° C., followed by stirring under N2 at −70° C. for 0.5 h. The reaction solution was quenched with saturated ammonium chloride (100 mL) at 0° C. and extracted with ethyl acetate (50 mL × 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 crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0 to 2:1) to give the title compound (400.0 mg, yield 67%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 6.89(d,1H),3.91(d,3H),2.30(s,3H),1.39(s,12H).

[0357] Step F: (4-chloro-3-fluoro-2-hydroxy-6-methylphenyl)boronic acid

[0358] To a solution of 2-(4-chloro-3-fluoro-2-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150.0 mg, 0.5 mmol, 1.0 equiv.) in DCM (2 mL) was added BBr3 (0.5 mL, 4.99 mmol, 10.0 equiv.) dropwise under N2 at -60 °C, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into 10 mL of water at 0 °C, and the pH was adjusted to 8 with 1 M NaOH solution. The mixture was then washed with ethyl acetate (10 mL × 3), and the aqueous phase was then acidified to pH = 4 with 1 N HCl solution. Extraction was performed with ethyl acetate (20 mL × 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 to give (4-chloro-3-fluoro-2-hydroxy-6-methylphenyl)boronic acid (40 mg, 39% yield) as a yellow oil.1 H NMR(400MHz,CD3OD)δ 6.73(d,1H),2.17(s,3H).

[0359] Step G: 5-Bromo-2-methylsulfanyl-oxazolo[4,5-b]pyridine

[0360] 1,1'-Thiocarbonyldiimidazole (5.42 g, 30.42 mmol, 1.15 equiv.) was added portionwise to a stirred solution of 2-amino-6-bromopyridin-3-ol (CAS No. 934758-27-7, 5.0 g, 26.45 mmol, 1.0 equiv.) in DMF (100 mL) at room temperature. The reaction mixture was stirred under nitrogen for 16 hours. Potassium carbonate (7.31 g, 52.91 mmol, 2.0 equiv.) was then added, followed by iodomethane (1.9 mL, 30.52 mmol, 1.15 equiv.), and the reaction was stirred for an additional 18 hours. The reaction mixture was cooled to 0°C and quenched by the slow addition of water (70 mL), upon which a precipitate formed. The reaction mixture was filtered, and the solid was washed with water. The product was dissolved in MeCN and concentrated in vacuo, then the product was dried in a vacuum oven overnight to give the title compound (4.89 g, 68% yield) as a brown solid. LC-MS: m / z 244.9 / 246.9 [M+H] + ,ESI pos.

[0361] Step H: 5-Bromo-N-[(3R)-1-ethyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine

[0362] Triethylamine (3.3 mL, 23.7 mmol, 5.0 equiv.), (3R)-1-ethylpiperidin-3-amine dihydrochloride (1.9 g, 9.47 mmol, 2.0 equiv.), and 5-bromo-2-methylsulfanyl-oxazolo[4,5-b]pyridine (CAS No. 1149384-63-3, 1.16 g, 4.73 mmol, 1.0 equiv.) were dissolved in dioxane (20 mL), and the reaction mixture was stirred at 90 °C for 24 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 40 g, 0–10% (0.7 N NH3 in MeOH) / DCM) to afford the title compound (1.61 g, 91% yield) as a brown semisolid. LC-MS: m / z 325.2 / 327.2 [M+H] + ,ESI pos.

[0363] Step I: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 2,2,2-trifluoroacetic acid salt

[0364] To a solution of (4-chloro-3-fluoro-2-hydroxy-6-methylphenyl)boronic acid (40 mg, 0.2 mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) and water (0.4 mL) was added 5-bromo-N-[(3R)-1-ethyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine; 2,2,2-trifluoroacetic acid. 2,2,2-Trifluoroacetic acid (68.77 mg, 0.16 mmol, 0.8 equiv.), K2CO3 (67.6 mg, 0.49 mmol, 2.5 equiv.), and Pd(dppf)Cl2 (28.64 mg, 0.04 mmol, 0.2 equiv.) were then added and stirred at 95 °C for 2 hours under a N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with acetonitrile (5 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (0.1% TFA, water-MeCN), and then the solvent was removed by lyophilization to give the title compound (13.9 mg, 13% yield) as a white solid. LC-MS: m / z 404.9 [M−H] - ,ESI neg.

[0365] Example 22: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 2,2,2-trifluoroacetic acid salt [ka]

[0366] Step A: 6-Bromo-4-chloro-3-fluoro-2-methylaniline

[0367] To a solution of 4-chloro-3-fluoro-2-methylaniline (4.50 g, 28.2 mmol, 1.0 equiv.) in MeCN (100 mL) was added NBS (6.02 g, 33.8 mmol, 1.2 equiv.) in one portion. The mixture was stirred at 20°C under a nitrogen atmosphere for 2 hours. The mixture was diluted with 50 mL of water and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether:ethyl acetate = 1:0 to 10:1) to give the title compound (5.00 g, 74% yield) as a dark brown solid. LC-MS: m / z 238.0 [M+H] + ,ESI pos.

[0368] Step B: 4-chloro-3-fluoro-6-methoxy-2-methylaniline

[0369] To a solution of 6-bromo-4-chloro-3-fluoro-2-methylaniline (3.00 g, 12.6 mmol, 1.0 equiv.) and CuI (2.38 g, 12.6 mmol, 1.0 equiv.) in DMF (60 mL) was slowly added NaOMe (9.06 g, 50.32 mmol, 4.0 equiv.) at 20 °C. The mixture was stirred at 120 °C for 3 h. The reaction mixture was cooled to room temperature, saturated ammonium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column (petroleum ether:ethyl acetate = 20:1 to 5:1) to give the title compound (900 mg, 38% yield) as a dark brown solid. LC-MS: m / z 190.1 [M+H] + ,ESI pos.

[0370] Step C: 2-Bromo-5-chloro-4-fluoro-1-methoxy-3-methylbenzene

[0371] To a solution of 4-chloro-3-fluoro-6-methoxy-2-methylaniline (250.0 mg, 1.32 mmol, 1.0 equiv.), CuBr (37.83 mg, 0.26 mmol, 0.2 equiv.), and CuBr (294.5 mg, 1.32 mmol, 1.0 equiv.) in MeCN (5 mL) was slowly added tert-butyl nitrite (314 μL, 2.64 mmol, 2.0 equiv.) at 0°C. The mixture was stirred under nitrogen at 20°C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic extracts were then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:0 to 10:1) to afford the title compound (150.0 mg, 45% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.23(d,1H),3.86(s,3H),2.32(d,3H).

[0372] Step D: 2-(4-chloro-3-fluoro-6-methoxy-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0373] To a solution of 2-bromo-5-chloro-4-fluoro-1-methoxy-3-methylbenzene (50.0 mg, 0.2 mmol, 1.0 equiv.) in THF (1 mL), 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (91.8 mg, 0.49 mmol, 2.5 equiv.) was added, and n-BuLi (0.12 mL, 0.3 mmol, 2.5 M in hexane, 1.5 equiv.) was added dropwise at -70 °C and stirred at -70 °C for 1 h. The reaction solution was quenched with saturated ammonium chloride solution (50 mL) at 0 °C and extracted with ethyl acetate (20 mL × 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 crude product was purified by preparative TLC (petroleum ether:ethyl acetate=20:1, Rf=0.4) to give the title compound (40.0 mg, 67% yield) as a white solid. 1H NMR(400MHz,CDCl3)δ 6.66(d,1H),3.73(s,3H),2.28(d,3H),1.41(s,12H).

[0374] Step E: (R)-5-(4-chloro-3-fluoro-6-methoxy-2-methylphenyl)-N-(1-ethylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine

[0375] To a solution of 2-(4-chloro-3-fluoro-6-methoxy-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30.0 mg, 0.1 mmol, 1.0 equiv.) in 1,4-dioxane (1 mL) and water (0.2 mL), (R)-6-bromo-N-(1-ethylpiperidin-3-yl)-3H-pyrrolo[2,3-b]pyridin-2-amine (43.8 mg, 0.1 mmol, 1.0 equiv.), CsF (37.9 mg, 0.25 mmol, 2.5 equiv.), and Xphos Pd G3 (16.92 mg, 0.02 mmol, 0.2 equiv.) were added, and the reaction mixture was stirred at 90 °C for 1 hour under a N2 atmosphere. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (20 mL × 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 crude product was purified by preparative TLC (dichloromethane:methanol=10:1, Rf=0.1) to give the title compound (40.0 mg, 63% yield) as a yellow oil. LC-MS: m / z 419.0 [M+H] + ,ESI pos.

[0376] Step F: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 2,2,2-trifluoroacetic acid salt

[0377] To a solution of (R)-5-(4-chloro-3-fluoro-6-methoxy-2-methylphenyl)-N-(1-ethylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine (30.0 mg, 0.07 mmol, 1.0 equiv.) in dichloromethane (1 mL) was added BBr3 (178.8 mg, 0.72 mmol, 10.0 equiv.) at −20° C., followed by stirring at 20° C. for 1 hour. The reaction mixture was quenched with water (0.5 mL) at 0° C., diluted with methanol (1 Ml), and then the pH was adjusted to about 7 with ammonium hydroxide. The mixture was purified by reverse-phase chromatography (C18, 0.1% TFA, water-ACN), and the solvent was removed by lyophilization to give the title compound (10.6 mg, 28% yield) as a white solid. LC-MS: m / z 405.0 [M+H] + ,ESI pos.

[0378] Example 23: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-benzonitrile [ka]

[0379] Step A: 2-Bromo-5-chloro-3-hydroxy-benzonitrile

[0380] N-Bromosuccinimide (3.60 g, 20.2 mmol, 1.04 equiv.) was added portionwise to a stirred solution of 3-chloro-5-hydroxybenzonitrile (CAS no. 473923-97-6, 3.0 g, 19.5 mmol, 1.0 equiv.) and diisopropylamine (1.0 mL, 7.14 mmol, 0.37 equiv.) in DCM (50 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 3 days. The solvent was concentrated in vacuo, and the crude material was purified by column chromatography (silica gel, 330 g, DCM) to afford the title compound (738 mg, 16% yield) as a white solid. LC-MS: m / z 229.9 [M−H] - ,ESI neg.

[0381] Step B: 2-Bromo-5-chloro-3-methoxy-benzonitrile

[0382] Potassium carbonate (875.0 mg, 6.33 mmol, 2.02 equiv) was added to a stirred solution of 2-bromo-5-chloro-3-hydroxybenzonitrile (730.0 mg, 3.14 mmol, 1.0 equiv) in acetone (8 mL) at room temperature, and the reaction was stirred for 5 minutes. Iodomethane (300.0 μL, 4.82 mmol, 1.53 equiv) was then added, and the reaction was stirred for an additional 16 hours. The reaction was concentrated in vacuo and then diluted with DCM (50 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted again with DCM (2 × 50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (752.0 mg, 92% yield) as a white solid, which was used without further purification. No LC-MS m / z was observed. 1 H NMR(500MHz,DMSO-d6)δ 7.72(d,1H),7.57(d,1H),3.95(s,3H).

[0383] Step C: 5-chloro-3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0384] Isopropylmagnesium chloride LiCl complex (1.3 M solution) (5.85 mL, 7.61 mmol, 2.5 equiv) was added dropwise to a stirred solution of 2-bromo-5-chloro-3-methoxy-benzonitrile (750.0 mg, 3.04 mmol, 1.0 equiv) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.1 mL, 15.21 mmol, 5.0 equiv) in THF (30 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was concentrated in vacuo and then diluted with water (100 mL) and DCM (100 mL), and the organic layer was separated. The aqueous layer was extracted again with DCM (2 x 100 mL) and the combined organic layers were washed with water (2 x 100 mL) and brine (100 mL), then dried over MgSO and concentrated in vacuo to give the title compound (914.6 mg, 72% yield) as a pale yellow waxy solid. LC-MS m / z 210.2 [M-BPin] - ,ESI neg.

[0385] Step D: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-benzonitrile

[0386] A mixture of 5-bromo-N-[(3R)-1-ethyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (Example 21, Step H) (200 mg, 0.62 mmol, 0.96 equiv), 5-chloro-3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (250.0 mg, 0.64 mmol, 1.0 equiv), cesium carbonate (620.0 mg, 1.9 mmol, 2.98 equiv), and Xphos Pd G3 (55.0 mg, 0.06 mmol, 0.1 equiv) in 1,4-dioxane (4.5 mL) and water (0.5 mL) was degassed with nitrogen for 5 minutes and then heated to 90° C. for 1 hour. The reaction was cooled to room temperature, concentrated, and then purified by silica gel column chromatography (40 g, 0-10% MeOH (0.7 M NH) / DCM) to give the title compound (131 mg, 17% yield) as a pale yellow solid. LC-MS m / z 412.3 [M+H] + ,ESI pos.

[0387] Step E: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-benzonitrile

[0388] BBr3 (1 M in DCM) (0.98 mL, 0.98 mmol, 10.23 equiv.) was added dropwise to a stirred solution of 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-benzonitrile (131.0 mg, 0.1 mmol, 1.0 equiv.) and tetrabutylammonium iodide (123.34 mg, 0.33 mmol, 3.5 equiv.) in DCM (5 mL) at 0 °C, and the reaction was allowed to warm to room temperature. After 24 h, the reaction was cooled to 0 °C, and an additional equivalent of BBr3 (1 M in DCM) (0.98 mL, 0.98 mmol, 10.23 equiv.) was added. The reaction was allowed to warm to room temperature and then stirred for an additional 24 h. The reaction was quenched by dropwise addition of NH3 in MeOH (100 mL, 7 M) at 0 °C. The solvent was concentrated in vacuo, and the resulting residue was dissolved in DCM (20 mL) and water (20 mL). The aqueous phase was adjusted to approximately pH 12 with aqueous NaOH (2 M), and the organic phase was separated. The aqueous phase was re-extracted with DCM (2 × 20 mL). The combined organic layers were dried over MgSO4, concentrated in vacuo, and then purified by column chromatography on silica gel (40 g cartridge, 0–5% MeOH (7 M NH3) / DCM). The product was then dissolved in DCM (5 mL), washed with water (5 × 5 mL), and then dried by passing through a phase separator and concentrated in vacuo to give the title compound (5.0 mg, 12% yield) as an off-white solid. LC-MS m / z 398.3 [M+H] + ,ESI pos, m / z 396.2[MH] - ,ESI neg.

[0389] Example 24: 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 2,2,2-trifluoroacetic acid salt [ka]

[0390] Step A: 5-chloro-3-hydroxy-2-iodo-benzaldehyde

[0391] To a mixture of 3-chloro-5-hydroxybenzaldehyde (7.5 g, 47.9 mmol, 1.0 equiv) in DMF (80 mL) was added NaH (2299.3 mg, 95.8 mmol, 2.0 equiv) under N2 at 0 °C and stirred for 30 min, then I2 (12157.98 mg, 47.9 mmol, 1.0 equiv) was added portionwise and stirred at 25 °C for 15.5 h. The mixture was poured into water (150 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1), purified by preparative HPLC (NH-H0), and lyophilized to give 5-chloro-3-hydroxy-2-iodo-benzaldehyde (1300 mg, 10% yield) as a pale green solid. 1 H NMR(400MHz,DMSO-d6)δ 11.45-11.27(m,1H),10.03-9.98(m,1H),7.21-7.19(m,1H),7.17-7.14(m,1H)

[0392] Step B: 5-chloro-2-iodo-3-(2-trimethylsilylethoxymethoxy)benzaldehyde

[0393] A mixture of CsCO (2249.34 mg, 6.9 mmol, 1.5 equiv) and 5-chloro-3-hydroxy-2-iodo-benzaldehyde (1300.0 mg, 4.6 mmol, 1.0 equiv) in DMF (2 mL) was degassed, purged with N three times, and stirred for 30 min. Then, SEMCl (1150.97 mg, 6.9 mmol, 1.5 equiv) was added to the mixture in one portion. The mixture was stirred at 25 °C for 2 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1200 mg, 63% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 10.02(s,1H),7.48(d,1H),7.38(d,1H),5.46(s,2H),3.79-3.73(m,2H),0.92-0.88(m,2H),-0.04(s,9H).

[0394] Step C: [5-chloro-2-iodo-3-(2-trimethylsilylethoxymethoxy)phenyl]methanol

[0395] Sodium borohydride (132.0 mg, 3.49 mmol, 1.2 equiv) was added portionwise to a solution of 5-chloro-2-iodo-3-(2-trimethylsilylethoxymethoxy)benzaldehyde (1200.0 mg, 2.91 mmol, 1.0 equiv) in methanol (12 mL) and water (1.2 mL). The mixture was stirred at 25° C. for 3 hours and then diluted with water (20 mL). The mixture was poured into water (15 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give [5-chloro-2-iodo-3-(2-trimethylsilylethoxymethoxy)phenyl]methanol (870 mg, 72% yield) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δ 7.13(d,1H),7.09(d,1H),5.59(t,1H),5.36(s,2H),4.40(d,2H),4.03(q ,1H),3.74(t,2H),1.99(s,2H),1.17(t,2H),0.88(t,2H),-0.04(s,9H).

[0396] Step D: 2-[[5-chloro-2-iodo-3-(methoxymethyl)phenoxy]methoxy]ethyl-trimethyl-silane

[0397] To a mixture of [5-chloro-2-iodo-3-(2-trimethylsilylethoxymethoxy)phenyl]methanol (870.0 mg, 2.1 mmol, 1.0 equiv.) and NaH (60.41 mg, 2.52 mmol, 1.2 equiv.) in THF (8 mL), MeI (0.13 mL, 2.1 mmol, 1.0 equiv.) was added in one portion at 25 °C under N2 and stirred for 5 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 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 = 0 / 1 to 5 / 1) and concentrated under reduced pressure to give the title compound (800 mg, 89% yield) as a colorless oil. 1 H NMR(400MHz,CD3OD)δ 7.11(d,1H),7.07(d,1H),5.32(s,2H),4.86(s,7H),4.44(s,2H),3.81(t,2H),3.47(s,3H),0.94(t,J=8.0 Hz,2H),0.01(s,9H).

[0398] Step E: 2-[[5-chloro-3-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methoxy]ethyl-trimethyl-silane

[0399] To a solution of 2-[[5-chloro-2-iodo-3-(methoxymethyl)phenoxy]methoxy]ethyl-trimethyl-silane (800.0 mg, 1.87 mmol, 1.0 equiv.) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (624.87 mg, 3.36 mmol, 1.8 equiv.) in THF (5 mL), nBuLi (1.12 mL, 2.8 mmol, 1.5 equiv.) was added dropwise over 10 min under N2 and stirred at -60 °C for 30 min. The mixture was poured into N4Cl solution (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer 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 (PE / EA 10:1) to give the title compound (260 mg, 33% yield) as a colorless oil. 1 H NMR(400MHz,CD3OD)δ 7.02(d,1H),6.93(s,1H),5.22(s,2H),4.43(s,2H),3.84-3.74(m,2H),3.30(s,3H),1.37(s,12H),0.98-0.92(m,2H),0.00(s,9H).

[0400] Step F: 5-chloro-3-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

[0401] A solution of 2-[[5-chloro-3-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methoxy]ethyl-trimethyl-silane (65.0 mg, 0.15 mmol, 1.0 equiv) and TFA (0.5 mL) in DCM (0.25 mL) was stirred at 25 °C for 12 h. The mixture was poured into water (10 mL) and extracted with EA (10 mL × 3). The combined organic layer 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 column chromatography (SiO, petroleum ether / ethyl acetate = 0 / 1 to 1 / 0) to afford the title compound (45.0 mg, 99% yield) as a colorless oil. 1H NMR(400MHz,CD3OD)δ 6.71(d,1H),6.67(d,1H),4.38(s,2H),3.38(s,3H),1.20(s,12H).

[0402] Step G: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 2,2,2-trifluoroacetic acid salt

[0403] A mixture of KCO (23.14 mg, 0.17 mmol, 2.5 equiv.), 5-chloro-3-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (20.0 mg, 0.07 mmol, 1.0 equiv.), and 5-bromo-N-[(3R)-1-ethyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine; 2,2,2-trifluoroacetic acid (38.3 mg, 0.09 mmol, 1.3 equiv.) in 1,4-dioxane (1 mL) and water (0.200 mL) was degassed and purged with N three times, and XphosPdG (5.63 mg, 0.01 mmol, 0.1 equiv.) was added to the mixture. The mixture was heated at 100 °C under microwave irradiation for 2 h. The mixture was concentrated under reduced pressure and purified by reversed-phase flash (0.1% TFA) and preparative HPLC (Method Column 3_Phenomenex Luna C 18 75 x 30 mm x 3 μm. Conditions: Water (TFA)-CAN; Start: B16; End: B46; Gradient time (min): 8; 100% B; Retention time (min): 2; Flow rate (mL / min): 25; Injection: 1. Purification by HPLC (99) afforded the title compound (TFA salt) (10.95 mg, 31% yield) as a white solid after lyophilization. LCMS: m / z 417.1 [M+H]+, ESI pos.

[0404] Example 25: 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile [ka]

[0405] Step A: 4-amino-3-methoxy-5-methyl-benzonitrile

[0406] Two batches were run in parallel. To a solution of 4-bromo-2-methoxy-6-methyl-aniline (25.0 g, 115 mmol, 1.0 equiv.) in DMF (250 mL) was added Zn(CN) (13.5 g, 115 mmol, 7.34 mL, 1.00 equiv.) and Pd(PPh) (66.8 g, 57.8 mmol, 0.50 equiv.). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was poured into H O (1.50 L) and extracted with ethyl acetate (1.00 L × 3). The organic phase was washed with brine (1.00 L × 3), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO , petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give the title compound (28.0 g, 75% yield) as a yellow solid.

[0407] Step B: 4-Bromo-3-methoxy-5-methyl-benzonitrile

[0408] To a solution of CuBr (46.4 g, 323 mmol, 9.86 mL, 1.50 equiv.) in MeCN (180 mL), t-BuONO (33.3 g, 323 mmol, 38.5 mL, 1.50 equiv.) was added and stirred at 65 °C. Then, a solution of 4-amino-3-methoxy-5-methyl-benzonitrile (35.0 g, 215 mmol, 1.00 equiv.) in MeCN (180 mL) was added at 65 °C. The mixture was stirred at 65 °C for 3.5 h. After cooling to room temperature, saturated aqueous NaSO (400 mL) and saturated aqueous NH Cl (200 mL) were added to the mixture, which was then extracted with ethyl acetate (500 mL × 3). The organic phase was washed with brine (500 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, R f=0.75) to give the title compound (20.7 g, 42% yield) as a white solid.

[0409] Step C: 3-Methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0410] To a solution of 4-bromo-3-methoxy-5-methyl-benzonitrile (18.0 g, 79.6 mmol, 1.00 equiv.) in DMF (180 mL) was added B2Pin2 (30.3 g, 119 mmol, 1.50 equiv.) and AcOK (35.1 g, 358 mmol, 4.50 equiv.). The mixture was stirred at 20 °C for 0.5 h, and Pd(dppf)Cl2·CHCl2 (13.0 g, 15.9 mmol, 0.20 equiv.) was added. The mixture was stirred at 100 °C for 12 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth, diluted with HO (500 mL), and extracted with ethyl acetate (800 mL × 3). The organic phase was washed with brine (800 mL × 3), dried over NaSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1, R f =0.30) to give the title compound (18.0 g, 83% yield) as a white solid.

[0411] Step D: (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid

[0412] 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 equiv) in DCM (170 mL) was cooled to 0 °C, and BBr (38.9 g, 155 mmol, 2.50 equiv) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was poured into HO (200 mL), filtered, and the cake collected and triturated with ethyl acetate (20 mL) to give the title compound (4.67 g, 42% yield) as a gray solid. LCMS: m / z 178.1 [M+H] +,ESI pos.

[0413] Step E: 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile

[0414] The (5-chlorooxazolo[4,5-b]pyridin-2-yl)-[(3R)-1-ethyl-3-piperidyl]amine (241 mg, 858.4 μmol, 1.0 equiv), the (4-cyano-2-hydroxy-6-methylphenyl)boronic acid (Example 25, Step D) (280.71 mg, 1.46 mmol, 1.7 equiv), and cesium carbonate (839.07 mg, 2.58 mmol, 3.0 equiv) were dissolved in 1,4-dioxane (5.9 mL) and water (1.48 mL). Argon was then bubbled through the mixture for 2 minutes, after which the catalyst methanesulfonate (2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium(ii) (XPhos Pd G3) (108.99 mg, 128.76 μmol, 0.15 equiv.) was added. The sealed tube was stirred at 100°C for 16 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (2 x 80 mL) and half-saturated aqueous ammonium chloride solution (80 mL). The organic layer was washed with water (80 mL) and brine (80 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO; 0-50% ethyl acetate in heptane; then crystallization using ethyl acetate:methanol 9:1 (v / v) followed by ethyl acetate / heptane to give the title compound (135 mg, 41% yield) as a pale yellow solid. LC-MS: 378.2 [M+H] + ,ESI pos.

[0415] Example 26: 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; [ka]

[0416] Step 1: 3-hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile

[0417] The above 5-chloro-N-[(3R)-1-methyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (Example 15, Step 1) (112 mg, 0.420 mmol, 1.0 equiv.), (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid (Example 25, Step D) (137.3 mg, 0.71 mmol, 1.7 equiv.), and potassium carbonate (261.2 mg, 1.9 mmol, 4.5 equiv.) were dissolved in 1,4-dioxane (3 mL) and water (1.5 mL). Argon was then bubbled through the mixture for 2 minutes, after which the catalyst 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)-dichloride dichloromethane complex (51.4 mg, 0.063 mmol, 0.15 equiv.) was added. The sealed tube was stirred at 90 °C for 16 h. The reaction mixture was then extracted with ethyl acetate (2 × 30 mL) and half-saturated aqueous ammonium chloride solution (30 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO; 0-50% ethyl acetate in heptane; then ethyl acetate:methanol 9:1 (v / v) followed by crystallization using ethyl acetate / heptane to afford the title compound (51 mg, 32% yield) as an off-white solid. LC-MS: 364.2 [M+H] + ,ESI pos.

[0418] Examples 27, 27a and 27b: (rac)-3-hydroxy-5-methyl-4-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]benzonitrile and its respective enantiomers 27A and 27B [ka]

[0419] Step 1: 5-chloro-2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridine

[0420] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 260 mg, 1.23 mmol, 1.00 equiv.) and 6-methyl-1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine (CAS No. 1443980-22-0, 224 mg, 1.60 mmol, 1.30 equiv.) in 1,4-dioxane (4.0 mL) and N-methyl-2-pyrrolidinone (2.0 mL) was added triethylamine (374 mg, 0.515 mL, 3.69 mmol, 3.00 equiv.). The reaction mixture was heated to 120 °C and stirred for 2 h and at 150 °C for 20 h. The reaction mixture was cooled to room temperature and extracted with a mixture of ethyl acetate:MTBE (1:1) and water. The aqueous layer was back-extracted with a mixture of ethyl acetate:MTBE (1:1). The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane) to afford the title compound (313 mg, 86% yield) as a yellow solid. LC-MS: m / z 293.1 [M+H] + ,ESI pos.

[0421] Step 2: (rac)-3-hydroxy-5-methyl-4-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]benzonitrile

[0422] To a mixture of 5-chloro-2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridine (Example 20, Step 1) (160 mg, 0.54 mmol, 1.00 equiv.) and (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid (Example 25, Step D) (208 mg, 1.08 mmol, 2.00 equiv.) in 1,4-dioxane (6.0 mL) and water (3.0 mL), potassium carbonate (359 mg, 2.60 mmol, 4.80 equiv.) was added under stirring at room temperature. Argon was bubbled through the reaction mixture for 3 minutes. Then, with stirring at room temperature, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (88 mg, 0.11 mmol, 0.20 equiv.) was added. The tube was sealed and stirred at 100 °C for 20 h. The reaction mixture was extracted with ethyl acetate and semi-saturated aqueous NH4Cl. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, 0% to 100% gradient in dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)) to afford the title compound (100 mg, 43% yield, 90% purity) as a dark brown foam. LC-MS: m / z 390.2 [M+H] + ,ESI pos.

[0423] Step 3: 4-[2-[(3aS,7aR or 3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile and 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile

[0424] Racemic (rac)-3-hydroxy-5-methyl-4-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]benzonitrile (Example 20, Step 2) was separated by chiral SFC (column: Chiralpak IJ, eluent B: 20% methanol + 0.2% diethylamine) to give the two enantiomers Example 27A (first eluting, Rt = 1.31 min) (35 mg, 38% yield) as a light brown foam; LC-MS: m / z 390.2 [M+H] + , ESI pos and Example 27B (2nd elution, Rt = 1.94 min) (28 mg, 30% yield) was obtained as a light brown foam. LC-MS: m / z 390.2 [M+H] + ,ESI pos.

[0425] Example 28: 4-[2-[[(3R,5S)-1-Ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; Formate [ka]

[0426] Step 1: (3R,5S)-3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

[0427] To the above 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 491 mg, 2.32 mmol, 1.0 equiv.) in 1,4-dioxane (3 mL) and N-methyl-2-pyrrolidinone (6 mL) was added (3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (653.6 mg, 3.02 mmol, 1.3 equiv.), followed by triethylamine (423.4 mg, 583.2 μL, 4.18 mmol, 1.8 equiv.). The light brown solution was stirred in a sealed tube at 150° C. for 16 hours. The reaction was then quenched with water (5 mL) and extracted with ethyl acetate (2×80 mL). The organic layer was washed with brine (80 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO, 25 g of SiO; 0-50% ethyl acetate in heptane; then ethyl acetate:methanol 9:1 (v / v) to give (3R,5S)-3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (441 mg, 49% yield) as a pale yellow foam. LC-MS: m / z 369.2 [M+H] + ,ESI pos.

[0428] Step 2: (3S,5R)-5-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]piperidin-3-ol; Hydrogen chloride salt

[0429] To a solution of (3R,5S)-3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (441 mg, 1.2 mmol, 1.0 equiv.) in DCM (10 mL) and methanol (5 mL) was added dropwise 4 M HCl (3.59 g, 3.0 mL, 12 mmol, 10 equiv.) in 1,4-dioxane at room temperature. The reaction mixture was stirred at 23° C. for 16 hours. The reaction mixture was concentrated in vacuo to give crude (3S,5R)-5-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]piperidin-3-ol; hydrochloride salt (415 mg, 102% yield) as a pale yellow foam, which was used in the next step without further purification. LC-MS: m / z 269.1 [M+H] + ,ESI pos.

[0430] Step 3: (3S,5R)-5-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]-1-ethyl-piperidin-3-ol

[0431] To a suspension of (3S,5R)-5-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]piperidin-3-ol; hydrochloride (414 mg, 1.22 mmol, 1.0 equiv.) in anhydrous DCM (16.9 mL) was added acetaldehyde (134.5 mg, 172 μL, 3.05 mmol, 2.5 equiv.) followed by sodium acetate (250 mg, 3.05 mmol, 2.5 equiv.) under ice bath cooling. Sodium triacetoxyborohydride (466 mg, 2.2 mmol, 1.8 equiv.) was added at 0° C. The reaction mixture was stirred at 0° C. for 5 minutes and at room temperature for 3 hours. The reaction mixture was then carefully basified with water. The mixture was extracted with NaHCO3 solution (25 mL) and then with dichloromethane (3×60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, 0% to 10% methanol in dichloromethane) to give the title compound (187 mg, 52% yield) as a light brown solid. LC-MS: m / z 297.1 [M+H]+ ,ESI pos.

[0432] Step 4: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; formate

[0433] A mixture of (3S,5R)-5-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]-1-ethyl-piperidin-3-ol (Example 28, Step 3) (55 mg, 166.8 μmol, 1.0 equiv), (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid (Example 25, Step D) (64.2 mg, 333.6 μmol, 2.0 equiv), potassium carbonate (103.7 mg, 750.6 μmol, 4.5 equiv) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (20.43 mg, 25.0 μmol, 0.15 equiv) in 1,4-dioxane (2 mL) and water (1 mL) was flushed with argon and stirred at 100° C. for 16 hours. The reaction mixture was extracted with ethyl acetate (2 × 20 mL) and half-saturated aqueous ammonium chloride solution (20 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% in DCM (DCM:methanol:NH4OH 110:10:1)) followed by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 μm, 100 × 30 mm, gradient 5 to 50% MeCN in water + 0.1% HCOOH) to afford the title compound (12 mg, 16% yield) as a white amorphous lyophilized solid. LC-MS: m / z 392.2 [M−H] - ,ESI neg.

[0434] Example 29: (rac)4-[2-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile [ka]

[0435] Step 1: (rac)-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-indolizidin-8-yl-amine

[0436] To a suspension of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 200 mg, 947 μmol, 1.0 equiv.) and rac-(8S,8aS)-octahydro-8-indolizinamine-dihydrochloride (262.4 mg, 1.23 mmol, 1.3 equiv.) in 1,4-dioxane (1.5 mL) and N-methyl-2-pyrrolidinone (1.5 mL) was added triethylamine (383 mg, 528 μL, 3.8 mmol, 4.0 equiv.) dropwise at room temperature. The brown suspension was sealed and heated at 120 °C for 16 h. The dark orange-brown reaction mixture was cooled to room temperature and extracted twice with ethyl acetate:tBME (v / v) 1:1 (2 × 50 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The aqueous layer was back-extracted with ethyl acetate:tBME (v / v) 1:1 (50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed onto ISOLUTE HM-N and purified by flash chromatography (SiO2; gradient 0% to 10% methanol in DCM) to afford the title compound (64 mg, 21%) as a light brown solid. LC-MS: m / z 293.1 M+H] + ,ESI pos.

[0437] Step 2: (rac) 4-[2-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile

[0438] (rac)-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-indolizidin-8-ylamine (64 mg, 0.2 mmol, 1.0 equiv.) and (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid (Example 25, Step D) (69.6 mg, 394 μmol, 2.0 equiv.) were dissolved in 1,4-dioxane (2 mL) and water (1 mL), and potassium carbonate (122.4 mg, 885.4 μmol, 4.5 equiv.) was added. The mixture was then flushed with argon for 3 minutes, followed by the addition of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (24.1 mg, 29.51 μmol, 0.15 equiv.). The dark red reaction suspension was sealed and stirred at 100° C. for 16 hours. The reaction mixture was then cooled to room temperature and extracted with DCM (2 x 20 mL) and saturated aqueous ammonium chloride (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL). The aqueous layer was back-extracted with DCM (20 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HN-M and purified by flash chromatography (SiO2; 0% to 60% DCM:methanol:NH4OH (v / v) in DCM 110:10:1), followed by further purification by crystallization (dissolved in heptane:ethyl acetate (v / v) 1:1; trituration and evaporation) to afford the title compound (27 mg, 35%) as a pink solid. LC-MS: m / z 390.3 [M+H] + ,ESI pos.

[0439] Example 30: 3-(Difluoromethyl)-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid salt [ka]

[0440] Step A: 3-Hydroxy-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide

[0441] To a mixture of 3-hydroxy-5-(trifluoromethyl)benzoic acid (3.00 g, 14.55 mmol, 1.0 equiv) and O,N-dimethylhydroxylamine HCl (1703.59 mg, 17.47 mmol, 1.2 equiv) in DMF (30 mL) was added DIEA (5880.07 mg, 58.22 mmol, 4.0 equiv), EDCI (4169.9 mg, 21.83 mmol, 1.5 equiv), and HOBt (1571.9 mg, 11.64 mmol, 0.8 equiv), and the mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched with 30 mL of water, then extracted with EtOAc (40 mL × 3), washed with brine (30 mL × 2), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE: EtOAc = 10: 1 to 3: 1) to give the title compound (2500 mg, 69% yield) as a white solid. LC-MS: m / z 250.0 [M+H] + ,ESI pos.

[0442] Step B: 3-Hydroxy-2-iodo-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide

[0443] To a mixture of 3-hydroxy-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (6.4 g, 25.7 mmol, 1.0 equiv.) in toluene (65 mL) was added NaH (2.05 g, 51.37 mmol, 2.0 equiv.) at 0 °C. The mixture was stirred at 0 °C for 10 min. Then, I2 (5.2 g, 20.55 mmol, 0.8 equiv.) was added to the mixture and stirred at 25 °C for 12 h. The reaction mixture was quenched with 20 mL of water, extracted with EA (30 mL × 3), washed with brine (40 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid. The solid was purified by column chromatography (PE:EA = 20:1 to 10:1) to give the title compound (3200 mg, 33% yield) as a yellow solid. 1H NMR(400MHz,CD3OD)δ 7.07(s,1H),7.05(s,1H),3.52(s,3H),3.38(s,3H).

[0444] Step C: 3-(benzyloxy)-2-iodo-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide

[0445] To a solution of 3-hydroxy-2-iodo-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (3.20 g, 8.53 mmol, 1.0 equiv) in DMF (35 mL) were added KCO (2354.7 mg, 17.06 mmol, 2.0 equiv) and BnBr (2.18 g, 12.8 mmol, 1.5 equiv), and the mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched with 10 mL of EA, extracted with EA (20 mL × 3), washed with brine (20 mL × 2), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid. The solid was purified by column (PE:EA=20:1 to 10:1) to give 3-(benzyloxy)-2-iodo-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (3.50 g, yield 88%) as a white solid. 1 H NMR(400MHz,CD3OD)δ 7.53(d,3H),7.41-7.38(m,3H),7.35-7.31(m,2H),7.27(s,1H),7.23(s ,1H),5.28(s,2H),3.91(s,1H),3.51(s,3H),3.39(s,3H),3.12(s,1H).

[0446] Step D: (3-(benzyloxy)-2-iodo-5-(trifluoromethyl)phenyl)methanol

[0447] To a mixture of 3-(benzyloxy)-2-iodo-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (3.50 g, 7.52 mmol, 1.0 equiv.) in THF (40 mL) was added DIBAL-H (22.57 mL, 22.57 mmol, 3.0 equiv.) dropwise at −60°C, and the mixture was stirred at −60°C for 3 h. The reaction mixture was added dropwise to 20 mL of saturated NH4Cl solution, followed by extraction with EA (20 mL × 3), washing with brine (20 mL × 2), filtering, and the filtrate was concentrated under reduced pressure to give a yellow solid. The solid was purified by column chromatography (PE:EA = 20:1 to 10:1) to give (3-(benzyloxy)-2-iodo-5-(trifluoromethyl)phenyl)methanol (1800 mg, 59% yield) as a white solid. 1 H NMR(400MHz,CD3OD)δ 7.45-7.40(m,3H),7.31-7.27(m,2H),7.24-7.20(m,1H),7.10(d,1H),5.16(s,2H).

[0448] Step E: 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)benzaldehyde

[0449] To a mixture of 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)benzaldehyde (1800.0 mg, 4.41 mmol, 1.0 equiv) in DCM (20 mL) was added MnO (5524.15 mg, 22.05 mmol, 5.0 equiv), and the mixture was stirred for 1 h at 25° C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)benzaldehyde (1500 mg, 84% yield) as a white solid. 1 H NMR(400MHz,CD3OD)δ 10.21(m,1H),7.56-7.52(m,3H),7.41-7.38(m,2H),7.34-7.31(m,1H),7.20(d,1H),5.26(s,2H).

[0450] Step F: 1-(benzyloxy)-3-(difluoromethyl)-2-iodo-5-(trifluoromethyl)benzene

[0451] To a mixture of 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)benzaldehyde (1500.0 mg, 3.69 mmol, 1.0 equiv.) in DCM (30 mL) was added diethylaminosulfur trifluoride (893.04 mg, 5.54 mmol, 1.5 equiv.) at 0 °C, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with 20 mL of ice water, extracted with EtOAc (30 mL × 3), washed with brine (20 mL × 2), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a white solid. The solid was purified by column chromatography (PE:EA = 20:1 to 10:1) to give 1-(benzyloxy)-3-(difluoromethyl)-2-iodo-5-(trifluoromethyl)benzene (1300 mg, 82% yield) as a white solid. 1 H NMR(400MHz,CD3OD)δ 7.54(d,2H),7.44-7.38(m,4H),7.36-7.32(m,1H),7.00(t,1H),5.31(s,2H)

[0452] Step G: 2-(2-(benzyloxy)-6-(difluoromethyl)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0453] To a mixture of 1-(benzyloxy)-3-(difluoromethyl)-2-iodo-5-(trifluoromethyl)benzene (400.0 mg, 0.93 mmol, 1.0 equiv.) and nBuLi (0.56 mL, 1.4 mmol, 1.5 equiv.) in THF (5 mL), 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (312.9 mg, 1.68 mmol, 1.8 equiv.) was added dropwise under N2, and the mixture was stirred at -60 °C for 30 min. The mixture was poured into NH4Cl solution (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 20:1 to 10:1) to give 2-(2-(benzyloxy)-6-(difluoromethyl)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.0 mg, yield 13%) as a white solid. 1 H NMR(400MHz,CD3OD)δ 7.51(s,1H),7.50(s,1H),7.41-7.32(m,5H),5.16(s,2H),1.26(s,12H).

[0454] Step H: 5-Bromo-N-[(3R)-1-methyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine

[0455] (3R)-1-Methylpiperidin-3-amine dihydrochloride (172.0 mg, 0.92 mmol, 1.12 equiv., CAS: 1157849-50-7) and triethylamine (0.4 mL, 2.87 mmol, 3.48 equiv.) were added to a stirred solution of 5-bromo-2-methylsulfanyl-oxazolo[4,5-b]pyridine (202.0 mg, 0.82 mmol, 1.0 equiv.) in 1,4-dioxane (4 mL), and the reaction mixture was heated to 90°C. The reaction was stirred for 3 days. Triethylamine (0.3 mL, 2.15 mmol, 2.6 equiv.) and (3R)-1-ethylpiperidin-3-amine dihydrochloride (164.0 mg, 0.82 mmol, 1.0 equiv.) were added, and the reaction was left stirring at 90°C for 2 hours. Additional (3R)-1-ethylpiperidin-3-amine dihydrochloride (42.0 mg, 0.21 mmol, 0.25 equiv) and triethylamine (0.15 mL, 1.08 mmol, 1.3 equiv) were then added, and the reaction was stirred at 90 °C for 18 h. The reaction was cooled to room temperature and concentrated in vacuo. The crude reaction mixture was purified by chromatography on silica gel (40 g, 0-20% MeOH (with 0.7 M NH3) / EtOAc) to afford the title compound (222.0 mg, 84% yield) as a light brown solid. LC-MS: m / z 311.1 / 313.1 [M+H] + ,ESI pos.

[0456] Step I: (R)-5-(2-(benzyloxy)-6-(difluoromethyl)-4-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine

[0457] To a solution of 2-(2-(benzyloxy)-6-(difluoromethyl)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.23 mmol, 1.0 equiv.) and 5-bromo-N-[(3R)-1-methyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (Example 30, Step H) (87.2 mg, 0.28 mmol, 1.2 equiv.) in 1,4-dioxane (5 mL) and water (1 mL) was added KCO (74.26 mg, 0.7 mmol, 3.0 equiv.) and Pd(dppf)Cl (6.74 mg, 0.02 mmol, 0.1 equiv.), and the mixture was stirred at 90° C. under N for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent and give a brown solid. The solid was purified by reverse-phase flash (0.1% TFA water / ACN condition). The eluate was dried by lyophilization to give the title compound (20.0 mg, 16% yield) as a white solid. LC-MS: m / z 533.2 [M+H] + ,ESI pos.

[0458] Step I: (R)-3-(difluoromethyl)-2-(2-((1-methylpiperidin-3-yl)amino)oxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol

[0459] To a mixture of (R)-5-(2-(benzyloxy)-6-(difluoromethyl)-4-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine (10.0 mg, 0.02 mmol, 1.0 equiv.) in EtOAc (1 mL) was added Pd / C (20.0 mg), and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a white solid. The solid was purified by reverse-phase flash (0.1% TFA water / ACN). The eluate was dried by lyophilization to give the title compound (4.47 mg, 42% yield) as a white solid. LC-MS: m / z 443.2 [M+H] + ,ESI pos.

[0460] Example 31: 2-[2-[[(3R)-1-Ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid salt [ka]

[0461] Step A: 3-Amino-5-(trifluoromethyl)phenol

[0462] A solution of 3-nitro-5-(trifluoromethyl)phenol (8000.0 mg, 38.63 mmol, 1.0 equiv) in methanol (80 mL) was evacuated and refilled with nitrogen three times, then Pd / C (200 mg, 10% purity) was added, and the mixture was evacuated and refilled with hydrogen three times. The reaction mixture was stirred under a hydrogen atmosphere (15 psi) at 25° C. for 3 hours. The reaction mixture was filtered, the solid was washed with MeOH (50 mL×3), and the filtrate was concentrated under reduced pressure to give 3-amino-5-(trifluoromethyl)phenol (6400 mg, 94% yield) as a yellow solid. LC-MS: m / z 178.0 [M+H] + ,ESI pos.

[0463] Step B: 5-(trifluoromethyl)benzene-1,3-diol

[0464] A solution of 3-amino-5-(trifluoromethyl)phenol (2000.0 mg, 11.29 mmol, 1.0 equiv) in concentrated sulfuric acid (8.0 mL, 150.1 mmol, 13.29 equiv) and water (7 mL) was cooled to 0 °C, then a solution of NaNO (1168.53 mg, 16.94 mmol, 1.5 equiv) in water (4 mL) was added dropwise and stirred for 15 min. After that, excess nitrous acid was destroyed by the addition of urea (339.07 mg, 5.65 mmol, 0.5 equiv), and then this cold solution was added dropwise to a solution of copper sulfate (25.0 g, 156.64 mmol, 13.87 equiv) in refluxing saturated water (100 mL) and stirred at this temperature for 30 min. After cooling to ambient temperature, the reaction mixture was extracted with EA (100 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 column chromatography (0.1% aqueous NH4OH / MeCN), and the desired fraction was extracted with EA (100 mL x 3), washed with brine (20 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-(trifluoromethyl)benzene-1,3-diol (1.20 g, 60% yield) as a red oil. LC-MS: m / z 354.9 [2M-H] - ,ESI neg.

[0465] Step C: 2-iodo-5-(trifluoromethyl)benzene-1,3-diol

[0466] To a solution of 5-(trifluoromethyl)benzene-1,3-diol (1200 mg, 6.74 mmol, 1.0 equiv) in THF (70 mL) and water (70 mL) was added a solution of iodine (1710.02 mg, 6.74 mmol, 1.0 equiv) in THF (10 mL) dropwise at 0 °C, followed by the addition of sodium bicarbonate (566.01 mg, 6.74 mmol, 1.0 equiv). After stirring at 0 °C for 10 min, the reaction mixture was warmed to 25 °C and stirred at this temperature for an additional 50 min. The reaction mixture was quenched with a saturated aqueous solution of sodium sulfite (100 mL), extracted with EA (100 mL × 3), and washed with brine (30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE-PE:EA=10:1) to obtain 2-iodo-5-(trifluoromethyl)benzene-1,3-diol (1000 mg, 49% yield) as a yellow solid. LC-MS: m / z 302.8, [M−H] - ,ESI neg.

[0467] Step D: 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)phenol

[0468] To a solution of 2-iodo-5-(trifluoromethyl)benzene-1,3-diol (200 mg, 0.66 mmol, 1.0 equiv.) in DMF (3 mL) was added potassium carbonate (136.38 mg, 0.99 mmol, 1.5 equiv.) and BnBr (112.52 mg, 0.66 mmol, 1.0 equiv.) at 25 °C. The reaction mixture was then stirred at this temperature for 2 h under a nitrogen atmosphere. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL), extracted with EA (100 mL × 2), 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 (PE:EA = 15:1) to give 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)phenol (110.0 mg, 42% yield) as a yellow oil. LC-MS: m / z 392.9, [M−H] - ,ESI neg.

[0469] Step E: 1-(benzyloxy)-2-iodo-3-methoxy-5-(trifluoromethyl)benzene

[0470] To a solution of 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)phenol (330.0 mg, 0.84 mmol, 1.0 equiv) in DMF (6 mL) was added potassium carbonate (47.98 mg, 1.26 mmol, 1.5 equiv) followed by CHI (237.69 mg, 1.67 mmol, 2.0 equiv) dropwise, and the reaction mixture was stirred under a nitrogen atmosphere at 25° C. for 1 h. The reaction mixture was quenched dropwise with a saturated aqueous solution of NH4Cl (50 mL) at 25° C., extracted with EA (200 mL × 3), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1-(benzyloxy)-2-iodo-3-methoxy-5-(trifluoromethyl)benzene (400.0 mg, 88% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.54-7.52(m,2H),7.44-7.33(m,4H),6.79(s,1H),6.74(s,1H),5.21(s,2H),3.96(s,3H).

[0471] Step F: 2-(2-(benzyloxy)-6-methoxy-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0472] To a solution of 1-(benzyloxy)-2-iodo-3-methoxy-5-(trifluoromethyl)benzene (200.0 mg, 0.49 mmol, 1.0 equiv.) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (266.47 mg, 1.43 mmol, 2.0 equiv.) in THF (3 mL) was added n-BuLi (0.43 mL, 1.07 mmol, 1.5 equiv.) dropwise at −60° C., and the reaction mixture was stirred at this temperature for 1 h under a nitrogen atmosphere. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL), extracted with EA (100 mL × 3), washed with brine (20 mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA=20:1) to give the title compound (50.0 mg) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.46-7.43(m,2H),7.36-7.31(m,3H),6.79(s,1H),6.72(s,1H),5.07(s,2H),3.83(s,3H),1.31(s,12H).

[0473] Step G: 3-Methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol

[0474] A solution of 2-(2-(benzyloxy)-6-methoxy-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30.0 mg, 0.06 mmol, 1.0 equiv) in ethyl acetate (4 mL) and methanol (1 mL) was evacuated and refilled with nitrogen three times, then Pd / C (15.0 mg, 10% purity) was added. The reaction was evacuated and refilled with hydrogen three times, then the reaction mixture was stirred under a hydrogen atmosphere (1100 mmHg) at 25° C. for 0.5 h. The reaction mixture was filtered, the solid was washed with MeOH (20 mL×2), and the filtrate was concentrated under reduced pressure to give 3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (22.0 mg, 92% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.79(s,1H),6.77(s,1H),6.57(s,1H),3.86(s,3H),1.39(s,12H).

[0475] Step H: 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid salt

[0476] To a solution of (R)-5-bromo-N-(1-ethylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine, 2,2,2-trifluoroacetic acid (20.0 mg, 0.05 mmol, 1.0 equiv.), 3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (18.83 mg, 0.06 mmol, 1.3 equiv.), and potassium carbonate (31.42 mg, 0.23 mmol, 5.0 equiv.) in 1,4-dioxane (2 mL) and water (0.2 mL) was added Pd(dppf)Cl (3.33 mg, 0.0 mmol, 0.1 equiv.). The reaction mixture was then evacuated and refilled with nitrogen three times, and the reaction mixture was stirred under a nitrogen atmosphere at 100 °C for 3 hours. After cooling to ambient temperature, the reaction mixture was directly purified by C18 column chromatography (0.1% TFA / MeCN in water) and then by preparative HPLC (instrument ACSWH-GX-N, method column Phenomenex Synergi Polar-RP 100x25mmx4um, condition water (TFA)-ACN, start B: 31, end B: 51. Gradient time (min): 7, 100% B. Retention time (min): 2, flow rate (mL / min): 25) to obtain (R)-2-(2-((1-ethylpiperidin-3-yl)amino)oxazolo[4,5-b]pyridin-5-yl)-3-methoxy-5-(trifluoromethyl)phenol as the TFA salt (6.57 mg, 26% yield) as a yellow solid. LC-MS: m / z 437.1 [M+H] + ,ESI pos.

[0477] Example 32: (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid salt [ka]

[0478] Step A: 5-(trifluoromethyl)-1,2,4-triazin-3-amine

[0479] To a stirred solution of benzyl alcohol (5.19 g, 47.98 mmol, 1.0 equiv) in tetrahydrofuran (100 mL) was added NaH (1.92 g, 47.98 mmol, 1.0 equiv) at 20° C. The mixture was stirred at ambient temperature for 10 minutes. 3-Bromo-6-chloro-pyrazin-2-amine, CAS: 212779-21-0 (10.0 g, 47.98 mmol, 1.0 equiv) was then added, and the reaction mixture was heated at 70° C. for 4 hours. The mixture was quenched with 5 mL of water, ethyl acetate (50 mL) and water (20 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL×2). The combined extracts were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography (eluted with petroleum ether:ethyl acetate = 10:1 to 3:1) to give 3-benzyloxy-6-chloro-pyrazin-2-amine (3.0 g, 25% yield) as a yellow solid. LC-MS: m / z 236.0 [M+H] + ,ESI pos.

[0480] Step B: 2-(6-amino-5-benzyloxy-pyrazin-2-yl)-3-methyl-5-(trifluoromethyl)phenol

[0481] The apparatus was dried by heating with a heat gun under vacuum. To a mixture of 3-benzyloxy-6-chloro-pyrazin-2-amine (1.3 g, 5.52 mmol, 1.0 equiv.), CsF (2.51 g, 16.55 mmol, 3.0 equiv.), and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (2.5 g, 8.27 mmol, 1.5 equiv.) in 1,4-dioxane (30 mL) and water (5 mL) was added XPhos Pd G3 (0.47 g, 0.55 mmol, 0.1 equiv.) at 25 °C, and the mixture was stirred at 100 °C under N2 for 16 h to give a brown solution. After cooling to 25°C, the mixture was quenched with 10 mL of water, ethyl acetate (50 mL) and water (20 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined extracts were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography (eluting with petroleum ether:ethyl acetate = 10:1 to 3:1) to give 2-(6-amino-5-benzyloxy-pyrazin-2-yl)-3-methyl-5-(trifluoromethyl)phenol (1.5 g, 60% yield) as a yellow solid. LC-MS: m / z 376.2 [M+H] + ,ESI pos.

[0482] Step C: (rac)-Benzyl 3-isothiocyanatopiperidine-1-carboxylate

[0483] To a stirred solution of TEA (862.2 mg, 8.54 mmol, 2.0 equiv.), benzyl 3-aminopiperidine-1-carboxylate, CAS 711002-74-3, was added a solution of 711002-74-3 (1.0 g, 4.27 mmol, 1.0 equiv.) in dichloromethane (5 mL) at 0 °C, dropwise, and thiophosgene (490.76 mg, 4.27 mmol, 1.0 equiv.) was added. After stirring at 25 °C for 2 h, the mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (eluting with petroleum ether:ethyl acetate = 10:1 to 3:1) to give benzyl 3-isothiocyanatopiperidine-1-carboxylate (1.0 g, 85% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.43-7.28(m,5H),5.19-5.04(m,2H),4.06-4.00(m,1H),3.94-3.66(m,2H), 3.40-3.38(m,1H),3.20-3.04(m,1H),1.94-1.83(m,2H),1.68-1.49(m,2H).

[0484] Step D: (rac)-3-(benzyloxy)-6-(2-methyl-4-(trifluoromethyl)-6-((2-(trimethylsilyl)ethoxy)-methoxy)phenyl)pyrazin-2-amine

[0485] The apparatus was dried by heating with a heat gun under vacuum. To a mixture of cesium carbonate (390.63 mg, 1.2 mmol, 1.5 equiv.) and 2-(6-amino-5-benzyloxy-pyrazin-2-yl)-3-methyl-5-(trifluoromethyl)phenol (300.0 mg, 0.8 mmol, 1.0 equiv.) in DMF (5 mL) was added SEMCl (199.8 mg, 1.2 mmol, 1.5 equiv.) and stirred at 25 °C for 30 min. The mixture was then partitioned between ethyl acetate (50 mL) and water (20 mL). The organic portion was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether:ethyl acetate = 10:1 to 3:1) to afford the title compound (200 mg, 50% yield) as a colorless oil. LC-MS: m / z 506.2 [M+H] + ,ESI pos.

[0486] Step E: (rac)-Benzyl 3-[[3-benzyloxy-6-[2-methyl-4-(trifluoromethyl)-6-(2-trimethylsilylethoxy-methoxy)phenyl]pyrazin-2-yl]carbamoylamino]piperidine-1-carboxylate

[0487] To a stirred solution of 3-benzyloxy-6-[2-methyl-4-(trifluoromethyl)-6-(2-trimethylsilylethoxy)phenyl]pyrazin-2-amine (150.0 mg, 0.3 mmol, 1.0 equiv.) in tetrahydrofuran (1.5 mL) was added NaH (23.73 mg, 0.59 mmol, 60%, 2.0 equiv.) and stirred at 25° C. for 0.5 h. Benzyl 3-isothiocyanatopiperidine-1-carboxylate (98.38 mg, 0.36 mmol, 1.2 equiv.) was then added and stirred at 25° C. for 3 h. The mixture was quenched with 5 mL of water. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with petroleum ether:ethyl acetate = 10:1 to 3:1) to give the title compound (60.0 mg, 26% yield) as a yellow solid. LC-MS: m / z 782.5 [M+H] + ,ESI pos.

[0488] Step F: (rac)-1-(3-hydroxy-6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyrazin-2-yl)-3-(piperidin-3-yl)thiourea; Trifluoroacetate

[0489] A stirred solution of benzyl 3-[[3-benzyloxy-6-[2-methyl-4-(trifluoromethyl)-6-(2-trimethylsilylethoxymethoxy)phenyl]pyrazin-2-yl]carbamothioylamino]piperidine-1-carboxylate (50.0 mg, 0.06 mmol, 1.0 equiv.), anisole (0.07 mL, 0.64 mmol, 10.0 equiv.), and TFA (1.0 mL) was stirred at 75° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (20 g, 0.1% TFA / MeCN in water), and the eluent was lyophilized to afford 1-[3-hydroxy-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazin-2-yl]-3-(3-piperidyl)thiourea; TFA salt (30.0 mg, 99% yield) as a yellow solid. LC-MS: m / z 428.2 [M+H] + (ESI pos).

[0490] Step G: (rac)-1-(1-ethyl-3-piperidyl)-3-[3-hydroxy-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazin-2-yl]thiourea; Trifluoroacetate

[0491] To a solution of 1-[3-hydroxy-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazin-2-yl]-3-(3-piperidyl)thiourea; TFA salt (25.0 mg, 0.05 mmol, 1.0 equiv.), acetic acid (3.33 mg, 0.06 mmol, 1.2 equiv.) in methanol (1 mL) was added acetaldehyde (0.03 mL, 0.23 mmol, 40%, 5.0 equiv.) and stirred at 25° C. for 0.5 h, followed by addition of NaBHCN (14.51 mg, 0.23 mmol, 5.0 equiv.) and stirring at 25° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (20 g, 0.1% TFA / MeCN in water), and the eluate was then lyophilized to give 1-(1-ethyl-3-piperidyl)-3-[3-hydroxy-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazin-2-yl]thiourea; TFA salt (25.0 mg, 94% yield) as a yellow solid. LC-MS: m / z 456.3 [M+H] + ,ESI pos.

[0492] Step H: (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid salt

[0493] To a mixture of 1-(1-ethyl-3-piperidyl)-3-[3-hydroxy-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazin-2-yl]thiourea (TFA salt (15.0 mg, 0.03 mmol, 1.0 equiv.), tetrabutylazanium; iodide (9.73 mg, 0.03 mmol, 1.0 equiv.) in tetrahydrofuran (0.5 mL) was added hydrogen peroxide (5.97 mg, 0.05 mmol, 2.0 equiv.) and stirred at 25° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by C18 column chromatography (20 g, 0.1% TFA / MeCN in water), and the eluent was lyophilized to afford the title compound (10.2 mg, 70% yield) as a yellow solid. LC-MS: m / z 422.2 [M+H]+ ,ESI pos.

[0494] Example 33: 3-Methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid salt [ka]

[0495] Step A: 6-chloro-4-methyl-2-nitropyridin-3-ol

[0496] The apparatus was dried by heating with a heat gun under vacuum. In a three-necked round-bottom flask, 6-chloro-4-methyl-pyridin-3-ol (CAS: 1227502-89-7) (800 mg, 5.57 mmol, 1.0 equiv.) was added to HSO (5.46 g, 55.72 mmol, 10.0 equiv.) at 0 °C. Then, a mixture of fuming nitric acid (657.0 mg, 10.43 mmol, 1.87 equiv.) and HSO (1.09 g, 11.14 mmol, 2.0 equiv.) was added to the mixture. The mixture was stirred at 0 °C for 1 hour, and then at 25 °C for 12 hours. The reaction mixture was quenched with 20 mL of ice water, extracted with EtOAc (30 mL × 3), washed with brine (20 mL × 2), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=20:1 to 10:1) to obtain the desired product, 6-chloro-4-methyl-2-nitropyridin-3-ol (1200.0 mg) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ 10.95(brs,1H),7.77(s,1H),2.32(s,3H).

[0497] Step B: 2-amino-6-chloro-4-methylpyridin-3-ol

[0498] To a solution of 6-chloro-4-methyl-2-nitropyridin-3-ol (500.0 mg, 2.65 mmol, 1.0 equiv.) in THF (15 mL) and water (3 mL), Fe (1.48 g, 26.52 mmol, 10.0 equiv.) and NHCl (1.42 g, 26.52 mmol, 10.0 equiv.) were added portionwise, and the reaction mixture was stirred at 70° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc: THF = 10:1:1) to afford the title compound (150.0 mg, 36% yield) as a yellow solid. LC-MS: m / z 159.0 [M+H] + ,ESI pos.

[0499] Step C: 5-chloro-7-methyloxazolo[4,5-b]pyridine-2-thiol

[0500] To a solution of 2-amino-6-chloro-4-methylpyridin-3-ol (150.0 mg, 0.95 mmol, 1.0 equiv) in N,N-dimethylformamide (3 mL) was added di(1H-imidazol-1-yl)methanethione (303.4 mg, 1.7 mmol, 1.8 equiv) in portions, and the reaction mixture was stirred under a nitrogen atmosphere at 20° C. for 12 hours. The reaction was quenched with 20 mL of water, extracted with EtOAc (100 mL × 2), washed with 1 N aqueous HCl (20 mL × 2), brine (20 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give 5-chloro-7-methyloxazolo[4,5-b]pyridine-2-thiol (180.0 mg, 71% yield) as a yellow solid, which was used in the next step without further purification. LC-MS: m / z 200.9, [M+H] + ,ESI pos.

[0501] Step D: 2,5-Dichloro-7-methyloxazolo[4,5-b]pyridine

[0502] To a mixture of 5-chloro-7-methyloxazolo[4,5-b]pyridine-2-thiol (150.0 mg, 0.75 mmol, 1.0 equiv.) in oxalyl chloride (4.74 g, 37.38 mmol, 50.0 equiv.), DMF (5.46 mg, 0.07 mmol, 0.1 equiv.) was added, and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was added to ice water (20 mL) at 0° C. and extracted with EtOAc (30 mL×2). The combined extracts were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (hexane / EtOAc, 5:1) to give the title compound (40.0 mg, 26% yield) as a white solid. LC-MS: m / z 203.0, [M+H] + ,ESI pos.

[0503] Step E: (R)-5-chloro-7-methyl-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine

[0504] To a solution of 2,5-dichloro-7-methyloxazolo[4,5-b]pyridine (40.0 mg, 0.2 mmol, 1.0 equiv.) in NMP (2 mL) was added (R)-1-methylpiperidin-3-amine (67.49 mg, 0.6 mmol, 3.0 equiv.) and DIEA (127.07 mg, 0.99 mmol, 5.0 equiv.). The mixture was stirred at 20° C. for 2 hours. The mixture was purified by C18 column chromatography (0.1% TFA / MeCN in water). The eluent was lyophilized to afford the desired product (R)-5-chloro-7-methyl-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine (60.0 mg, 77% yield, TFA salt) as a yellow solid. LC-MS: m / z 281.1, [M+H] + ,ESI pos.

[0505] Step F: 3-methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid salt

[0506] To a solution of 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (36.73 mg, 0.12 mmol, 1.2 equiv.) and (R)-5-chloro-7-methyl-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine (40.0 mg, 0.1 mmol, 1.0 equiv.) in 1,4-dioxane (1.5 mL) and water (0.3 mL) was added CsF (61.56 mg, 0.41 mmol, 4.0 equiv.) and Xphos Pd G3 (17.17 mg, 0.02 mmol, 0.2 equiv.) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 3 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (Method: Column: Phenomenex Synergi Polar-RP 100 x 25 mm x 4 μm; Conditions: Water (TFA)-MeCN, Start B: 27; End B: 47; Gradient time (min): 7; 100% B retention time (min): 2; Flow rate (mL / min): 25.). The eluent was lyophilized to give the title compound (19.4 mg, 34% yield, TFA salt) as a yellow solid. LC-MS: m / z 421.1, [M+H] + (ESI pos).

[0507] Example 34: 5-Methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol [ka]

[0508] Step A: 2-iodo-5-methoxy-3-methyl-phenol

[0509] To a stirred solution of 3-methoxy-5-methylphenol (1.0 g, 7.24 mmol, 1.0 equiv) (CAS: 3209-13-0) in toluene (42 mL) was added 60% sodium hydride in oil (614.0 mg, 15.35 mmol, 2.12 equiv) and the reaction was allowed to stir for 1 h. After this time, iodine (1.86 g, 7.33 mmol, 1.01 equiv) was added and the reaction was allowed to stir for 4 h. The reaction mixture was carefully poured into a mixture of ice-cold water (90 mL) and 1 M HCl (10 mL) and stirred for 10 min. The resulting solution was diluted with water (50 mL) and DCM (50 mL). The separated aqueous layer was further extracted with DCM (2 × 50 mL), and the combined organic layers were dried (NaSO), filtered, and concentrated. The crude reaction mixture was purified by column chromatography on silica gel (40 g, 25-100% DCM:isohexane) to afford the title compound (779.0 mg, 40% yield) as a white crystalline solid. LC-MS m / z 264.9 [M+H] + ,ESI pos.

[0510] Step B: 1-benzyloxy-2-iodo-5-methoxy-3-methyl-benzene

[0511] A suspension of potassium carbonate (833.0 mg, 6.03 mmol, 3.0 equiv) in acetone (30 mL) was sonicated for 5 minutes, then 2-iodo-5-methoxy-3-methyl-phenol (530.0 mg, 2.01 mmol, 1.0 equiv) was added, and the mixture was sonicated for an additional 5 minutes before the addition of benzyl bromide (265.0 uL, 2.23 mmol, 1.11 equiv). The resulting stirred mixture was heated at reflux for 2.5 hours, then cooled to room temperature and concentrated. The residue was dissolved in DCM (50 mL) and washed with 50 v% brine (100 mL). The aqueous layer was re-extracted with DCM (2 x 50 mL), and the combined organic layers were dried (MgSO), filtered, and concentrated. The crude product was purified by column chromatography on silica gel (40 g, 0-50% DCM:isohexane) to give the title compound (628.0 mg, 86% yield) as a colorless oil. LC-MS m / z 355.2 [M+H] +,ESI pos.

[0512] Step C: 2-(2-benzyloxy-4-methoxy-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0513] To a stirred solution of 1-benzyloxy-2-iodo-5-methoxy-3-methyl-benzene (256.0 mg, 0.72 mmol, 1.0 equiv) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (165.0 μL, 0.81 mmol, 1.12 equiv) in THF (5 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 350 μL, 0.88 mmol, 1.21 equiv) and the reaction was stirred for 2 h. Additional n-BuLi (2.5 M in hexanes, 350.0 μL, 0.88 mmol, 1.21 equiv) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (165.0 μL, 0.81 mmol, 1.12 equiv) were added, and the reaction was stirred for 30 minutes. The reaction mixture was warmed to approximately 0°C and quenched with saturated NH4Cl (5 mL), then diluted with water (45 mL) and DCM (50 mL) and separated. The separated aqueous layer was further extracted with DCM (2 × 50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography on silica gel (40 g, 0–20% MTBE:isohexane) to afford the title compound (133 mg, 50% yield) as a colorless oil. LC-MS m / z 355.6[M+H] + ,ESI pos.

[0514] Step D: 5-(2-benzyloxy-4-methoxy-6-methyl-phenyl)-N-[(3R)-1-methyl-3-piperidyl]oxazolo-[4,5-b]pyridin-2-amine

[0515] 2-(2-benzyloxy-4-methoxy-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (67.0 mg, 0.19 mmol, 0.84 equiv.), 5-bromo-N-[(3R)-1-methyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (Example 30, Step H) (70.0 mg, 0.22 mmol, 1.0 equiv.) and potassium carbonate (61.0 mg, 0.44 mmol, 1.96 equiv.) were dispersed in 1,4-dioxane (4 mL) and water (1 mL) (sonicated with nitrogen bubbling for 10 minutes). Xphos Pd G3 (9.0 mg, 0.01 mmol, 0.05 equiv) and XPhos (3.0 mg, 0.01 mmol, 0.03 equiv) were added and the reaction mixture was stirred for 4 h at 90° C. The reaction was cooled to room temperature and additional Xphos Pd G3 (10.0 mg, 0.01 mmol, 0.05 equiv), XPhos (3.0 mg, 0.01 mmol, 0.03 equiv) and potassium carbonate (58.0 mg, 0.42 mmol, 1.87 equiv) were added and the reaction mixture was stirred at 90° C. for 16 h. After the reaction was cooled and degassed, 2-(2-benzyloxy-4-methoxy-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (66.0 mg, 0.19 mmol, 0.83 equiv) in 1,4-dioxane (0.5 mL) was added, followed by Xphos Pd G3 (5.0 mg, 0.01 mmol, 0.03 equiv) and XPhos (2.0 mg, 0.0 mmol, 0.02 equiv) and the reaction was heated at 90° C. for 2 h. The reaction mixture was cooled to room temperature, concentrated, and the crude product was purified by silica gel chromatography (40 g, 0-20% MeOH (0.7 M NH): EtOAc) and then by reverse-phase column chromatography (C18, 43 g, 10-60% acetonitrile (0.1% formic acid): water (0.1% formic acid)) to give the title compound (18.0 mg, 17% yield) as a brown solid. LC-MS m / z 459.4 [M+H] + ,ESI pos.

[0516] Step E: 5-Methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol

[0517] A stirred solution of 5-(2-benzyloxy-4-methoxy-6-methyl-phenyl)-N-[(3R)-1-methyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (17.0 mg, 0.04 mmol, 1.0 equiv) and Pd / C (Type 87) (6.0 mg, 0.0 mmol, 0.08 equiv) in EtOAc (4 mL) was placed under 1 bar of H in a hydrogenation vessel. The reaction was left stirring at room temperature for 32 h. The reaction mixture was diluted with EtOH (1 mL), additional Pd / C (Type 87) (6.0 mg, 0.0 mmol, 0.08 equiv) was added, and the reaction was placed in a hydrogenation vessel under 1 bar of H for an additional 19 h. The reaction mixture was filtered through Celite, the filter cake rinsed with EtOH (50 mL), and concentrated to give the title compound (6.1 mg, 39% yield) as a light brown solid. LC-MS m / z 369.3[M+H] + ,ESI pos.

[0518] Example 35: 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-6-methyl-oxazolo[4,5-b]pyridin-5-yl]-2,3-dihydrobenzofuran-4-ol [ka]

[0519] Step A: 6-Bromo-5-chloro-3H-oxazolo[4,5-b]pyridine-2-thione

[0520] Under an argon atmosphere, 1,1'-thiocarbonyldiimidazole (972.2 mg, 5.46 mmol, 1.15 equiv.) was added to a solution of commercially available 2-amino-5-bromo-6-chloro-pyridin-3-ol (CAS No. 1131041-72-9, 1.06 g, 4.74 mmol, 1.00 equiv.) in N,N-dimethylformamide (13.7 mL). The reaction mixture was stirred overnight at room temperature. Potassium carbonate (1.31 g, 9.49 mmol, 2.00 equiv.) was then added, followed by methyl iodide (343 μL, 5.48 mmol, 1.16 equiv.). The reaction mixture was stirred at room temperature for 2 hours to reach completion. The reaction mixture was cooled to 0°C, approximately 30 mL of water was added dropwise (a precipitate formed), and the mixture was further stirred at 0°C for 30 minutes. The suspension was filtered and rinsed with water to give the desired product (850 mg, 61% yield) as a light brown solid. LC-MS: m / z 280.9 [M+H] + ,ESI pos.

[0521] Step B: 6-Bromo-5-chloro-N-[(3R)-1-ethyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine

[0522] To a solution of the above 6-bromo-5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 850 mg, 2.89 mmol, 1.00 equiv.) in 1,4-dioxane (6.1 mL) was added [(3R)-1-ethyl-3-piperidyl]amine (411.1 mg, 457.8 μL, 3.21 mmol, 1.11 equiv.), followed by triethylamine (327.4 mg, 450.9 μL, 3.24 mmol, 1.12 equiv.). The orange solution was stirred at 90 °C overnight. LC-MS indicated the reaction was complete. The reaction mixture was cooled to room temperature and extracted with approximately 40 mL of ethyl acetate and approximately 5 mL of saturated NaHCO3 solution. The aqueous layer was back-extracted with approximately 40 mL of ethyl acetate. The organic layer was washed with approximately 5 mL of water and approximately 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 25 g, DCM, MeOH 0-20% MeOH) to give the title compound (691 mg, 63% yield) as a light brown solid. LC-MS: m / z 359.1 [M+H] + ,ESI pos. Step C: 5-chloro-N-[(3R)-1-ethyl-3-piperidyl]-6-methyl-oxazolo[4,5-b]pyridin-2-amine

[0523] A solution of the above (6-bromo-5-chloro-N-[(3R)-1-ethyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (698 mg, 1.94 mmol, 1.00 equiv.) in N,N-dimethylformamide (11.7 mL) was treated under argon with commercially available tributyl(methyl)stannane (CAS number 1528-01-4, 769.7 mg, 706.2 μL, 2.52 mmol, 1.30 equiv.), PdCl (P PdCl2(PPh3) (136.2 mg, 0.194 mmol, 0.100 equiv.) was added to the reaction mixture. The reaction was stirred at 100 °C for 1 h. LC-MS showed only starting material, so additional PdCl2(PPh3) (136.0 mg, 0.194 mmol, 0.10 equiv.) was added to the reaction mixture. The mixture was stirred at 100 °C for 4 h until complete. The reaction mixture was filtered through dicalite and washed with DCM. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, DCM / MeOH 0-20% MeOH). The product and the corresponding debrominated product could not be separated. All fractions containing the product were combined and concentrated in vacuo to give (460 mg) as a brown solid. LC-MS: m / z 281.1 [M+H] + ,ESI pos.

[0524] Step D: 5-Bromo-2,3-dihydrobenzofuran-4-ol

[0525] To a solution of coumaran-4-ol (5.0 g, 36.7 mmol, 1.0 equiv) in methanol (100 mL) was added pyridinium tribromide (12.3 g, 38.6 mmol, 1.05 equiv) portionwise at -50°C to -40°C. The reaction mixture was stirred at -50°C to -40°C for 30 minutes, then warmed to room temperature and stirred overnight. The reaction mixture was extracted with DCM and 1 M aqueous HCl. The organic layer was washed with 1 M aqueous HCl and aqueous brine. The aqueous layer was back-extracted three times with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 220 g, gradient 0% to 20% ethyl acetate in heptane) to afford the title compound (4.59 g, 55% yield) as an off-white solid. LC-MS: m / z=214.9 / 216.9 (Br isotope) [M+H] + ,ESI pos. Step E: 4-benzyloxy-5-bromo-2,3-dihydrobenzofuran

[0526] To a solution of 5-bromo-2,3-dihydrobenzofuran-4-ol (4.59 g, 20.26 mmol, 1.0 equiv) in acetonitrile (40 mL) was added potassium carbonate (5.6 g, 40.51 mmol, 2.0 equiv), followed by benzyl bromide (4.89 g, 3.4 mL, 28.57 mmol, 1.4 equiv). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate (140 mL) and water (30 mL). The aqueous layer was back-extracted with ethyl acetate (140 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 220 g, gradient 0% to 10% ethyl acetate in heptane) to give the title compound (6.17 g, 95% yield) as a colorless oil. LC-MS: m / z = 305.1 / 307.0 (Br isotope) [M+H] + ,ESI pos.

[0527] Step F: 2-(4-benzyloxy-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0528] To a solution of 4-benzyloxy-5-bromo-2,3-dihydrobenzofuran (6.16 g, 19.18 mmol, 1.0 equiv.) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.47 g, 6 mL, 29.41 mmol, 1.5 equiv.) in THF (80 mL) was added 1.6 M n-butyllithium in hexanes (19 mL, 30.4 mmol, 1.6 equiv.) dropwise at −76° C. within 40 min. The mixture was stirred at −76° C. for 2.5 h. The reaction mixture was warmed to −60° C., quenched with saturated aqueous NH4Cl (40 mL) at −60° C., warmed to room temperature, and then extracted with ethyl acetate (300 mL) and saturated aqueous NH4Cl (40 mL). The aqueous layer was back-extracted with ethyl acetate (300 mL). The organic layer was washed with brine (80 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 120 g, gradient 0% to 10% ethyl acetate in heptane) to afford the title compound (5.78 g, 81% yield) as a colorless oil. LC-MS: m / z=353.1 [M+H] + ,ESI pos.

[0529] Step G: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol

[0530] A solution of 2-(4-benzoxycoumaran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.77 g, 15.6 mmol, 1.0 equiv.) in ethyl acetate (70 mL) was alternately evacuated and flushed with argon three times. Palladium on activated carbon, 10% Pd basis (577 mg, 0.542 mmol, 0.035 equiv.) was then carefully added. The reaction flask was evacuated, flushed with argon, evacuated, and flushed with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 3 hours. LC / MS indicated that starting material still remained, so methanol (10 mL) was added. The reaction flask was alternately evacuated, flushed with argon, evacuated, and then flushed with hydrogen three times. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 1 hour. The reaction mixture was then filtered and rinsed thoroughly with ethyl acetate / methanol. The filtrate was concentrated in vacuo to give the title compound (4.22 g, 98% yield) as an off-white solid. LC-MS: m / z=263.2 [M+H] + ,ESI pos.

[0531] Step H: 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-6-methyl-oxazolo[4,5-b]pyridin-5-yl]-2,3-dihydrobenzofuran-4-ol

[0532] To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)coumaran-4-ol (106.7 mg, 0.407 mmol, 1.50 equiv.) in 1,4-dioxane (1.85 mL) was added a mixture of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (26.6 mg, 0.033 mmol, 0.120 equiv.), and the corresponding debrominated compound (156.2 mg, 0.271 mmol, 1.00 equiv.) and water (0.923 mL) contaminated with 5-chloro-N-[(3R)-1-ethyl-3-piperidyl]-6-methyl-oxazolo[4,5-b]pyridin-2-amine. The reaction was flushed with argon for 5 minutes, then potassium carbonate (168.8 mg, 1.22 mmol, 4.50 equiv) was added. The reaction was stirred at 100° C. overnight. After complete conversion, the reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back-extracted twice with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane). The product and by-product could not be separated. All fractions containing the product were combined and concentrated in vacuo. The crude material (60 mg) was purified by preparative HPLC (YMC-Triart C). 18 , 12 nm, 5 μm, 100 × 30 mm, ACN / water + 0.1% TEA) to give the title compound (10 mg, 9%) as an off-white solid and the by-product 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]coumaran-4-ol (25 mg, 23% yield) as a gray solid. LC-MS (title compound) m / z 393.2 [M−H] - ,ESI neg.

[0533] Example 36: 5-Cyclopropyl-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol [ka]

[0534] Step A: 3-Cyclopropyl-5-methyl-phenol

[0535] A mixture of 3-bromo-5-methylphenol (5.0 g, 26.73 mmol, 1.0 equiv.), KCO (7.39 g, 53.47 mmol, 2.0 equiv.), and cyclopropylboronic acid (6.89 g, 80.2 mmol, 3.0 equiv.) in 1,4-dioxane (50 mL) and water (10 mL) was evacuated and refilled with N three times, and Pd(dppf)Cl (1956.16 mg, 2.67 mmol, 0.1 equiv.) was added to the mixture. The mixture was stirred at 100 °C for 12 h. The mixture was poured into 1N HCl (200 mL) and then extracted with ethyl acetate (40 mL × 3). The combined organic layers 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 silica gel column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) and C18 column chromatograph (0.1% TFA / MeCN in water). After lyophilization, 3-cyclopropyl-5-methyl-phenol (1.7 g, 43% yield) was obtained as a yellow oil. 1 H NMR(400MHz,CD3OD)δ 6.37(s,2H),6.27(s,1H),2.20(s,3H),1.80-1.72(m,1H),0.91-0.84(m,2H),0.62-0.57(m,2H).

[0536] Step B: 5-Cyclopropyl-2-iodo-3-methyl-phenol

[0537] To a mixture of 3-cyclopropyl-5-methylphenol (1.20 g, 8.1 mmol, 1.0 equiv) in toluene (100 mL) was added NaH (388.66 mg, 16.19 mmol, 60% w / w, 2.0 equiv) under N2 at 0 °C and stirred for 30 min. Then, I2 (1.64 g, 6.48 mmol, 0.8 equiv) was added and stirred at 25 °C for 15.5 h. The mixture was poured into 1 N HCl (100 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium hydroxide, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) and C18 column chromatography (0.1% TFA / MeCN in water). After lyophilization, 2-iodo-3,5-dimethyl-phenol (6.9 g, 34% yield) was obtained as a yellow solid. 1 H NMR(400MHz,CD3OD)δ 6.53(d,1H),6.36(d,1H),2.35(s,3H),1.77(dd,1H),0.94-0.89(m,2H),0.65-0.57(m,2H)

[0538] Step C: 1-benzyloxy-5-cyclopropyl-2-iodo-3-methyl-benzene

[0539] To a solution of 5-cyclopropyl-2-iodo-3-methylphenol (350.0 mg, 1.28 mmol, 1.0 equiv.) in DMF (7 mL), KCO (352.94 mg, 2.55 mmol, 2.0 equiv.) was added portionwise, followed by dropwise addition of benzyl bromide (0.46 mL, 3.83 mmol, 3.0 equiv.), and the reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 2 h. The reaction was quenched with water (50 mL), extracted with EA (100 mL × 3), washed with brine (20 mL), the organic layer was dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO, petroleum ether / ethyl acetate = 20:1) to give 1-benzyloxy-5-cyclopropyl-2-iodo-3-methylbenzene (450 mg) as a colorless oil. 1H NMR(400MHz,CD3OD)δ 7.42(d,2H),7.29(d,2H),7.22(d,1H),6.55(d,1H),6.38(d,1H),5.01(s,2H),2.29 (s,3H),1.78-1.68(m,1H),0.88-0.81(m,2H),0.80-0.74(m,2H),0.58-0.51(m,2H)

[0540] Step D: 2-(2-benzyloxy-4-cyclopropyl-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0541] To a mixture of 1-benzyloxy-5-cyclopropyl-2-iodo-3-methyl-benzene (250.0 mg, 0.69 mmol, 1.0 equiv.) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (229.88 mg, 1.24 mmol, 1.8 equiv.) in THF (3 mL), nBuLi (0.41 mL, 1.03 mmol, 1.5 equiv.) was added dropwise under N2 for 1 h. The mixture was then stirred at -60 °C for 30 min. The mixture was poured into NH4Cl solution (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer 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 silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1) to give 2-(2-benzyloxy-4-cyclopropyl-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250.0 mg) as a colorless oil. 1 H NMR(400MHz,CD3OD)δ 7.47(d,2H),7.38-7.25(m,3H),6.49(d,2H),5.00(s,2H),2.27(s,3H),1.84(dd,1H),1.27(s,12H),0.96-0.84(m,3H),0.68-0.62(m,2H).

[0542] Step E: 5-(2-benzyloxy-4-cyclopropyl-6-methyl-phenyl)-N-[(3R)-1-methyl-3-piperidyl]oxazolo-[4,5-b]pyridin-2-amine

[0543] A mixture of 2-(2-benzyloxy-4-cyclopropyl-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105.36 mg, 0.29 mmol, 2.0 equiv.), KCO (39.97 mg, 0.29 mmol, 2.0 equiv.), and 5-bromo-N-[(3R)-1-methyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (45.0 mg, 0.14 mmol, 1.0 equiv.) in 1,4-dioxane (1 mL) and water (0.2 mL) was degassed and purged with N three times, and Pd(dppf)Cl (10.58 mg, 0.01 mmol, 0.1 equiv.) was added to the mixture. The mixture was stirred at 90 °C for 2 h. The reaction was quenched with water (20 mL), extracted with EA (20 mL x 3), washed with brine (20 mL), the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (30.0 mg, 36% yield) as a yellow oil. LC-MS: m / z 469.3 [M+H] + ,ESI pos.

[0544] Step F: 5-cyclopropyl-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol

[0545] A solution of 5-(2-benzyloxy-4-cyclopropyl-6-methyl-phenyl)-N-[(3R)-1-methyl-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (15.0 mg, 0.03 mmol, 1.0 equiv.) in DCM (0.5 mL) and BBr3 (0.5 mL, 0.6 mmol, 4.39 equiv.) was added to the mixture. The mixture was stirred at -65 °C for 1 h. Ice cubes were first added to the reaction solution, followed by the slow addition of methanol to quench the reaction. Finally, the pH was adjusted using ammonia. The mixture was concentrated under reduced pressure and purified by reverse-phase flash (0.1% TFA) and preparative HPLC (Method: Column 3, Phenomenex Luna C18, 75 x 30 mm x 3 um, Conditions: Water (TFA)-ACN, Start B16, End B36, Gradient Time (min): 8; 100% B, Retention Time (min): 2; Flow Rate (mL / min): 25; Injection 1, HPLC 99). After lyophilization, the title compound was obtained as a yellow solid (2.77 mg, 5% yield). LC-MS: m / z 379.2 [M+H] + ,ESI pos.

[0546] Examples 37a and 37b:

[0547] 2-[2-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol or 2-[2-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol and and 2-[2-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol or 2-[2-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol [ka]

[0548] In a sealed tube, to a yellow suspension of 5-chloro-2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridine (Example 20, Step 1) (70 mg, 237 μmol, 1.00 equiv.) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS no. 2557358-06-0, 107.3 mg, 88.7 μL, 355 μmol, 1.50 equiv.) in 1,4-dioxane (2.4 mL) and water (0.60 mL) was added cesium carbonate (231 mg, 710 μmol, 3.00 equiv.) with stirring at room temperature, followed by XPhos under argon atmosphere. Pd G3 (20.0 mg, 23.7 μmol, 0.10 equiv.) was added. Argon was then bubbled through the yellow reaction mixture for 3 minutes. The dark yellow reaction mixture was heated to 100°C (oil bath) for 16 hours. The black reaction mixture was cooled to room temperature and extracted twice with ethyl acetate (2 x approx. 50 mL). The organic layer was washed with water (approx. 20 mL) and brine (approx. 20 mL). The aqueous layer was re-extracted with ethyl acetate (approx. 40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel; 0% to 10% methanol in dichloromethane) to afford the title compound (86 mg, 76%) as a light brown foam, which was directly subjected to chiral separation (column Chiral IJ, 5 μm, 250 × 20 mm, flow rate: 90 mL / min; SFC). LC-MS: m / z 433.2 [M+H] + ,ESI pos; The first fraction 37a (39 mg, 43% yield) and the second fraction 37b (37 mg, 40% yield) were both obtained as light brown foams. LCMS m / z: 433.2 [M+H] + ,ESI pos.

[0549] Example 38: (rac)-3-Methyl-2-[2-(tetrahydrofuran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol [ka]

[0550] Step A: 5-chloro-N-tetrahydrofuran-3-yl-oxazolo[4,5-b]pyridin-2-amine

[0551] To a solution of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS no. 1783370-92-2, 131 mg, 0.62 mmol, 1.0 equiv.) in 1,4-dioxane was added extra-dry (2 mL), commercially available tetrahydrofuran-3-ylamine (CAS no. 88675-24-5, 64.8 mg, 63.6 μL, 0.744 mmol, 1.20 equiv.), followed by triethylamine (81.6 mg, 112 μL, 0.806 mmol, 1.30 equiv.). The light brown solution was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (30 mL) and saturated NaHCO solution (15 mL). The aqueous layer was back-extracted with ethyl acetate (30 mL). The organic layer was washed with water (10 mL) and brine (10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO; 0-90% ethyl acetate in heptane) to give the title compound (133 mg, 90%) as a white solid. LC-MS: m / z 240.1; 242.1 (Cl isotope) [M+H], ESI pos

[0552] Step B: (rac)-3-methyl-2-[2-(tetrahydrofuran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol

[0553] A mixture of the above (5-chlorooxazolo[4,5-b]pyridin-2-yl)-tetrahydrofuran-3-ylamine (40 mg, 0.167 mmol, 1.00 equiv.), [2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (CAS No. 2557358-06-0, 51.4 mg, 0.234 mmol, 1.40 equiv.), and potassium carbonate (103.8 mg, 0.751 mmol, 4.50 equiv.) was stirred in 1,4-dioxane (2.29 mL) and water (1.14 mL) in a sealable tube. Argon was bubbled through the mixture for 2 minutes, and then the catalyst 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (16.4 mg, 0.02 mmol, 0.12 equiv.) was finally added. The sealed tube was stirred at 90°C for 16 hours. The reaction mixture was extracted with ethyl acetate (2 x 20 mL) and semi-saturated NH4Cl solution (20 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue (112 mg) was purified by preparative RP HPLC (column: YMC-triart C 18 , 12 nm, 5 μm, 100 × 30 mm; CAN / water + 0.1% HCOOH) to give the title compound (5 mg, 8%) as a white amorphous lyophilized solid. LC-MS: m / z 380.2 [M+H] + ,ESI pos.

[0554] Examples 39, 40 and 41:

[0555] 5-Chloro-3-methyl-2-[2-[[rac-(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol, 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol and 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol [ka]

[0556] Step A: 5-chloro-N-[rac-(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]oxazolo[4,5-b]pyridin-2-amine

[0557] To a solution of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 150 mg, 0.710 mmol, 1.00 equiv.) in 1,4-dioxane (1.5 mL), [rac-(8R,8aS)-indolizidin-8-yl]amine (CAS No. 1993250-73-9, 115.9 mg, 0.785 mmol, 1.106 equiv.) was added, followed by triethylamine (111 μL, 0.796 mmol, 1.121 equiv.). The light brown solution was stirred at 90 °C overnight. The reaction mixture was stirred at 100 °C for an additional 4 h. A precipitate formed, which was triturated in ether to give the desired product as a white solid (105 mg, 51%). LC-MS: m / z 293.2 [M+H] + ,ESI pos.

[0558] Step B: 2-[2-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol (rac anti)

[0559] The above 5-chloro-N-[rac-(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]oxazolo[4,5-b]pyridin-2-amine (Step A) (105 mg, 0.359 mmol, 1.00 equiv.), (4-chloro-2-hydroxy-6-methyl- A mixture of (phenyl)boronic acid (CAS number 1207961-50-9, 96.3 mg, 0.516 mmol, 1.440 equiv.), cesium carbonate (172.9 mg, 0.531 mmol, 1.48 equiv.), and Xphos-Pd-G3 (31.3 mg, 0.037 mmol, 0.103 equiv.) was flushed with argon and stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and extracted with approximately 30 mL of ethyl acetate and approximately 5 mL of water. The aqueous layer was back-extracted with approximately 30 mL of ethyl acetate. The organic layer was washed with approximately 5 mL of water and approximately 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient 0% to 10% (methanol + 2% NHOH) in dichloromethane) to give the title compound as a pale yellow powder (34 mg). LC-MS: m / z 397.3 [MH]-, ESI neg.

[0560] Step C: 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol and 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol

[0561] The mixed fraction was purified by RP HPLC (SFC, 20-40% MeOH + 0.2% DEA, Column AD-H) to give two fractions: the first fraction (Example 41) eluted at rt = 3.11 min (11.7 mg, 100% ee), and the second fraction (Example 40) eluted at rt = 3.97 min (13 mg, 100% ee), both as light brown solids. LC-MS: m / z 397.3 [M−H]-, ESI neg.

[0562] Example 42: 5-chloro-3-methyl-2-[2-(6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl)oxazolo[4,5-b]pyridin-5-yl]phenol; [ka]

[0563] Step A: 4-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine

[0564] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 242 mg, 1.21 mmol, 1.00 equiv.) and 6-methyl-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazine (245 mg, 1.57 mmol, 1.30 equiv.) in 1,4-dioxane, extra-dry (4 mL), and N-methyl-2-pyrrolidinone, extra-dry (2 mL) triethylamine (244 mg, 336 μL, 2.41 mmol, 2.00 equiv.) was added at room temperature. The reaction mixture was stirred in a sealed tube at 110 °C for 16 h. Since the reaction was not complete, the temperature was increased to 150 °C, and stirring was continued for 4 h. The reaction mixture was quenched with water (10 mL) and 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 concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0–50% ethyl acetate in heptane). It was then purified with ethyl acetate:methanol 9:1 (v / v) to give the title compound (233 mg, 63%) as a light brown foam. LC-MS: m / z 309.1 ([{35Cl}M+H]+), 311.1 ([{37Cl}M+H]+), ESI pos.

[0565] Step B: 5-chloro-3-methyl-2-[2-(6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl)oxazolo[4,5-b]pyridin-5-yl]phenol

[0566] In a sealable tube, 4-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine (73 mg, 0.236 mmol, 1.00 equiv.), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS no. 120 A mixture of 7961-50-9 (88.1 mg, 0.473 mmol, 2.00 equiv.) and potassium carbonate (147 mg, 1.06 mmol, 4.50 equiv.) was stirred, argon was bubbled through the mixture for 2 minutes, and then catalyst 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (28.9 mg, 0.035 mmol, 0.15 equiv.) was finally added. The sealed tube was stirred at 100 °C for 16 hours. The reaction mixture was extracted with ethyl acetate (2 × 20 mL) and half-saturated NH4Cl solution (20 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue (110 mg) was purified by flash chromatography (silica gel, gradient 0% to 100% in dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)) followed by further purification by preparative HPLC to give the title compound (4 mg, 4%) as a white amorphous lyophilized solid. LC-MS: m / z 413.1 ([{35Cl}MH] + ), 415.1([{37Cl}MH] + ),ESI neg.

[0567] Example 43: 2-[2-(2-azabicyclo[2.1.1]hexan-1-ylmethylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; dihydrochloride [ka]

[0568] Step A: tert-Butyl 1-[[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]methyl]-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0569] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 111 mg, 553.2 μmol, 1.000 equiv.) and triethylamine (112 mg, 154 μL, 1.11 mmol, 2.00 equiv.) in 1,4-dioxane, extra dry (1 mL), and N-methyl-2-pyrrolidinone, extra dry (1 mL), was added tert-butyl 1-(aminomethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (153 mg, 719 μmol, 1.30 equiv.) at room temperature. The reaction mixture was stirred in a sealed tube at 120 °C for 16 h. The temperature was raised to 150 °C, and stirring was continued for 2 h until complete conversion. The reaction mixture was quenched with water (10 mL) and 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 concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-50% ethyl acetate in heptane) to give the title compound (156 mg, 77.29%) as a pale yellow solid. LC-MS: m / z 365.2 ([{35Cl}M+H]+), 367.2 ([{37Cl}M+H]+), ESI pos.

[0570] Step B: tert-butyl 1-[[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]methyl]-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0571] A mixture of the above tert-butyl 1-2.1.1[[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]methyl]-2-azabicyclohexane-2-carboxylate (154 mg, 422 μmol, 1.00 equiv.), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (283.4 mg, 844 μmol, 2.000 equiv.) and potassium carbonate (280 mg, 2.03 mmol, 4.80 equiv.) was dissolved in 1,4-dioxane (4 mL) and water (2 mL). A sealable tube was flushed with argon and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (51.7 mg, 63.3 μmol, 0.15 equiv.) was added. The tube was flushed with argon again and stirred at 100 °C (oil bath) for 16 h. Under argon, methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Pd G3) (71.5 mg, 84.4 μmol, 0.20 equiv.) and cesium carbonate (137.5 mg, 422 μmol, 1.00 equiv.) were added, and stirring was continued at 110 °C (oil bath) for an additional 4 h. The reaction mixture was cooled to room temperature, quenched with water (20 mL) and saturated NH4Cl sol (20 mL), and then extracted with dichloromethane (3 x 30 mL). The organic layer was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2; 0-50% ethyl acetate in heptane) and then triturated in heptane to give the title compound (91 mg, 43%) as a white solid. LC-MS: m / z 505.3 [M+H]+, ESI pos.

[0572] Step C: 2-[2-(2-azabicyclo[2.1.1]hexan-1-ylmethylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; dihydrochloride

[0573] To a solution of tert-butyl 1-[[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]methyl]-2-azabicyclo[2.1.1]hexane-2-carboxylate (89 mg, 176 μmol, 1.00 equiv.) in dichloromethane (4 mL) and methanol (2 mL) was added 4 M HCl in dioxane (441 μL, 1.76 mmol, 10.0 equiv.) dropwise at room temperature. The reaction mixture was stirred at 23 °C for 20 h. The reaction mixture was concentrated in vacuo, fol...

Claims

1. Formula Ic 【Chemical 1】 (In the formula, A １ is -N- or -CR １０ - and A ２ is -O-, -NH-, -NCH ３ - or -S-, R １ is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl, or alkylsulfonyl; R ９ is H, alkyl, halo or cyano; or R １ and R ９ forms a 4-6 membered cycloalkyl or heterocycle containing a single O heteroatom, R ２ is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or hydroxyalkyl; R ３ is H, halo or alkyl, and R ２ and R ３ is not H, R ８ is H or halo, R １０ are selected from H, alkyl, acetyl, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, halo, haloalkyl, alkoxy, haloalkoxy and NR'R'', where R' and R'' are independently selected from H and alkyl, or R' and R'' and the N atom to which they are attached form either a 4-6 membered N-containing heterocycle optionally substituted with -OH, or a 5 membered lactam ring; n may be 0 or 1; R Ｘ is H, alkyl, alkoxyalkyl or hydroxyalkyl, W is A 4- to 10-membered heterocycle containing up to three heteroatoms independently selected from N and O, where the maximum number of O heteroatoms is 1, and includes oxo, —OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, cyano, haloalkyl, alkyl ester, alkylsulfone, cycloalkyl, a heterocycle containing a single O heteroatom, cycloalkyl substituted with —OH, cycloalkyl substituted with —OH-CH ２ a 4- to 10-membered heterocycle optionally substituted by one or two substituents selected from -, a 6-membered heteroaryl substituted with alkoxy, and a 5-membered heteroaryl having two N heteroatoms; a 4-6 membered heterocycle -CH containing up to two heteroatoms independently selected from N and O, where the maximum number of O heteroatoms is 1, optionally substituted with alkyl; ２ -, a 3- to 6-membered cycloalkyl optionally substituted with 1 to 2 substituents independently selected from —OH, alkylamino, and dialkylamino; 4-membered cycloalkyl-CH optionally substituted with 1 or 2 substituents independently selected from —OH and alkyl ２ - and 5-membered heteroaryl containing two N heteroatoms -CH ２ - (selected from and pharmaceutically acceptable salts thereof.

2. A ２ The compound according to claim 1, wherein is —O— or —NH—.

3. A ２ The compound according to claim 1 or 2, wherein is —O—.

4. R １ is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl, or alkylsulfonyl; R ９ is H, alkyl, halo or cyano; or R １ and R ９ 3. The compound of claim 1 or 2, wherein: forms a 5-membered heterocycle containing a single O heteroatom.

5. R １ is halo, alkyl, haloalkyl, or cyano; R ９ is H or or R １ and R ９ 3. The compound of claim 1 or 2, wherein: forms a 5-membered heterocycle containing a single O heteroatom.

6. R １ is halo or cyano, and R ９ 3. The compound of claim 1 or 2, wherein is H.

7. R ２ is alkyl or alkoxyalkyl, and R ３ 3. The compound of claim 1 or 2, wherein is H.

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

9. R １０ is selected from H, alkyl, acetyl, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, alkoxy and NR'R'', and R' and R'' and the N atom to which they are attached form either a 4-5 membered N-containing heterocycle or a 5 membered lactam ring optionally substituted with -OH.

10. R １０ 3. The compound of claim 1 or 2, wherein is selected from H, cyano and alkoxy.

11. R １０ 3. The compound of claim 1 or 2, wherein is H.

12. R Ｘ 3. The compound of claim 1 or 2, wherein is H, alkoxyalkyl, or hydroxyalkyl.

13. R Ｘ 3. The compound of claim 1 or 2, wherein is H.

14. W is, A 4- to 10-membered heterocycle containing up to three heteroatoms independently selected from N and O, where the maximum number of O heteroatoms is 1, and includes oxo, —OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, haloalkyl, 4-membered cycloalkyl, a 4-membered heterocycle containing one O heteroatom, a 4-membered cycloalkyl substituted with —OH, and a 4-membered cycloalkyl-CH substituted with —OH. ２ a 4- to 10-membered heterocycle optionally substituted by one or two substituents selected from a 4-6 membered heterocycle -CH containing up to two heteroatoms independently selected from N and O, where the maximum number of O heteroatoms is 1, optionally substituted with alkyl; ２ -, 3- to 6-membered cycloalkyl optionally substituted with —OH, alkylamino, or dialkylamino; 4-membered cycloalkyl-CH optionally substituted with 1 or 2 substituents independently selected from —OH and alkyl ２ - and 5-membered heteroaryl containing two N heteroatoms -CH ２ - 3. The compound of claim 1 or 2, selected from:

15. W is, a 6- to 9-membered heterocycle containing up to three heteroatoms independently selected from N and O, where the maximum number of O heteroatoms is 1, and optionally substituted with 1 or 2 substituents selected from oxo, —OH, halo, alkyl, and hydroxyalkyl; Alkyl-substituted 6-membered heterocycle containing a single N heteroatom -CH ２ - and 5-membered cycloalkyl substituted with dialkylamino 3. The compound of claim 1 or 2, selected from:

16. 3. The compound of claim 1 or 2, wherein W is a 6-membered heterocycle containing a single N heteroatom, optionally substituted with either alkyl or oxo, or both alkyl and -OH.

17. A １ is -N- or -CR １０ - and A ２ is —O— or —NH—, R １ is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl, or alkylsulfonyl; R ９ is H, alkyl, halo or cyano; or R １ and R ９ forms a 5-membered heterocycle containing a single O heteroatom, R ２ is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or hydroxyalkyl; R ３ is H, halo, or alkyl, and R ２ and R ３ is not H, R ８ is H or halo, R １０ is selected from H, alkyl, acetylalkylamino, dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, alkoxy and NR'R'', and R' and R'' and the N atom to which they are attached form either a 4-5 membered N-containing heterocycle optionally substituted with -OH or a 5 membered lactam ring; n may be 0 or 1; R Ｘ is H, alkoxyalkyl or hydroxyalkyl; W is, 4-10 membered heterocycles containing up to three heteroatoms independently selected from N and O, where the maximum number of O heteroatoms is 1, including oxo, —OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, haloalkyl, 4-membered cycloalkyl, a 4-membered heterocycle containing a single O heteroatom, 4-membered cycloalkyl substituted with —OH, and 4-membered cycloalkyl-CH substituted with —OH. ２ a 4- to 10-membered heterocycle optionally substituted by one or two substituents selected from a 4-6 membered heterocycle -CH containing up to two heteroatoms independently selected from N and O, where the maximum number of O heteroatoms is 1, optionally substituted with alkyl; ２ -, 3- to 6-membered cycloalkyl optionally substituted with —OH, alkylamino, or dialkylamino; 4-membered cycloalkyl-CH optionally substituted with 1 or 2 substituents independently selected from —OH and alkyl ２ - and 5-membered heteroaryl containing two N heteroatoms -CH ２ - 2. The compound of claim 1 selected from:

18. A １ is -N- or -CR １０ - and A ２ is -O-, R １ is halo, alkyl, haloalkyl, or cyano; R ９ is H or or R １ and R ９ forms a 5-membered heterocycle containing a single O heteroatom, R ２ is alkyl or alkoxyalkyl, and R ３ is H, R ８ is H, R １０ is selected from H, cyano and alkoxy; n may be 0 or 1; R Ｘ is H, W is, a 6- to 9-membered heterocycle containing up to three heteroatoms independently selected from N and O, where the maximum number of O heteroatoms is 1, and optionally substituted with 1 or 2 substituents selected from oxo, —OH, halo, alkyl, and hydroxyalkyl; Alkyl-substituted 6-membered heterocycle containing a single N heteroatom -CH ２ - and 5-membered cycloalkyl substituted with dialkylamino 2. The compound of claim 1 selected from:

19. A １ is -N- or -CR １０ - and A ２ is -O-, R １ is halo or cyano; R ９ is H, R ２ is alkyl or alkoxyalkyl, and R ３ is H, R ８ is H, R １０ is H, n may be 0 or 1; R Ｘ is H, 2. The compound of claim 1, wherein W is a 6-membered heterocycle containing a single N heteroatom optionally substituted with either alkyl or oxo, or both alkyl and -OH, and pharmaceutically acceptable salts thereof.

20. (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; (rac)-2-[2-[3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(3R or 3S)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(3S or 3R)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; (rac)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol; (3R or 3S)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol; (3S or 3R)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidin-3-ol; 3-methyl-2-(2-morpholinoxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-[2-[2-(hydroxymethyl)morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-[2-[[3-(methylamino)cyclohexyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-(2-piperazin-1-yl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidin-2-one; (rac)-3-methyl-2-[2-[3-(methylamino)-1-piperidyl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-[2-(tetrahydropyran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]azetidin-3-ol; 2-[2-[(3-hydroxycyclohexyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-(2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-(2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (rac)-2-[2-[(1-ethyl-3-piperidyl)amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R or 3S)-1-ethyl-3-piperidyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3S or 3R)-1-ethyl-3-piperidyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol 2. The compound of claim 1 selected from: and pharmaceutically acceptable salts thereof.

21. 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aS,7aR or 3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methylphenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-benzonitrile; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 4-[2-[(3aS,7aR or 3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-(difluoromethyl)-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5-(trifluoromethyl)phenol; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 5-methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-6-methyl-oxazolo[4,5-b]pyridin-5-yl]-2,3-dihydrobenzofuran-4-ol; 5-cyclopropyl-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol 2. The compound of claim 1 selected from: and pharmaceutically acceptable salts thereof.

22. 2-[2-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol or 2-[2-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol or 2-[2-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-[2-(tetrahydrofuran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 5-chloro-3-methyl-2-[2-[[rac-(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-chloro-3-methyl-2-[2-(6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl)oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-(2-azabicyclo[2.1.1]hexan-1-ylmethylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; dihydrochloride salt; 5-chloro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-fluoro-3-methylphenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-propyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-chloro-2-[2-[[(3R)-1-cyclobutyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-methyl-piperidin-3-ol; 5-fluoro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; (3S,5R)-1-ethyl-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]piperidin-3-ol; 2-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-fluoro-5-(trifluoromethyl)phenol; 5-chloro-2-[2-[[(3R,5S)-1-ethyl-5-fluoro-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 2-[2-[[(1R,2R)-2-(dimethylamino)cyclopropyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methyl-benzonitrile; cis-2-[2-[(3-hydroxy-3-methyl-cyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; trans-2-[2-[(3-hydroxy-3-methyl-cyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-chloro-2-[2-[(1-ethylazetidin-3-yl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 1-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)-2-[[rac-(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-7-yl]pyrrolidin-2-one; 2-[2-[[(3R)-1-(3-hydroxycyclobutyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-(oxetan-3-yl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 3-methyl-2-[2-[rel-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 2-[2-[(4aS,7aS)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; N-(1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl)-5-chloro-oxazolo[4,5-b]pyridin-2-amine; 3-methyl-2-[2-[[(2S)-1-methylazetidin-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol or 3-methyl-2-[2-[[(2R)-1-methylazetidin-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[2-[[(2R)-1-methylazetidin-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol or 3-methyl-2-[2-[[(2S)-1-methylazetidin-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[2-[(1-methylazetidin-2-yl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 5-chloro-2-[2-(1H-imidazol-5-ylmethylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; (3RS,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidin-3-ol; Formic acid; 3,6-dimethyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; (3R,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidin-3-ol; Formic acid; 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or (5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; (5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 5-chloro-2-[2-[[(3R)-1-(3,3-difluoropropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-[(3-hydroxycyclobutyl)methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-chloro-2-[2-(1H-imidazol-2-ylmethylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 2-[2-[3-(hydroxymethyl)-1-piperidyl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[4-(hydroxymethyl)-1-piperidyl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(1-ethyl-1,7-diazaspiro[3.5]nonan-7-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-hydroxy-5-methyl-4-[2-[rac trans-6-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]-oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 3-hydroxy-5-methyl-4-[2-(7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 2-hydroxy-4-methyl-3-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 2,2,2-trifluoroacetic acid; 5-chloro-3-methyl-2-[2-[(1-methyl-3-piperidyl)methyl]oxazolo[4,5-b]pyridin-5-yl]phenol; Methyl 4-[(3R)-3-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-piperidyl]butanoate; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methyl-benzonitrile; Methyl 3-[(3R)-3-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-piperidyl]propanoate; 5-chloro-2-[2-[[6-(hydroxymethyl)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[(4-isopropylmorpholin-2-yl)methyl]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; formic acid; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methylsulfonylphenol; 2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[2-methoxyethyl-[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; formic acid; 2-[2-[[(3R)-1-ethylazepan-3-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-chloro-2-[2-[(3-hydroxycyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-3-(hydroxymethyl)-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-chloro-2-[2-[[(3R)-1-(3-hydroxypropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-3-methyl-2-[2-[[rac-(3R)-1-(2-hydroxypropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-chloro-2-[2-[2-hydroxyethyl-[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-2-[2-[[(3S,4R)-1-ethyl-4-fluoro-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-chloro-2-[2-[[(3R,4S)-1-ethyl-4-fluoro-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; (3S,5R)-5-[[5-[4-chloro-2-hydroxy-6-(methoxymethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]-1-methyl-piperidin-3-ol; 1-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-7-yl]azetidin-3-ol; 1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-7-yl]ethanone; 2,2,2-trifluoroacetic acid; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-(methylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl))phenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[7-(1-hydroxy-1-methyl-ethyl)-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 2-[7-(1-hydroxyethyl)-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-chloro-4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-hydroxy-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(1R,2R)-2-(dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[[(1R,2R)-2-(dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methylphenol; 2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(trifluoromethoxy)phenol; 2,2,2-trifluoroacetic acid; 3-hydroxy-5-methyl-4-[2-[[(2S)-2-hydroxy-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 2,2,2-trifluoroacetic acid; 2-[7-(dimethylamino)-2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl))phenol; 2-[[(3R)-1-ethyl-3-piperidyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-7-carbonitrile; 5-chloro-2-[2-[[(3R)-1-[[rac trans-2-hydroxycyclobutyl]methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol or 5-chloro-2-[2-[[(3R)-1-[[rac cis-2-hydroxycyclobutyl]methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-[[rac trans-2-hydroxycyclobutyl]methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol or 5-chloro-2-[2-[[(3R)-1-[[rac cis-2-hydroxycyclobutyl]methyl]-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-benzonitrile; 3-methyl-2-[2-[(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl))phenol; 5-(difluoromethyl)-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-(difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 2,2,2-trifluoroacetic acid; 5-(difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3,5-dimethylphenol; 3-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidin-4-ol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-fluoro-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 5-chloro-2-[6-chloro-2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 3,5-dimethyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 2,2,2-trifluoroacetic acid; 3-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-fluorophenol; 2,2,2-trifluoroacetic acid; 5-(difluoromethoxy)-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 2,2,2-trifluoroacetic acid; 2-[2-[(1-ethylpyrrolidin-3-yl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3,5-dichloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 2,2,2-trifluoroacetic acid; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-6-fluoro-1H-imidazo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidin-3-ol; 3-methyl-2-[2-[4-(methylamino)tetrahydropyran-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-3H-imidazo[4,5-b]pyridin-5-yl]-3-methylphenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethoxy)phenol; 2,2,2-trifluoroacetic acid; 2-[2-(1-ethyl-3-piperidyl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile 2. The compound of claim 1 selected from: and pharmaceutically acceptable salts thereof.

23. (rac)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidin-2-one; 2-[2-[[(3R or 3S)-1-ethyl-3-piperidyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-benzonitrile; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 5-methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-6-methyl-oxazolo[4,5-b]pyridin-5-yl]-2,3-dihydrobenzofuran-4-ol 2. The compound of claim 1 selected from: and pharmaceutically acceptable salts thereof.

24. (rac)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidin-2-one; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-benzonitrile; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxymethyl)phenol; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-Methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol 2. The compound of claim 1 selected from: and pharmaceutically acceptable salts thereof.

25. 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 3-hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(1-ethyl-3-piperidyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoromethyl)phenol 2. The compound of claim 1 selected from: and pharmaceutically acceptable salts thereof.

26. 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile 2. The compound of claim 1 selected from: and pharmaceutically acceptable salts thereof.

27. 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; (3S,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-methyl-piperidin-3-ol; 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methyl-benzonitrile; 3-methyl-2-[2-[rel-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; (3R,5R)-5-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidin-3-ol; Formic acid; 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; (5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 5-chloro-3-methyl-2-[2-[(1-methyl-3-piperidyl)methyl]oxazolo[4,5-b]pyridin-5-yl]phenol; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methyl-benzonitrile; 5-chloro-2-[2-[[(3S,4R)-1-ethyl-4-fluoro-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; (3S,5R)-5-[[5-[4-chloro-2-hydroxy-6-(methoxymethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]-1-methyl-piperidin-3-ol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 4-[2-[[(1R,2R)-2-(dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 2-[[(3R)-1-ethyl-3-piperidyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-7-carbonitrile; 5-(difluoromethyl)-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-(difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3,5-dimethylphenol; 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile 2. The compound of claim 1 selected from: and pharmaceutically acceptable salts thereof.

28. 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; (5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 2. The compound of claim 1 selected from: and pharmaceutically acceptable salts thereof.

29. 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; formate salt; (5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid 2. The compound of claim 1 selected from: and pharmaceutically acceptable salts thereof.

30. The compound of formula X can be prepared according to the following scheme: 【Chemistry 2】 (In the formula, R １ , R ２ , R ３ , R ８ , R ９ , R Ｘ , n and W are as defined above, and A １ is N and A ２ is O) 3. A method for preparing a compound of claim 1 or 2, comprising reacting a compound of formula Ic according to

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

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

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

34. 34. A pharmaceutical composition according to claim 33 for use in the treatment or prevention of a disease, disorder or condition.

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

36. 34. A pharmaceutical composition according to claim 33 for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

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

Images