NLRP3 inhibitors

Abstract

The present invention relates to General Formula I TIFF2026514037000054.tif37161 A novel compound having, in the formula, R 1 , R 2 , R 3 A and W are as described herein, relating to compounds, compositions containing the compounds, and methods of using the compounds.

Description

Technical Field

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

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

Chemical formula

Chemical formula

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

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

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

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

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

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

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

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

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

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

[0013] There is a need to provide compounds with improved pharmacological and / or physiological and / or physicochemical properties, and / or compounds that provide useful substitutes for known compounds. [Overview of the project]

[0014] This invention relates to formula I [ka] A novel compound of which, in the formula, R 1 is H, alkyl, hydroxyalkyl, or alkoxyalkyl, R 2 These are halo, haloalkyl, or cyano, R 3 Is it H? or R 2 and R 3 , and the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom optionally substituted with one or two substituents independently selected from halo and alkyl, or R 2 and R 3 , and the atoms to which they are bonded form a 3- to 6-membered cycloalkyl ring optionally substituted with one or two substituents independently selected from halo and alkyl, A is either CH or N, W is as follows: [ka] p is either 1 or 2. q is either 1 or 2. m is either 0 or 1. Y1 is C=O, CH, CH2, CR x , N, or NH Y2 is C=O, CH, CR y , O, N, NH, or N-CH3, Y3 is C=O, CH, CH2, CR y , N, NH, or NR z and Y4 is C=O, CH, CR y , N, NH or N-CH3 R x H is H, and each R y is independently selected from -OH, alkyl, alkoxy, cyano and halo, or R x +R y They form a heterocycle through the atoms to which they are bonded. R z is H, alkyl, or hydroxyalkyl. The present invention provides compounds and pharmaceutically acceptable salts thereof.

[0015] The term "alkyl" refers to a monovalent linear or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. In some embodiments, unless otherwise stated, alkyl refers to a monovalent linear or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms (C 1-6 -alkyl) or 1 to 4 carbon atoms (C 1-4 -Contains alkyl) C 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl. A specific alkyl group is methyl.

[0016] The term "alkoxy" is derived from the fact that R' is C 1-6 - Represents an alkyl group, the group of formula -O-R'. C 1-6Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A specific alkoxy group is methoxy.

[0017] The term "alkoxyalkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl group is replaced by an alkoxy group. Examples of alkoxyalkyls are methoxymethyl and methoxyethyl.

[0018] The term "cycloalkyl" refers to monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbons. In some embodiments, unless otherwise stated, cycloalkyls contain 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, cycloalkyls are saturated monocyclic or polycyclic hydrocarbons. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0019] The terms “halogen,” “halide,” and “halo” are used interchangeably herein and refer to fluoro, chloro, bromo, or iodine. Specific examples of halos are fluoro and chloro.

[0020] The term "haloalkyl" is C 1-6 - At least one hydrogen atom of the alkyl group is replaced by the same or a different halogen atom C 1-6 - Represents an alkyl group. Examples of haloalkyls include fluoromethyl, difluoromethyl, and trifluoromethyl. Specific examples of haloalkyls include trifluoromethyl and difluoromethyl.

[0021] The term "heterocyclic" refers to a monocyclic or bicyclic ring system of 4 to 9 ring atoms, which contains 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocyclic rings include azetidinyl, diazepanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and piperazinyl. Examples of polycyclic saturated heterocyclic rings include azaspiroheptanyl, diazaspiroheptanyl, azaspirooctanyl, diazospirooctanyl, diazaspirononanyl, oxazaspirooctanyl, and oxadiazaspirononanyl.

[0022] The term "hydroxy" refers to the -OH group.

[0023] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a hydroxyl group. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylethyl, hydroxymethylpropyl, and dihydroxypropyl. Specific examples of hydroxyalkyl groups include hydroxymethyl and hydroxyethyl.

[0024] The term "cyano" represents a -C≡N group.

[0025] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid and is not biologically or otherwise undesirable. Salts are formed from inorganic acids, such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic base or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, and magnesium. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins. Compounds of formula I can also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of compounds of formula I are salts formed with formic acid, and salts formed with hydrochloric acid that yield hydrochloride, dihydrochloride, or trihydrochloride.

[0026] The abbreviation uM stands for micromoles and is equivalent to the symbol μM.

[0027] The abbreviation uL stands for microliter and is equivalent to the symbol μL.

[0028] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0029] Compounds of formula I may contain several chiral centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers, or mixtures of racemates of diastereoisomers.

[0030] According to the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can have either an "R" or "S" stereoconfiguration. [Modes for carrying out the invention]

[0031] Furthermore, one embodiment of the present invention provides a compound according to formula I described herein and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula I described herein and a pharmaceutically acceptable salt thereof, and more specifically a compound according to formula I described herein.

[0032] One embodiment of the present invention is R 1 This specification provides compounds according to formula I, wherein is alkyl or hydroxyalkyl.

[0033] One embodiment of the present invention is R 1 This specification provides compounds according to formula I, wherein the alkyl group is present.

[0034] One embodiment of the present invention provides a compound according to formula I described herein, wherein n is 1.

[0035] One embodiment of the present invention provides a compound according to formula I described herein, wherein q is 1.

[0036] One embodiment of the present invention provides a compound according to formula I described herein, wherein m is 1.

[0037] One embodiment of the present invention is in which Y1 is CH, CR x The present specification provides compounds according to formula I, wherein the compound is N or NH.

[0038] One embodiment of the present invention provides a compound according to formula I described herein, wherein Y1 is CH, N, or NH.

[0039] One embodiment of the present invention provides a compound according to formula I described herein, wherein Y1 is CH.

[0040] One embodiment of the present invention is in which Y2 is C=O, CH, CR y The present specification provides compounds according to formula I, wherein the compound is N or NH.

[0041] One embodiment of the present invention provides a compound according to formula I described herein, wherein Y2 is C=O or N.

[0042] One embodiment of the present invention is in which Y3 is C=O, CH, CR y , N, NH or NR z This specification provides a compound according to formula I described herein.

[0043] One embodiment of the present invention is one in which Y3 is CH, N, NH or NR z This specification provides a compound according to formula I described herein.

[0044] One embodiment of the present invention is one in which Y3 is CH, NH, or NR z This specification provides a compound according to formula I described herein.

[0045] One embodiment of the present invention is in which Y4 is C=O, CH, CR y , N, NH or N-CH3, R x H is and each R y is independently selected from OH, alkyl, alkoxy, cyano and halo, or R x +R y The present specification provides compounds according to formula I, wherein, via the atoms to which they are bonded, they form a heterocycle containing one or two oxygen heteroatoms.

[0046] One embodiment of the present invention is each R yThe present invention provides compounds according to Formula I, which are independently selected from OH, alkyl, alkoxy, cyano, and halo.

[0047] One embodiment of the present invention is each R y This specification provides compounds according to formula I, wherein the alkyl group is present.

[0048] One embodiment of the present invention is each R z This specification provides compounds according to formula I, wherein is H, alkyl, or hydroxyalkyl.

[0049] One embodiment of the present invention is each R z This specification provides compounds according to formula I, wherein is a hydroxyalkyl group.

[0050] One embodiment of the present invention is a compound according to formula I described herein, wherein, R 1 is alkyl or hydroxyalkyl, R 2 These are halo, haloalkyl, or cyano, R 3 H is, A is either CH or N, p is either 1 or 2. q is either 1 or 2. m is either 0 or 1. Y1 is CH, CR x , N, or NH, Y2 is C=O, CH, CR y , N, or NH, Y3 is C=O, CH, CR y , N, NH or NR z And, Y4 is C=O, CH, CR y , N, NH, or N-CH3, R x H is H, and each R y is independently selected from OH, alkyl, alkoxy, cyano and halo, or R x +Ry These atoms form a heterocycle containing one or two oxygen heteroatoms through the atoms to which they are bonded. R z is H, alkyl, or hydroxyalkyl. The present invention provides compounds and pharmaceutically acceptable salts thereof.

[0051] One embodiment of the present invention is a compound according to formula I described herein, wherein, R 1 It is an alkyl, R 2 These are halo, haloalkyl, or cyano, R 3 H is, A is either CH or N, p is either 1 or 2. q is 1, m is either 0 or 1. Y1 is CH, N, or NH. Y2 is C=O, CH, CR y , N, or NH, Y3 is CH, N, NH, or NR z And, Y4 is CH or N, In the formula, each R y It is an alkyl, R z is H, alkyl, or hydroxyalkyl. The present invention provides compounds and pharmaceutically acceptable salts thereof.

[0052] One embodiment of the present invention is a compound according to formula I described herein, wherein, R 1 It is an alkyl, R 2 These are halo, haloalkyl, or cyano, R 3 H is, A is either CH or N, p is either 1 or 2. q is 1, m is 0 or 1, Y1 is CH, N, or NH, Y2 is C=O, CH, C-R y , N, or NH, Y3 is CH, N, NH or NR z and Y4 is CH or N, wherein each R y is alkyl, R z is hydroxyalkyl. There are provided compounds and their pharmaceutically acceptable salts.

[0053] One embodiment of the present invention is a compound according to formula I described herein, wherein R 1 is alkyl, R 2 is halo, haloalkyl, or cyano, R 3 is H, A is CH or N, p is 1, q is 1, m is 1, Y1 is CH, Y2 is C=O or N, Y3 is CH, NH or NR z and Y4 is CH, R z is hydroxyalkyl. There are provided compounds and their pharmaceutically acceptable salts.

[0054] Specific examples of the compounds of formula I described herein are selected from the following: 2-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridin-6-one; 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5-methyl-1,3-dihydropyrrololo[3,4-c]pyridine-6-one; 3-Hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-one; 5-Chloro-2-(2-isoindoline-2-yloxazolo[4,5-b]pyridine-5-yl)-3-methylphenol; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]isoindorin-5-ol; 5-Chloro-2-[2-(4-fluoroisoindoline-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 4-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-Chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 2-[2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; formic acid; 5-Chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 3-Hydroxy-4-(2-isoindoline-2-yloxazolo[4,5-b]pyridine-5-yl)-5-methylbenzonitrile; 4-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 7-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-2,5,6,8-tetrahydro-2,7-naphthyridine-3-one; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-1H-pyrrolo[3,4-b]pyridine-2-one; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1-methyl-5,7-dihydropyrrololo[3,4-b]pyridine-2-one; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-2-methyl-5,7-dihydropyrrolo[3,4-c]pyridazine-3-one; 2-[2-(5,7-dihydropyrrolo[3,4-b]pyrazine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 5-(difluoromethyl)-2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 7-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-2,5,6,8-tetrahydro-2,7-naphthyridine-3-one; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; formic acid; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-(hydroxymethyl)phenol: 5-Chloro-2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol: 5-Chloro-2-[2-(2-methoxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol: 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-3,4-dihydro-1H-isoquinoline-5-carbonitrile; 5-Chloro-2-[2-(5-methoxy-3,4-dihydro-1H-isoquinoline-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(7-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-1,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-one: 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-1,5,7,8-tetrahydro-1,6-naphthyridine-2-one; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-2H-pyrrolo[3,4-c]pyridazine-3-one; 5-Chloro-2-[2-(7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-one; 5-Chloro-2-(2-(6,8-dihydro-7H-[1,3]dioxolo[4,5-e]isoindole-7-yl)oxazolo[4,5-b]pyridine-5-yl)-3-methylphenol, and its pharmaceutically acceptable salts.

[0055] Other specific examples of compounds of formula I described herein are selected from the following: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-ol; 2,2,2-trifluoroacetic acid; 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-ol; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-1H-pyrrolo[3,4-d]pyrimidine-2,4-dione; and its pharmaceutically acceptable salts.

[0056] Preferred examples of compounds of formula I described herein are selected from the following: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5-methyl-1,3-dihydropyrrololo[3,4-c]pyridine-6-one; 3-Hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-one; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; formic acid; 5-Chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; formic acid; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-1,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-one; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-2H-pyrrolo[3,4-c]pyridazine-3-one; and its pharmaceutically acceptable salts.

[0057] More preferred examples of compounds of Formula 1 described herein are selected from the following: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 3-Hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-one; 5-Chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; formic acid; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-1,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-one; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-2H-pyrrolo[3,4-c]pyridazine-3-one; and its pharmaceutically acceptable salts.

[0058] The most preferred examples of compounds of Formula 1 described herein are selected from the following: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 3-Hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-one; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; formic acid; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; and its pharmaceutically acceptable salts.

[0059] Another embodiment of the present invention provides a pharmaceutical composition or pharmaceutically acceptable

[0060] The composition is formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical symptoms, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the healthcare professional.

[0061] The compounds of the present invention may be administered by any suitable means, including orally, topically (including buccal and sublingual), rectally, vaginally, percutaneously, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, intrathecally and epidurally, as well as intranasally, and, if desired for topical treatment, intrafocal administration. Parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0062] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components that are conventional in pharmaceutical preparations, such as diluents, carriers, pH modifiers, sweeteners, fillers, and further activators.

[0063] Typical formulations are prepared by mixing the compound of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C., Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow enhancers, processing aids, colorants, sweeteners, flavorings, diluents, and other known additives for providing a drug (i.e., the compound of the present invention or its pharmaceutical composition) in an appealing manner or for assisting in the manufacture of a pharmaceutical product (i.e., a pharmaceutical).

[0064] Compounds of formula I and pharmaceutically acceptable salts thereof can be treated with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injectable solutions or topical formulations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules, for example.

[0065] Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0066] Suitable adjuvants for the production of liquid and syrup formulations include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0067] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerol, and vegetable oil.

[0068] Suitable adjuvants for suppositories include, for example, natural or hydrogenated oils, waxes, fats, and semi-solid or liquid polyols.

[0069] Suitable adjuvants for topical ophthalmic formulations include, for example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0070] Furthermore, pharmaceutical preparations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other substances of therapeutic value.

[0071] Dosages can vary widely and, naturally, are adapted to the individual requirements of each specific case. Generally, for oral administration, a daily dose of approximately 0.1 mg to 20 mg per kg of body weight, preferably approximately 0.5 mg to 4 mg per kg of body weight (e.g., approximately 300 mg per person), is preferably divided into 1 to 3 individual doses, which, if appropriate, may consist of equal amounts, for example. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be 0.1 to 25 mg, can be administered by a single dose per day or per week, or by multiple doses per day (2 to 4 times), or by multiple doses per week, however, where indicated, it will be clear that the upper or lower limits given herein may be exceeded.

[0072] One embodiment of the present invention is a compound according to formula I described herein, for use as a therapeutically active substance.

[0073] One embodiment of the present invention is a compound according to Formula I described herein, for use in the treatment or prevention of a disease, disorder, or condition, wherein the disease, disorder, or condition is responsive to NLRP3 inhibition.

[0074] One embodiment of the present invention is a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

[0075] As used herein, the term "NLRP3 inhibition" refers to a complete or partial reduction of the activity level of NLRP3, including, for example, inhibition of active NLRP3 and / or inhibition of NLRP3 activation.

[0076] There is evidence regarding the roles of IL-1 and IL-18 in NLRP3-induced inflammatory responses in conjunction with numerous other disorders (Menu et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

[0077] 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 germline or somatic non-silent mutations in NLRP3

[0078] 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 diseases, and (vii) Skin diseases.

[0079] In a further typical embodiment of the present invention, the disease, disorder, or condition is inflammation. Examples of inflammation that can be treated or prevented include inflammatory responses related to or resulting from the following: (i) Skin conditions such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (ii) Joint conditions such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, or Reiter's disease); (iii) Muscle symptoms such as polymyositis or myasthenia gravis; (iv) Gastrointestinal 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 outside the gut (e.g., migraine, rhinitis, or eczema); (v) Respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (eosinophilic, bronchial, allergic, endogenous, exogenous, or dust-induced asthma, especially chronic or refractory asthma, e.g., late-stage asthma and airway hyperresponsiveness), bronchitis, rhinitis (acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, zaprotic rhinitis, hypertrophic rhinitis, panlenta rhinitis, xerotic rhinitis, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis, e.g., hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, ash-induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (vi) Vascular conditions such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (vii) Autoimmune conditions such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type 1 diabetes, idiopathic thrombocytopenic purpura, or Graves' disease; (viii) Eye symptoms such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (ix) Neurological symptoms such as multiple sclerosis or encephalomyelitis; (x) Infections or infection-related conditions such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial 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 co-infection with mycobacterium tuberculosis and HIV), mycobacterium avium intracellulare, pneumocystis carinii pneumonia, orchitis / epidydimitis, 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-associated glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritis syndrome, renal fibrosis including chronic crystalline nephropathy, or renal hypertension; (xii) Lymphatic symptoms such as Castleman disease; (xiii) Immune system symptoms such as hyper-IgE syndrome, leprotic leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease, or symptoms related thereto; (xiv) Liver conditions such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, hepatic fibrosis, or liver failure; (xv) Cancers including the cancers listed above; (xvi) burns, wounds, injuries, bleeding, or stroke; (xvii) radiation exposure; (xviii) metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or (xix) Pain such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.

[0080] One embodiment of the present invention is a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or condition selected from the following: inflammation; autoimmune diseases; cancer; infectious diseases; Central nervous system disorders; metabolic diseases; cardiovascular disease; respiratory diseases; Liver disease; kidney disease; eye diseases; skin diseases; Lymphatic symptoms; Psychological disorders; Graft-versus-host disease; Allodynia; Symptoms related to diabetes, and Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0081] One embodiment of the present invention is the use of a compound according to Formula I described herein in the treatment or prevention of a disease, disorder, or condition, wherein the disease, disorder, or condition is responsive to NLRP3 inhibition.

[0082] One embodiment of the present invention is the use of a compound according to Formula I described herein in the treatment or prevention of a disease, disorder, or condition selected from Alzheimer's disease and Parkinson's disease.

[0083] One embodiment of the present invention is the use of a compound according to Formula I described herein in the treatment or prevention of a disease, disorder, or condition selected from multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

[0084] One embodiment of the present invention is the use of a compound according to Formula I described herein for use in the treatment or prevention of a disease, disorder, or condition selected from asthma and COPD.

[0085] One embodiment of the present invention is the use of a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or condition selected from cryopyrin-associated periodic syndromes.

[0086] One embodiment of the present invention is a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or condition selected from Alzheimer's disease and Parkinson's disease.

[0087] One embodiment of the present invention is a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or condition selected from multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

[0088] One embodiment of the present invention is a compound according to Formula I described herein for the treatment or prevention of a disease, disorder, or condition selected from asthma and COPD.

[0089] One embodiment of the present invention is a compound according to Formula I described herein for treating or preventing a disease, disorder, or condition selected from cryopyrin-associated periodic syndromes.

[0090] One embodiment of the present invention is the use of a compound according to Formula I described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder, or condition selected from Alzheimer's disease and Parkinson's disease.

[0091] One embodiment of the present invention is the use of a compound according to Formula I described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder, or condition selected from multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

[0092] One embodiment of the present invention is the use of a compound according to Formula I described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder, or condition selected from asthma and COPD.

[0093] One embodiment of the present invention is the use of a compound according to Formula I described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder, or condition selected from cryopyrin-associated periodic syndromes.

[0094] One embodiment of the present invention is a method for treating or preventing 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.

[0095] One embodiment of the present invention is a method for treating or preventing a disease, disorder, or condition selected from multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), the method comprising administering an effective amount of a compound according to Formula I described herein.

[0096] One embodiment of the present invention is a method for treating or preventing a disease, disorder, or condition selected from asthma and COPD, the method comprising administering an effective amount of a compound according to Formula I described herein.

[0097] One embodiment of the present invention is a method for treating or preventing a disease, disorder, or condition selected from cryopyrin-associated periodic syndromes, comprising administering an effective amount of a compound of formula I described herein.

[0098] One embodiment of the present invention relates to a method for inhibiting NLRP3, comprising administering an effective amount of a compound according to formula I described herein.

[0099] Furthermore, one embodiment of the present invention is a compound of formula I described herein, when manufactured according to any one of the processes described.

[0100] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to Formula I described herein and a therapeutically inert carrier.

[0101] Assay procedure NLRP3 and pyroptosis It is well established that NLRP3 activation leads to cellular pyroptosis, and that this characteristic plays a crucial role in the manifestation of clinical diseases (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, inhibitors of NLRP3 are expected to block pyroptosis and the release of pro-inflammatory cytokines (e.g., IL-1β) from cells.

[0102] THP-1 cells: culture and preparation THP-1 cells (ATCC number TIB-202) were grown in RPMI containing L-glutamine (Gibco number 11835) supplemented with 1 mM sodium pyruvate (Sigma number S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma number P4333) in 10% fetal bovine serum (FBS) (Sigma number F0804). The cells were periodically passaged until confluence (approximately 10) 6Cells were grown to a concentration of 625,000 cells / ml. On the day of the experiment, THP-1 cells were harvested and resuspended in RPMI medium (without FBS). The cells were then counted, and viability (>90%) was confirmed by trypan blue (Sigma#T8154). Appropriate dilution was performed to obtain a concentration of 625,000 cells / ml. LPS (Sigma#L4524) was added to this diluted cell solution to obtain a final assay concentration (FAC) of 1 μg / ml. 40 μl of the final preparation was dispensed into each well of a 96-well plate. The plates prepared in this way were used for compound screening.

[0103] THP-1 cell pyroptosis assay For compound screening, we followed the stepwise assay method described below. THP-1 cells (25,000 cells / well) containing 1.0 μg / ml LPS are seeded into 40 μl of RPMI medium (without FBS) in a 96-well black-walled, transparent-bottom cell culture plate (VWR#734-0317) coated with poly-D-lysine. Add 5 μl of the compound (8-point semi-logarithmic dilution using the highest dose of 10 μM) or the vehicle (DMSO 0.1% FAC) to the appropriate well. Incubate at 37°C and 5% CO2 for 3 hours. Add 5 μl of nigericin (Sigma number N7143) (FAC 5 μM) to all wells. Incubate at 37°C and 5% CO2 for 1 hour. At the end of the incubation period, rotate the plate at 300 x g for 3 minutes and remove the supernatant. Next, add 50 μl of resazurin (Sigma number R7017) (resazurin with 100 μM FAC in RPMI medium without FBS), and incubate the plate at 37°C and 5% CO2 for a further 1-2 hours. The plate was read with an Envision reader at Ex 560nm and Em 590nm. I C 50 Fitting the data to a nonlinear regression equation (log-inhibitor versus response variable gradient, 4 parameters) The results of the pyroptosis assay were obtained from THP IC. 50 This is summarized in Table 1 below.

[0104] Human whole blood IL-1β release assay For systemic delivery, the ability of a compound to inhibit NLRP3 when present in the bloodstream is crucial. Therefore, the NLRP3 inhibitory activity of numerous compounds in human whole blood was investigated according to the following protocol.

[0105] Human whole blood in Li-heparin tubules was obtained from healthy donors selected from a volunteer donor panel.

[0106] Plate out 80 μl of whole blood containing 1 μg / ml of LPS into a 96-well clear-bottom cell culture plate (Corning #3585). Add 10 μl of the compound (8-point semi-logarithmic dilution using the highest dose of 10 μM) or the vehicle (DMSO 0.1% FAC) to the appropriate wells. Incubate at 37°C and 5% CO2 for 3 hours. Add 10 μl of nigericin (Sigma number N7143) (10 μM FAC) to all wells. Incubate at 37°C and 5% CO2 for 1 hour. At the end of the incubation period, rotate the plate at 300×g for 5 minutes to pellet the cells, remove 20 μl of supernatant, and add it to a 96-well v-bottom plate for IL-1β analysis. (Note: These plates, including the supernatant, can be stored at -80°C for analysis on a later date.) IL-1β was measured according to the manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000). I C 50 Fitting the data to a nonlinear regression equation (log-inhibitor versus response variable gradient, 4 parameters) Human whole blood assay results HWB IC 50 This is summarized in Table 1 below.

[0107] Microsomal stability: Microsomes (0.5 mg / mL) and 1 μM of the test compound in cofactor NADPH were incubated in a 96-well plate at 37°C using a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system. After a 10-minute pre-incubation step with the microsomes and test compound, the enzymatic reaction was initiated by adding the cofactor. Aliquots of the incubation were taken at 1, 3, 6, 9, 15, 25, 35, and 45 minutes and quenched with 1:3 (v / v) acetonitrile containing an internal standard. The samples were then cooled, centrifuged, and the supernatant was analyzed by LC-MS / MS2.

[0108] Metabolic stability in hepatocytes: Assay description: Biological materials. Obtain cryopreserved hepatocytes [mouse, rat, rabbit, monkey, and human (mixed sexes)]. The viability of reconstituted hepatocytes should be at least 80% throughout the entire experiment. Obtain ready-to-use rat / human HepatoPac® culture medium [long-term hepatocyte co-culture medium; pool (human male n=5, and female n=5)], stromal mouse fibroblasts (negative control; pool), incubation plates, application medium, and maintenance medium.

[0109] Metabolism by suspended hepatocytes. First, pooled cryopreserved hepatocytes were reconstituted in pre-warmed William's E medium containing 10% FCS, 0.05 mg / mL streptomycin and 50 U / mL penicillin, 0.4 mM L-glutamine, as well as 0.01 mg / mL gentamicin, 0.048 mg / mL hydrocortisone, and 0.004 mg / mL insulin, to a final suspension density of 1 × 10⁶ cells / mL. Incubation was performed fully automated using a Liquid Handling System (Tecan) equipped with a CO₂ incubator with an orbital shaker. After adding, for example, 1 μM of the test compound to each well (1 × 10⁵ cells / well), the 96-well hepatocyte suspension culture plate was incubated at 5% CO₂, 37°C. The sample was quenched at specified time points up to 2 hours by adding acetonitrile (containing the internal standard) to the incubation wells.

[0110] Metabolism by HepatoPac®. The test substance used in the suspension assay (e.g., 1 μM, 0.1% v / v DMSO) is incubated in a 96-well plate containing either adherent hepatocytes and mouse fibroblast control cells, or control cells alone (5% CO2 atmosphere, 37°C). The incubation medium for human HepatoPac® is the same as that used in the suspended hepatocytes. At predetermined time points (2, 18, 26, 48, 72, and 96 hours), all wells are quenched with ice-cold acetonitrile containing an internal standard.

[0111] Subsequently, the sample is properly centrifuged, and the supernatant is analyzed by LC-MS / MS. Incubation is performed with n=1 or n=2. [Table 1]

[0112] Herein, the present invention is illustrated by the following embodiments, which do not have limiting features.

[0113] If the preparation is obtained as a mixture of enantiomers or diastereoisomers, the pure enantiomers or diastereoisomers can be obtained by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography or crystallization.

[0114] Experimental method [Table 2] [Examples]

[0115] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen atmosphere.

[0116] Preparation of intermediates Intermediate 1: 5-(4-chloro-2-hydroxy-6-methylphenyl)-3H-oxazolo[4,5-b]pyridine-2-thione [ka]

[0117] Process A: 2-amino-6-(4-chloro-2-hydroxy-6-methylphenyl)pyridine-3-ol (4-Chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS No. 1207961-50-9, 1972.4 mg, 10.6 mmol, 1.0 equivalent), XPhos Pd G3 (269.02 mg, 0.32 mmol, 0.03 equivalent), saturated aqueous NaHCO3 (5 mL) and 2-amino-6-bromopyridin-3-ol (CAS No. 934758-27-7, 2000.0 mg, 10.6 mmol, 1.0 equivalent) were suspended in dioxane (40 mL) and degassed with N2 (for 5 minutes). The reaction mixture was heated to 80 °C and stirred for 18 hours. The reaction mixture was filtered through a Celite plug and then dry loaded onto silica and purified by flash chromatography on silica gel (80 g column, 0-10% MeOH / DCM) to give the title compound (1001 mg, yield 37%) as a light brown solid. LCMS m / z 251.1 [M+H] + ESI pos.

[0118] Step B: 5-(4-Chloro-2-hydroxy-6-methyl-phenyl)-3H-oxazolo[4,5-b]pyridine-2-thione 1,1'-Thiocarbonyldiimidazole (938.4 mg, 5.27 mmol, 1.2 equivalents) was added to a stirred solution of 2-amino-6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridin-3-ol (1100.0 mg, 4.39 mmol, 1.0 equivalent) in DMF (20 mL) at room temperature and the reaction mixture was stirred for 18 hours. The mixture was poured into 1N HCl (100 mL) aqueous solution. The mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with 10 wt% aqueous LiCl (3 × 50 mL), dried (phase separator) and concentrated in vacuo to give the title compound (1102.0 mg, yield 77%) as a light brown solid. LCMS m / z 293.0 [M+H] + ESI pos.

[0119] Intermediate 2: 5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-3H-oxazolo[4,5-b]pyridine-2-thione

Chem.

[0120] Process A: 2-amino-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridine-3-ol A solution of 2-amino-6-bromopyridine-3-ol (250.0 mg, 1.32 mmol, 1.0 equivalent), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (359.6 mg, 1.19 mmol, 0.9 equivalents), and XPhos Pd G3 (112.09 mg, 0.13 mmol, 0.1 equivalent) in 1,4-dioxane (1 mL) was spurged with nitrogen for 5 minutes. Saturated Na2CO3 aqueous solution (0.5 mL) and water (0.1 mL) were added, and the reaction mixture was then heated to 80°C and stirred at this temperature for 18 hours. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The resulting residue was dissolved in ELISA (20 mL) and filtered through a Celite pad. The filtrate was diluted with 1:1 water:brine (20 mL), and the layers were separated. The aqueous layer was extracted with SiO2 (2 × 20 mL), and the combined organic layers were concentrated under vacuum. The crude product was dried and packed onto Celite and purified by silica gel chromatography (12 g cartridge, 0-100% ((3:1 SiO2:2% EtOH containing NH3OH) / isohexane)) to obtain the title compound (119.0 mg, yield 31%) as a pale gray solid. LCMS m / z 285.1[M+H] + ESI pos.

[0121] Step B: 5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-3H-oxazolo[4,5-b]pyridine-2-thione A solution of 1,1'-thiocarbonyldiimidazole (89.5 mg, 0.5 mmol, 1.2 eq) and 2-amino-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridin-3-ol (119.0 mg, 0.42 mmol, 1.0 eq) in DMF (3 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (10 mL) and 1:1 water:brine (10 mL), and then the layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL), and then the combined organic layers were concentrated in vacuo. Trituration of the crude product with isohexane (10 mL) afforded the title compound (156 mg, 78% yield) as a light brown solid. LCMS m / z 327.1 [M+H] + ESI pos.

[0122] Preparation Example Example 1: 2-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridin-6-one

Chemical Structure

[0123] Step A: tert-Butyl 6-benzyloxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxylate Potassium tert-butoxide (579 mg, 5.16 mmol, 1.40 equivalents) was added to a mixture of tert-butyl 6-chloro-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxylate (CAS No. 1700330-18-2, 988 mg, 3.68 mmol, 1.00 equivalent) and benzyl alcohol (603 mg, 0.58 mL, 5.58 mmol, 1.51 equivalents) in 1,4-dioxane (11 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, heptane gradient 0%-20% ethyl acetate) to obtain the title compound (898 mg, yield 71%) as a purple solid. LCMS: m / z 327.2[M+H] + ,ESI pos.

[0124] Step B: tert-butyl6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxylate The reaction flask was alternately flushed three times with ethyl acetate (10 mL) and methanol (10 mL) with tert-butyl 6-benzyloxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxylate (Example 1, Step A) (895 mg, 2.61 mmol, 1.00 equivalent), evacuated, and argon. Activated carbon-supported palladium, 10% Pd base (90 mg, 0.08 mmol, 0.03 equivalent) was carefully added. The reaction flask was alternately flushed three times with evacuated, and argon. The reaction flask was then evacuated again and flushed with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 4 hours. The reaction mixture was filtered and thoroughly rinsed with warm ethyl acetate / methanol. The filtrate was concentrated under vacuum to obtain the title compound (654 mg, yield 96%, purity 90%) as a grayish-white solid, which was used without further purification. LCMS: m / z 237.1[M+H] + ,ESI pos.

[0125] Step C: 2-(5-chlorooxazolo[4,5-b]pyridine-2-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one To a solution of tert-butyl 6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxylate (Example 1, Step B) (60 mg, 0.24 mmol, 1.13 equivalents) in dichloromethane (0.70 mL) and methanol (0.30 mL), 4M HCl in dioxane (720 mg, 0.60 mL, 2.40 mmol, 11.3 equivalents) was added dropwise. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in 1,4-dioxane (0.50 mL), and 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 45 mg, 0.21 mmol, 1.00 equivalent) was added, followed by the addition of triethylamine (73 mg, 0.10 mL, 0.72 mmol, 3.37 equivalents). The reaction mixture was stirred at 90°C for 25 hours and then left at room temperature for 4 days. The reaction mixture was extracted three times with a mixture of dichloromethane / methanol (9:1) and a semi-saturated aqueous solution of NaHCO3 (solid was present in the aqueous layer). The aqueous layer was filtered and rinsed with water. The filter cake was dried using a rotary evaporator and then placed under high vacuum to obtain the title compound (20 mg, 31% yield) as a dark brown solid. LCMS: m / z 289.1[M+H] + ,ESI pos.

[0126] Step D: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one 1,4-Dioxane (0.60 mL) and water (0.15 mL) containing 2-(5-chlorooxazolo[4,5-b]pyridine-2-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one (Example 1, Step C) (20 mg, 0.07 mmol, 1.00 equivalent), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8, 38 mg, 0.11 mmol, 1.72 equivalents, 90% purity), cesium carbonate (65 mg, 0.20 mmol, 3.03 equivalents), and XPhos Pd A mixture of G3 (9 mg, 0.01 mmol, 0.16 equivalents) was flashed with argon and stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with a mixture of dichloromethane / methanol (9:1) and a semi-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted twice with a mixture of dichloromethane / methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0%-10% methanol) to obtain the title compound (14 mg, yield 47%) as a grayish-white solid. LCMS: m / z 429.2[M+H] + ,ESI pos.

[0127] Example 2: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5-methyl-1,3-dihydropyrrololo[3,4-c]pyridine-6-one; [ka]

[0128] Step A: tert-butyl 5-methyl-6-oxo-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxylate To a mixture of tert-butyl 6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxylate (Example 1, Step B) (170 mg, 0.68 mmol, 1.00 equivalent) in N,N-dimethylformamide (0.80 mL), potassium carbonate (222 mg, 1.61 mmol, 2.35 equivalents) was added, followed by the addition of iodomethane (227 mg, 0.10 mL, 1.60 mmol, 2.34 equivalents). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was added to a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NH4Cl solution and water. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0%-10% methanol) to obtain the title compound (144 mg, 80% yield) as a grayish-white solid. LCMS: m / z 251.1 [M+H] + ,ESI pos.

[0129] Step B: 2-(5-chlorooxazolo[4,5-b]pyridine-2-yl)-5-methyl-1,3-dihydropyrrolo[3,4-c]pyridine-6-one To a solution of tert-butyl 5-methyl-6-oxo-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxylate (Example 2, Step A) (106 mg, 0.40 mmol, 1.21 equivalents) in dichloromethane (1.0 mL) and methanol (0.50 mL), 4M HCl in dioxane (1.20 g, 1.0 mL, 4.00 mmol, 12.1 equivalents) was added dropwise. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in 1,4-dioxane (0.70 mL), and 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 70 mg, 0.33 mmol, 1.00 equivalent) was added, followed by the addition of triethylamine (112 mg, 0.154 mL, 1.10 mmol, 3.33 equivalents). The reaction mixture was stirred at 90°C for 2 days. The reaction mixture was cooled to room temperature and extracted three times with a mixture of dichloromethane / methanol (9:1) and a semi-saturated aqueous solution of NaHCO3. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient dichloromethane 0%~100% (dichloromethane:methanol:NH4OH 9:1:0.05)) to obtain the title compound (20 mg, yield 19%) as a grayish-white solid. LCMS: m / z 303.1 [M+H] + ,ESI pos.

[0130] Step C: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5-methyl-1,3-dihydropyrrololo[3,4-c]pyridine-6-one; 1,4-Dioxane (0.80 mL) and water (0.20 mL) containing 2-(5-chlorooxazolo[4,5-b]pyridine-2-yl)-5-methyl-1,3-dihydropyrrolo[3,4-c]pyridine-6-one (Example 2, Step B) (27 mg, 0.08 mmol, 1.00 equivalent), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8, 49 mg, 0.15 mmol, 1.72 equivalents, 90% purity), cesium carbonate (84 mg, 0.26 mmol, 3.04 equivalents), and XPhos Pd A mixture of G3 (12 mg, 0.01 mmol, 0.17 equivalents) was flashed with argon and stirred at 100°C for 3.5 hours. The reaction mixture was cooled to room temperature and extracted with a mixture of dichloromethane / methanol (9:1) and a semi-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted twice with a mixture of dichloromethane / methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0%-5% methanol) to obtain the title compound (25 mg, yield 63%) as a grayish-white solid. LCMS: m / z 443.2[M+H] + ,ESI pos.

[0131] Example 3: 3-Hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]benzonitrile [ka]

[0132] Step A: 2-(5-bromooxazolo[4,5-b]pyridine-2-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one A solution of tert-butyl 6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxylate (Example 1, Step B) (165 mg, 0.63 mmol, 1.16 eq., purity 90%) in dichloromethane (1.6 mL) and methanol (0.80 mL) was added dropwise with 4M HCl in dioxane (1.80 g, 1.5 mL, 6.00 mmol, 11.1 eq.). Stir at room temperature for 3.5 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in 1,4-dioxane (1.3 mL), 5-bromo-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1780768-09-3, 140 mg, 0.54 mmol, 1.00 eq.) was added, followed by triethylamine (189 mg, 0.26 mL, 1.87 mmol, 3.44 eq.). The reaction mixture was stirred at 95 °C for 2 days. The reaction mixture was diluted with a small amount of dichloromethane / methanol (19:1) and semi-saturated aqueous NaHCO3. The mixture was sonicated, filtered, and washed with a minimum amount of water and a mixture of dichloromethane / methanol (19:1). The filter cake was dried using a rotary evaporator and then placed under high vacuum to give the title compound (74 mg, yield 37%, purity 90%) as a grey solid. LCMS: m / z 333.0 / 335.0 [M+H] + ,ESI pos.

[0133] Step A`: 4-Amino-3-methoxy-5-methyl-benzonitrile

Chemical Structure

[0134] A solution of commercially available 4-bromo-2-methoxy-6-methylbenzeneamine (CAS No. 348169-39-1, 25.0 g, 115 mmol, 1.0 equivalent) was added to DMF (250 mL) with Zn(CN)2 (13.5 g, 115 mmol, 7.34 mL, 1.00 equivalent) and Pd(PPh3)4 (66.8 g, 57.8 mmol, 0.5 equivalent). The reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was poured into water (1.50 L) and extracted with ethyl acetate (1 L x 3). The organic phase was washed with brine (1 L x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain the title compound (28.0 g, yield 75%) as a yellow solid. 1 H NMR(DMSO-d6)δ 7.05(s,2H),5.47(bs,2H),3.81(s,3H),2.09(s,3H).

[0135] Process B': 4-bromo-3-methoxy-5-methylbenzonitrile To a solution of CuBr (46.4 g, 323 mmol, 9.86 mL, 1.50 equivalents) in MeCN (180 mL), t-BuONO (33.3 g, 323 mmol, 38.5 mL, 1.50 equivalents) was added and the mixture was stirred at 65°C. Then, the above intermediate 2B 4-bromo-3-methoxy-5-methylbenzonitrile (35.0 g, 215 mmol, 1.00 equivalent) in MeCN (180 mL) was added at 65°C. The mixture was stirred at 65°C for 3.5 hours. After completion, saturated Na2SO3 aqueous solution (400 mL) and saturated NH4Cl aqueous solution (200 mL) were added to the mixture and extracted with ethyl acetate (500 mL x 3). The organic phase was washed with brine (500 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue is analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, R f The compound was purified using a solution of 0.75 to obtain the title compound (20.7 g, 42% yield) as a white solid. 1H NMR(DMSO-d6)δ 7.43,7.40(2s,1H each),3.90(s,3H),2.37(s,3H).

[0136] Step C': 3-Methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile To a solution of 4-bromo-3-methoxy-5-methylbenzonitrile (18.0 g, 79.6 mmol, 1.00 equivalent) in DMF (180 mL), B2Pin2 (30.3 g, 119 mmol, 1.50 equivalent) and AcOK (35.1 g, 358 mmol, 4.50 equivalent) were added. The mixture was stirred at 20°C for 0.5 hours, and Pd(dppf)Cl2·CH2Cl2 (13.0 g, 15.9 mmol, 0.20 equivalent) was added. The mixture was stirred at 100°C for 12 hours. The mixture was filtered through diatomaceous earth, diluted with H2O (500 mL), and extracted with ethyl acetate (800 mL x 3). The organic phase was washed with brine (800 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue is analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1, R f The compound was purified using a solution of 0.30 to obtain the title compound (18.0 g, 83% yield) as a white solid. 1 H NMR(DMSO-d6)δ 7.22,7.21(2s,1H each),3.75(s,3H),2.27(s,3H),1.30(s,12H).

[0137] Process D': (4-Cyano-2-hydroxy-6-methylphenyl)boronic acid The above-mentioned solution of 3-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (17.0 g, 96.0 mmol, 1.00 equivalent) in dichloromethane (170 mL) was cooled to 0°C, and BBr3 (38.9 g, 155 mmol, 2.50 equivalents) was added dropwise at 0°C. The mixture was stirred at 0°C for 0.5 hours. The mixture was poured into H2O (200 mL), filtered, and the cake was recovered. Polishing with siRNA (20 mL) yielded the title compound (4.67 g, 42% yield) as a gray solid. LCMS: m / z 178.1 [M+H] + ,ESI pos.

[0138] Step B: 3-Hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]benzonitrile A mixture of 2-(5-bromooxazolo[4,5-b]pyridine-2-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one (Example 3, Step A) (35 mg, 0.09 mmol, 1.00 equivalent, 90% purity), (4-cyano-2-hydroxy-6-methylphenyl)boronic acid (Step D') (9 mg, 0.16 mmol, 1.73 equivalents), cesium carbonate (93 mg, 0.29 mmol, 3.02 equivalents), and XPhos Pd G3 (13 mg, 0.02 mmol, 0.16 equivalents) in 1,4-dioxane (1.0 mL) and water (0.25 mL) was flushed with argon and stirred at 95°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with a mixture of dichloromethane / methanol (9:1) and a semi-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted twice with a mixture of dichloromethane / methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient dichloromethane with 0%-20% methanol). All fractions containing the product were combined and concentrated under vacuum. The residue was polished with ethyl acetate to obtain the title compound (7.7 mg, 20% yield) as a grayish-white powder. LCMS: m / z 386.1[M+H] + ,ESI pos.

[0139] Example 4: 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one [ka] 1,4-Dioxane (0.80 mL) and water (0.40 mL) containing 2-(5-bromooxazolo[4,5-b]pyridine-2-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one (Example 3, Step A) (37 mg, 0.10 mmol, 1.00 equivalent, 90% purity), (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (CAS A mixture of (13 mg, 0.02 mmol, 0.16 equivalents) potassium carbonate (50 mg, 0.36 mmol, 3.62 equivalents) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (13 mg, 0.02 mmol, 0.16 equivalents) was flushed with argon and stirred at 95°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with a mixture of dichloromethane / methanol (19:1) and a semi-saturated aqueous NH4Cl solution. The organic layer was washed with water and brine. The aqueous layer was back-extracted twice with a mixture of dichloromethane / methanol (19:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 4g, gradient: 0% to 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). All fractions containing the product were combined and concentrated under vacuum. The residue was polished with ethyl acetate to obtain the title compound (18mg, 43% yield) as a light brown powder. LCMS: m / z 395.1 [M+H] + ,ESI pos.

[0140] Example 5: 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-one [ka]

[0141] Step A: tert-butyl 5-(2-hydroxyethyl)-6-oxo-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxylate To a suspension of tert-butyl 6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxylate (Example 1, Step B) (100 mg, 0.38 mmol, 1.00 equivalent, purity 90%) in N,N-dimethylformamide (0.50 mL), cesium carbonate (290 mg, 0.89 mmol, 2.34 equivalents) was added, followed by the addition of 2-iodoethanol (132 mg, 0.06 mL, 0.77 mmol, 2.02 equivalents). The reaction mixture was stirred at 90°C for 16 hours and then left at room temperature for 16 hours. The reaction mixture was extracted with 5% LiCl aqueous solution and ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed three times with 5% LiCl aqueous solution and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (120 mg, 96% yield, 85% purity) as a grayish-white solid, which was used without further purification. LCMS: m / z 281.1[M+H] + ,ESI pos.

[0142] Step B: 2-(5-bromooxazolo[4,5-b]pyridine-2-yl)-5-(2-hydroxyethyl)-1,3-dihydropyrrolo[3,4-c]pyridine-6-one To a solution of tert-butyl 5-(2-hydroxyethyl)-6-oxo-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxylate (Example 5, Step A) (117 mg, 0.35 mmol, 1.14 equivalents, purity 85%) in dichloromethane (0.92 mL) and methanol (0.46 mL), 4M HCl (1.03 g, 0.86 mL, 3.44 mmol, 11.1 equivalents) in dioxane was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in 1,4-dioxane (0.74 mL) and water (0.08 mL), and 5-bromo-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1780768-09-3, 80 mg, 0.31 mmol, 1.00 equivalent) was added, followed by the addition of N,N-diisopropylethylamine (129 mg, 0.17 mL, 1.00 mmol, 3.22 equivalents). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and then extracted with a mixture of dichloromethane / methanol (9:1) and a semi-saturated aqueous solution of NaHCO3. The aqueous layer was back-extracted five times with a mixture of dichloromethane / methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0%-10% methanol). The title compound (54 mg, yield 42%, purity 90%) was obtained as a grayish-white solid. LCMS: m / z 377.0 / 379.0 [M+H] + ,ESI pos.

[0143] Step C: 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-one 1,4-Dioxane (1.2 mL) and water (0.30 mL) containing 2-(5-bromooxazolo[4,5-b]pyridine-2-yl)-5-(2-hydroxyethyl)-1,3-dihydropyrrolo[3,4-c]pyridine-6-one (Example 5, Step B) (53 mg, 0.13 mmol, 1.00 equivalent, 90% purity), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8, 73 mg, 0.22 mmol, 1.72 equivalents, 90% purity), cesium carbonate (125 mg, 0.38 mmol, 3.03 equivalents), and XPhos Pd A mixture of G3 (17 mg, 0.02 mmol, 0.16 equivalents) was flushed with argon and stirred at 95°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with a mixture of dichloromethane / methanol (9:1) and a semi-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted twice with a mixture of dichloromethane / methanol (9:1). The organic layer was washed with water and brine (a precipitate was present in the aqueous layer). The combined aqueous layers were filtered and rinsed with water and ethyl acetate. The filter cake was dried on a rotary evaporator and then placed under high vacuum to obtain the title compound (32 mg, 51% yield) as a grayish-white powder. LCMS: m / z 473.1[M+H] + ,ESI pos.

[0144] Examples 6-9: 5-(4-chloro-2-hydroxy-6-methylphenyl)-3H-oxazolo[4,5-b]pyridine-2-thion intermediate 1 (1320.0 mg, 4.51 mmol, 1.0 equivalent) was dissolved in DCM (50 mL), oxalyl chloride (5.8 mL, 67.6 mmol, 15.0 equivalents) was added, and then DMF (1.5 mL) was added. The mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The resulting residue was dissolved in DCM (45 mL) and saturated K2CO3 aqueous solution (15 mL) was added. The DCM layer was isolated, and the aqueous layer was back-extracted with DCM (30 mL). The combined organic extracts were dried using a phase separator. The resulting solution (containing 5-chloro-2-(2-chlorooxazolo[4,5-b]pyridine-5-yl)-3-methylphenol) was diluted to 92 mL with DCM and used as a stock solution in a series of reactions using the following general procedure: [ka] Amine (5.41 mmol, 1.2 equivalents) was dissolved in DMF (0.1 mL), triethylamine (0.02 mL, 0.15 mmol, 3.0 equivalents) was added, and then 1 mL of stock solution of 5-chloro-2-(2-chlorooxazolo[4,5-b]pyridine-5-yl)-3-methylphenol (1 equivalent) was added. The mixture was shaken at room temperature for 20 minutes. The DCM was evaporated overnight, and the resulting residue was diluted to 1 mL with DMF and then filtered. The resulting filtrate was purified by preparative HPLC. [Table 3]

[0145] Example 10: 4-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile [ka]

[0146] Step A: 5-Chloro-2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine N,N-diisopropylethylamine (243 mg, 0.32 mL, 1.88 mmol, 3.97 equivalents) was added to a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 100 mg, 0.47 mmol, 1.00 equivalent) and 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine dihydrochloride (CAS No. 6000-50-6, 128 mg, 0.66 mmol, 1.40 equivalent) in 1,4-dioxane (0.90 mL) and water (0.10 mL). The reaction mixture was stirred at 90°C for 72 hours. The reaction mixture was cooled to room temperature, extracted with a semi-saturated aqueous NaHCO3 solution, and extracted three times with a dichloromethane / methanol (19:1) mixture. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM and purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0%-5% methanol) to obtain the title compound (117 mg, yield 86%) as a grayish-white solid. LCMS: m / z 273.1[M+H] + ,ESI pos.

[0147] Step B: 4-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile Starting from 5-chloro-2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine (Example 10, Step A) and (4-cyano-2-hydroxy-6-methylphenyl)boronic acid (Example 3, Step D'), and using the same chemistry as described in Example 3, Step B, the title compound was obtained as a grayish-white solid, LCMS: m / z 370.1 [M+H]. + It was obtained as ESI pos.

[0148] Example 11: 5-Chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]phenol [ka]

[0149] Step A: 5-Chloro-2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine N,N-diisopropylethylamine (106 mg, 0.14 mL, 0.82 mmol, 2.17 equivalents) was added to a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 80 mg, 0.38 mmol, 1.00 equivalent) and 2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (CAS No. 676994-65-3, 74 mg, 0.50 mmol, 1.31 equivalents) in 1,4-dioxane (0.90 mL) and water (0.10 mL). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was cooled to room temperature, extracted with a semi-saturated aqueous NaHCO3 solution, and extracted three times with a dichloromethane / methanol (19:1) mixture. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient dichloromethane with 0%-5% methanol) to obtain the title compound (99 mg, yield 82%) as a grayish-white solid. LCMS: m / z 302.1[M+H] + ,ESI pos.

[0150] Step B: 5-Chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]phenol Starting with 5-chloro-2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine (Example 11, Step A) and (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (CAS No. 1207961-50-9), and using the same chemistry as described in Example 4, a grayish-white foamy substance was produced, LCMS: m / z 408.2 [M+H]. + The title compound was obtained as ESI pos.

[0151] Example 12: 2-[2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol [ka]

[0152] Step A: 6-Methoxy-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine A mixture of 6-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (CAS No. 905273-90-7, 210 mg, 1.36 mmol, 1.00 equivalent) in 1,4-dioxane (2.8 mL) was mixed with sodium methoxide solution (25% by weight in methanol) (1.42 g, 1.5 mL, 6.56 mmol, 4.83 equivalents) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, poured into a semi-saturated aqueous NH4Cl solution, and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient dichloromethane with 0%-20% methanol) to obtain the title compound (175 mg, yield 81%) as a purple solid. LCMS: m / z 151.1[M+H] + ,ESI pos.

[0153] Step B: 5-Chloro-2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine N,N-diisopropylethylamine (152 mg, 0.20 mL, 1.18 mmol, 2.16 equivalents) was added to a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 115 mg, 0.54 mmol, 1.00 equivalent) and 6-methoxy-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (Example 12, Step A) (114 mg, 0.72 mmol, 1.32 equivalents) in 1,4-dioxane (1.3 mL) and water (0.14 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, extracted with a semi-saturated aqueous NaHCO3 solution, and extracted three times with a mixture of dichloromethane / methanol (19:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0%-5% methanol) to obtain the title compound (159 mg, 92% yield) as a pink solid. LCMS: m / z 303.1[M+H] + ,ESI pos.

[0154] Step C: 2-[2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol Starting from 5-chloro-2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine (Example 12, Step B) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8), the title compound was produced as a light brown solid, LCMS: m / z 443.2 [M+H] using the same chemistry as described in Step D of Example 1. + It was obtained as ESI pos.

[0155] Example 13: 5-Chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol formate [ka]

[0156] Step A: 5-Chloro-2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine A mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 200 mg, 1.00 mmol, 1.00 equivalent) and 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (CAS No. 53493-80-4, 133 mg, 1.10 mmol, 1.10 equivalent) in 1,4-dioxane (2.1 mL) was mixed with triethylamine (113 mg, 0.16 mL, 1.12 mmol, 1.12 equivalent) under argon. The reaction mixture was stirred at 90°C for 16 hours. Further addition of 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (CAS No. 53493-80-4, 121 mg, 1.00 mmol, 1.00 equivalent) was added, and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and semi-saturated NaHCO3 aqueous solution. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, heptane gradient 0%-80% ethyl acetate) to obtain the title compound (70 mg, yield 26%) as a brown solid. LCMS: m / z 274.0 [M+H] + ,ESI pos.

[0157] Process B: 5-Chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol formate Starting with 5-chloro-2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine (Example 13, Step A) and (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (CAS No. 1207961-50-9), and using the same chemistry as described in Example 4, the following reverse-phase chromatography was performed to obtain a white solid, LCMS: m / z 380.1 [M+H]. + The title compound was obtained as ESI pos (column: YMC-Triart C18, eluent: water + 0.1% HCOOH in acetonitrile).

[0158] Example 14: 5-Chloro-2-[2-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol [ka]

[0159] Step A: 5-Chloro-2-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-yl)oxazolo[4,5-b]pyridine N,N-diisopropylethylamine (135 mg, 0.178 mL, 1.05 mmol, 2.21 equivalents) was added to a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 100 mg, 0.47 mmol, 1.00 equivalent) and 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (67 mg, 0.61 mmol, 1.30 equivalents) in 1,4-dioxane (1.0 mL) and water (0.11 mL). The reaction mixture was stirred at 90°C for 72 hours and at 110°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with a semi-saturated aqueous NaHCO3 solution, then extracted three times with a dichloromethane / methanol (19:1) mixture, and four times with a dichloromethane / methanol (9:1) mixture. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM and purified by flash chromatography (silica gel, gradient dichloromethane with 0%-5% methanol) to obtain the title compound (77 mg, yield 56%, purity 90%) as a white solid. LCMS: m / z 262.1[M+H] + ,ESI pos.

[0160] Step B: 5-Chloro-2-[2-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol Starting with 5-chloro-2-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-yl)oxazolo[4,5-b]pyridine (Example 14, Step A) and (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (CAS No. 1207961-50-9), and using the same chemistry as described in Example 4, the title compound was converted to a grayish-white solid, LCMS: m / z 368.2 [M+H]. + It was obtained as ESI pos.

[0161] Example 15: 5-Chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol [ka]

[0162] Step A: 5-Chloro-2-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)oxazolo[4,5-b]pyridine N,N-diisopropylethylamine (243 mg, 0.32 mL, 1.88 mmol, 3.97 equivalents) was added to a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 100 mg, 0.47 mmol, 1.00 equivalent) and 1,2,3,4-tetrahydro-2,7-naphthirizine hydrochloride (CAS No. 1354940-72-9, 113 mg, 0.66 mmol, 1.40 equivalent) in 1,4-dioxane (0.90 mL) and water (0.10 mL). The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, extracted with a semi-saturated aqueous NaHCO3 solution, and extracted three times with a dichloromethane / methanol (19:1) mixture. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient dichloromethane with 0%-5% methanol) to obtain the title compound (116 mg, yield 81%) as a pale yellow solid. LCMS: m / z 287.1[M+H] + ,ESI pos.

[0163] Step B: 5-Chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol Starting with 5-chloro-2-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)oxazolo[4,5-b]pyridine (Example 15, Step A) and (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (CAS No. 1207961-50-9), the title compound was obtained as a white solid, LCMS: m / z 393.2 [M+H] using the same chemistry as described in Example 4. +It was obtained as ESI pos.

[0164] Example 16: 3-Hydroxy-4-(2-isoindoline-2-yloxazolo[4,5-b]pyridine-5-yl)-5-methylbenzonitrile [ka]

[0165] Step A: 5-Chloro-2-isoindoline-2-yl-oxazolo[4,5-b]pyridine N,N-diisopropylethylamine (143 mg, 0.189 mL, 1.11 mmol, 1.50 equivalents) was added to a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 150 mg, 0.74 mmol, 1.00 equivalent) and isoindoline (CAS No. 496-12-8, 121 mg, 0.115 mL, 0.96 mmol, 1.30 equivalent) in 1,4-dioxane (1.8 mL) and water (0.20 mL). The reaction mixture was stirred in a sealed tube at 100°C for 16 hours. The reaction mixture was extracted with ethyl acetate and 1 M Na2CO3 solution. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 12 g, gradient dichloromethane with 0%-20% ethyl acetate) to obtain the title compound (151 mg, 71% yield) as a pale gray solid. LCMS: m / z 272.0 [M+H] + ,ESI pos.

[0166] Step B: 3-Hydroxy-4-(2-isoindoline-2-yloxazolo[4,5-b]pyridine-5-yl)-5-methylbenzonitrile Starting from 5-chloro-2-isoindoline-2-yl-oxazolo[4,5-b]pyridine (Example 16, Step A) and (4-cyano-2-hydroxy-6-methylphenyl)boronic acid (Example 3, Step D'), and using the same chemistry as described in Example 3, Step B, the title compound was converted to a grayish-white solid, LCMS: m / z 369.2 [M+H]. + It was obtained as ESI pos.

[0167] Example 17: 4-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile [ka]

[0168] Step A: 5-Chloro-2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine A mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 253 mg, 1.20 mmol, 1.00 equivalent) and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (CAS No. 192869-50-4, 227 mg, 1.68 mmol, 1.40 equivalent) in 1,4-dioxane (3.0 mL) was mixed with triethylamine (218 mg, 0.30 mL, 2.16 mmol, 1.80 equivalent) under argon. The reaction mixture was stirred at 90°C for 48 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and aqueous NaHCO3. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, gradient dichloromethane with 0%-10% methanol) to obtain the title compound (270 mg, 74% yield) as a pale yellow solid. LCMS: m / z 288.0 [M+H] + ,ESI pos.

[0169] Step B: 4-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile Starting from 5-chloro-2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine (Example 17, Step A) and (4-cyano-2-hydroxy-6-methylphenyl)boronic acid (Example 3, Step D'), and using the same chemistry as described in Example 3, Step B, the title compound was obtained as a white solid, LCMS: m / z 385.1 [M+H]. + It was obtained as ESI pos.

[0170] Example 18: 2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol [ka] Starting from 5-chloro-2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine (Example 13, Step A) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8), the title compound was obtained as a grayish-white solid, LCMS: m / z 414.1 [M+H] using the same chemistry as described in Step D of Example 1. + It was obtained as ESI pos.

[0171] Example 19: 7-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-2,5,6,8-tetrahydro-2,7-naphthyridine-3-one [ka]

[0172] Step A: tert-butyl6-benzyloxy-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate Potassium tert-butoxide (88 mg, 0.78 mmol, 1.40 equivalents) was added to a mixture of tert-butyl 6-chloro-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (CAS No. 1396777-92-6, 150 mg, 0.56 mmol, 1.00 equivalent) and benzyl alcohol (91 mg, 0.087 mL, 0.84 mmol, 1.50 equivalent) in 1,4-dioxane (2.0 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 12 g, heptane gradient, 0%-30% ethyl acetate) to obtain the title compound (80 mg, 40% yield) as a colorless oil. LCMS: m / z 341.2 [M+H] + ,ESI pos.

[0173] Process B: 6-benzyloxy-1,2,3,4-tetrahydro-2,7-naphthirizine hydrochloride To a solution of tert-butyl 6-benzyloxy-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (Example 19, Step A) (78 mg, 0.22 mmol, 1.00 equivalent) in dichloromethane (2.0 mL) and methanol (1.0 mL), 4M HCl (0.54 mL, 2.18 mmol, 10.00 equivalent) in 1,4-dioxane was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The white suspension was concentrated under vacuum to obtain the title compound (53 mg, 84% yield) as a white solid. LCMS: m / z 241.1 [M+H] + ,ESI pos.

[0174] Step C: 2-(6-benzyloxy-3,4-dihydro-1H-2,7-naphthyridine-2-yl)-5-chloro-oxazolo[4,5-b]pyridine Triethylamine (48 mg, 0.067 mL, 0.48 mmol, 3.00 equivalent) was added to a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 32 mg, 0.16 mmol, 1.00 equivalent) and 6-benzyloxy-1,2,3,4-tetrahydro-2,7-naphthirizine hydrochloride (Example 19, Step B) (51 mg, 0.18 mmol, 1.10 equivalent) in 1,4-dioxane (1.0 mL) and water (0.10 mL). The reaction mixture was stirred at 100 °C for 48 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and aqueous NaHCO3. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, heptane gradient 0%-50% ethyl acetate) to obtain the title compound (31 mg, yield 47%) as pale yellow foam. LCMS: m / z 393.1 [M+H] + ,ESI pos.

[0175] Process D: 7-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-2,5,6,8-tetrahydro-2,7-naphthyridine-3-one [ka] A mixture of 1,4-dioxane (1.6 mL) and water (0.40 mL) containing 2-(6-benzyloxy-3,4-dihydro-1H-2,7-naphthyridine-2-yl)-5-chlorooxazolo[4,5-b]pyridine (Example 19, Step C) (30 mg, 0.07 mmol, 1.00 equivalent), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8, 35 mg, 0.12 mmol, 1.60 equivalent), and cesium carbonate (71 mg, 0.22 mmol, 3.00 equivalent) was placed under argon, and XPhos Pd G3 (9 mg, 0.01 mmol, 0.15 equivalent) was added. The reaction mixture was stirred at 95°C for 3 hours. Further XPhos Pd G3 (9 mg, 0.01 mmol, 0.15 equivalents) was added, and stirring was continued at 95°C for 2 hours and at room temperature for 16 hours. The reaction mixture was cooled to room temperature, quenched with water and an equal volume of saturated NH4Cl aqueous solution, and then extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, 0%-50% in gradient dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)), followed by crystallization using ethyl acetate / heptane 1:1 (v / v) to obtain the title compound (9 mg, 27% yield) as a white solid. LCMS: m / z 443.1[M+H] + ,ESI pos.

[0176] Example 20: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-1H-pyrrolo[3,4-b]pyridine-2-one [ka]

[0177] Step A: tert-butyl 2-benzyloxy-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate Potassium tert-butoxide (200 mg, 1.79 mmol, 1.40 equivalents) was added at room temperature to a mixture of tert-butyl 2-chloro-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (CAS No. 1257854-60-6, 325 mg, 1.28 mmol, 1.00 equivalent) and benzyl alcohol (207 mg, 0.199 mL, 1.91 mmol, 1.50 equivalents) in 1,4-dioxane (5.0 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 25 g, heptane gradient, 0%-30% ethyl acetate) to obtain the title compound (305 mg, yield 69%) as a purple oily substance. LCMS: m / z 327.2 [M+H] + ,ESI pos.

[0178] Step B: tert-butyl 2-oxo-5,7-dihydro-1H-pyrrolo[3,4-b]pyridine-6-carboxylate A solution of tert-butyl 2-benzyloxy-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (Example 20, Step A) (303 mg, 0.87 mmol, 1.00 equivalent) in ethyl acetate (10 mL) and methanol (10 mL) was alternately flushed three times with evacuation and argon. Activated carbon-supported palladium, 10% Pd base (93 mg, 0.09 mmol, 0.10 equivalent) was carefully added. The reaction flask was evacuated, flushed with argon, evacuated again, and flushed with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 4 hours. The reaction mixture was filtered and thoroughly rinsed with ethyl acetate / methanol. The filtrate was concentrated under vacuum to obtain the title compound (208 mg, 96% yield) as a white solid, which was used without further purification. LCMS: m / z 237.1[M+H]+ ,ESI pos.

[0179] Process C: 1,5,6,7-tetrahydropyrrolo[3,4-b]pyridine-2-one hydrochloride To a solution of tert-butyl 2-oxo-5,7-dihydro-1H-pyrrolo[3,4-b]pyridine-6-carboxylate (Example 20, Step B) (97 mg, 0.41 mmol, 1.00 equivalent) in dichloromethane (2.0 mL) and methanol (1.0 mL), 4M HCl in 1,4-dioxane (1.23 g, 1.03 mL, 4.11 mmol, 10.0 equivalent) was added dropwise at ambient temperature. The reaction mixture was stirred at room temperature for 16 hours. When the reaction mixture was concentrated under vacuum, the title compound (87 mg, 98% yield) was obtained as a pale gray solid. LCMS: m / z 137.1 [M+H] + ,ESI pos.

[0180] Process D: 6-(5-chlorooxazolo[4,5-b]pyridine-2-yl)-5,7-dihydro-1H-pyrrolo[3,4-b]pyridine-2-one N,N-diisopropylethylamine (274 mg, 0.36 mL, 2.12 mmol, 5.00 equivalent) was added to a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 85 mg, 0.42 mmol, 1.00 equivalent) and 1,5,6,7-tetrahydropyrrolo[3,4-b]pyridine-2-one hydrochloride (Example 20, Step C) (88 mg, 0.51 mmol, 1.20 equivalent) in 1,4-dioxane (1.0 mL) and water (0.10 mL). The reaction mixture was stirred in a sealed tube at 100°C for 24 hours to obtain a gray suspension. The reaction mixture was cooled and diluted with a small amount of ethyl acetate, water, and a semi-saturated aqueous NaHCO3 solution. The solid was removed by filtration, washed with an ethyl acetate / water mixture, and then rinsed with diethyl ether. The filter cake was placed under high vacuum and dried at 50°C for 1 hour to obtain the title compound (67 mg, 52% yield) as a gray solid. LC-MS: m / z 287.0 [MH] - ,ESI pos.

[0181] Step E: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-1H-pyrrolo[3,4-b]pyridine-2-one [ka] A mixture of 6-(5-chlorooxazolo[4,5-b]pyridine-2-yl)-5,7-dihydro-1H-pyrrolo[3,4-b]pyridine-2-one (Example 20, Step D) (66 mg, 0.23 mmol, 1.00 equivalent), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8, 111 mg, 0.37 mmol, 1.60 equivalent), and cesium carbonate (223 mg, 0.69 mmol, 3.00 equivalent) in 1,4-dioxane (1.0 mL), water (1.0 mL), and N,N-dimethylformamide (3.0 mL) was flushed with argon and XPhos Pd G3 (29 mg, 0.03 mmol, 0.15 equivalents) was added. The reaction mixture was stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature and quenched with water and an equal volume of saturated NH4Cl aqueous solution. The mixture was extracted twice with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, 0% to 50% in gradient dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)), followed by crystallization using ethyl acetate / heptane 1:1 (v / v) to obtain the title compound (49 mg, yield 48%) as a grayish-white solid. LCMS: m / z 429.1 [M+H] + ,ESI pos.

[0182] Example 21: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1-methyl-5,7-dihydropyrrolo[3,4-b]pyridine-2-one [ka]

[0183] Step A: tert-butyl 1-methyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate Starting with tert-butyl 2-oxo-5,7-dihydro-1H-pyrrolo[3,4-b]pyridine-6-carboxylate (Example 20, Step B) and iodomethane, the title compound was prepared as a light brown oily substance, LCMS: m / z 251.0 [M+H] using the same chemistry as described in Step A of Example 2. + It was obtained as ESI pos.

[0184] Step B: 1-Methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-one hydrochloride Starting with tert-butyl 1-methyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (Example 21, Step A), the title compound was obtained as a light brown solid, LCMS: m / z 151.0 [M+H] using the same chemistry as described in Example 20, Step C. + It was obtained as ESI pos.

[0185] Step C: 6-(5-chlorooxazolo[4,5-b]pyridine-2-yl)-1-methyl-5,7-dihydropyrrolo[3,4-b]pyridine-2-one Starting from 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2) and 1-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-one hydrochloride (Example 21, Step B), the title compound was obtained as a pale gray solid, LCMS: m / z 303.0 [M+H] using the same chemistry as described in Example 20, Step D. +It was obtained as ESI pos.

[0186] Step D: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1-methyl-5,7-dihydropyrrolo[3,4-b]pyridine-2-one Starting from 6-(5-chlorooxazolo[4,5-b]pyridine-2-yl)-1-methyl-5,7-dihydropyrrolo[3,4-b]pyridine-2-one (Example 21, Step C) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8), the title compound was produced as a grayish-white foam, LCMS: m / z 443.1 [M+H] using the same chemistry as described in Example 20, Step E. + It was obtained as ESI pos.

[0187] Example 22: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-2-methyl-5,7-dihydropyrrolo[3,4-c]pyridazine-3-one [ka]

[0188] Step A: tert-butyl 2-methyl-3-oxo-5,7-dihydropyrrolo[3,4-c]pyridazine-6-carboxylate Starting with tert-butyl 3-oxo-5,7-dihydro-2H-pyrrolo[3,4-c]pyridazine-6-carboxylate (CAS No. 1395493-25-0) and iodomethane, the title compound was converted to a dark brown solid, LCMS: m / z 252.1 [M+H] using the same chemistry as described in step A of Example 2. + It was obtained as ESI pos.

[0189] Process B: 2-methyl-6,7-dihydro-5H-pyrrolo[3,4-c]pyridazine-3-one hydrochloride Starting with tert-butyl 2-methyl-3-oxo-5,7-dihydropyrrolo[3,4-c]pyridazine-6-carboxylate (Example 22, Step A), the title compound was converted to a black solid, LCMS: m / z 152.0 [M+H] using the same chemistry as described in Example 20, Step C. + It was obtained as ESI pos.

[0190] Process C: 6-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-2-methyl-5,7-dihydropyrrolo[3,4-c]pyridazine-3-one N,N-diisopropylethylamine (419 mg, 0.55 mL, 3.24 mmol, 5.00 equivalent) was added to a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 130 mg, 0.65 mmol, 1.00 equivalent) and 2-methyl-6,7-dihydro-5H-pyrrolo[3,4-c]pyridazin-3-one hydrochloride (Example 22, Step B) (162 mg, 0.78 mmol, 1.20 equivalent, purity 90%) in 1,4-dioxane (2.6 mL) and water (0.26 mL). The reaction mixture was stirred in a sealed tube at 100°C for 60 hours. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient dichloromethane 0%-50% (dichloromethane:methanol:NH4OH 110:10:1)) to obtain the title compound (32 mg, yield 15%) as a light brown solid. LCMS: m / z 304.0 [M+H] + ,ESI pos.

[0191] Process D: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-2-methyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-one Starting from 6-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-2-methyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-one (Example 22, Step C) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8), the title compound was obtained as a grayish-white solid, LCMS: m / z 444.1 [M+H] using the same chemistry as described in Example 20, Step E. + It was obtained as ESI pos.

[0192] Example 23: 2-[2-(5,7-dihydropyrrolo[3,4-b]pyrazine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol [ka]

[0193] Step A: 5-Chloro-2-(5,7-dihydropyrrolo[3,4-b]pyrazine-6-yl)oxazolo[4,5-b]pyridine N,N-diisopropylethylamine (357 mg, 0.47 mL, 2.76 mmol, 4.00 equivalents) was added to a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 140 mg, 0.69 mmol, 1.00 equivalent) and 6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine hydrochloride (CAS No. 1255099-34-3, 163 mg, 1.04 mmol, 1.50 equivalent) in 1,4-dioxane (2.0 mL) and water (0.20 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (2.0 mL) and water (2.0 mL). The mixture was stirred for 5 minutes. Next, the solid was filtered and rinsed with water and diethyl ether to obtain the title compound (148 mg, 74% yield) as a gray solid, which was used without further purification. LCMS: m / z 274.0 [M+H] +,ESI pos.

[0194] Step B: 2-[2-(5,7-dihydropyrrolo[3,4-b]pyrazine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol Starting from 5-chloro-2-(5,7-dihydropyrrolo[3,4-b]pyrazine-6-yl)oxazolo[4,5-b]pyridine (Example 23, Step A) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8), the title compound was obtained as a white solid, LCMS: m / z 414.2 [M+H] using the same chemistry as described in Step D of Example 1. + It was obtained as ESI pos.

[0195] Example 24: 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol [ka] Starting from 5-chloro-2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine (Example 17, Step A) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS No. 2557358-38-8), the title compound was obtained as a white solid, LCMS: m / z 428.3 [M+H] using the same chemistry as described in Step D of Example 1. + It was obtained as ESI pos.

[0196] Example 25: 5-Chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)oxazolo[4,5-b]pyridine-5-yl]phenol [ka]

[0197] Step A: 5-Chloro-2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)oxazolo[4,5-b]pyridine A mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 200 mg, 0.95 mmol, 1.00 equivalent) and 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (CAS No. 933742-87-1, 117 mg, 0.95 mmol, 1.00 equivalent) in 1,4-dioxane (2.0 mL) was mixed with triethylamine (172 mg, 0.24 mL, 1.70 mmol, 1.80 equivalent) under argon. The reaction mixture was stirred at 95°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated NaHCO3 aqueous solution. The aqueous layer was back-extracted three times with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, gradient dichloromethane with 0%-10% methanol) to obtain the title compound (178 mg, 65% yield) as a pale yellow solid. LCMS: m / z 275.9 [M+H] + ,ESI pos.

[0198] Step B: 5-Chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)oxazolo[4,5-b]pyridine-5-yl]phenol In a sealed tube, 5-chloro-2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)oxazolo[4,5-b]pyridine (Example 25, Step A) (100 mg, 0.33 mmol, 1.00 equivalent) was dissolved in 1,4-dioxane (2.0 mL) and water (0.50 mL). Then, (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (CAS No. 1207961-50-9, 103 mg, 0.55 mmol, 1.70 equivalent), cesium carbonate (319 mg, 0.98 mmol, 3.00 equivalent), and XPhos Pd G3 (41 mg, 0.05 mmol, 0.15 equivalent) were added under an argon atmosphere. The reaction mixture was stirred at 95°C for 16 hours. The reaction mixture was quenched with a semi-saturated aqueous NH4Cl solution and extracted twice with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (Si-amine, 25 g, 0%-20% methanol gradient in ethyl acetate) to obtain the title compound (75 mg, yield 57%) as a white solid. LCMS: m / z 382.1 [M+H] + ,ESI pos.

[0199] Example 26: 5-(difluoromethyl)-2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol [ka]

[0200] Process A': 3-bromo-5-methylbenzaldehyde Two batches were carried out in parallel. To a solution of compound 1 (50.0 g, 200 mmol, 1.0 equivalent) in THF (500 mL), n-BuLi (2.50 M, 96.0 mL, 1.50 equivalent) was added dropwise under N2 at -70°C, and then DMF (43.9 g, 600 mmol, 46.2 mL, 2.00 equivalent) was added, and the mixture was stirred at -70°C for 1 hour. TLC (petroleum ether / ethyl acetate = 10 / 1, material R) was used. f =0.8, product R f The reaction (=0.7) indicated that the starting material was consumed and new spots were formed. The reaction mixture was quenched with water (1000 mL) and extracted with ethyl acetate (3 × 800 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~50 / 1, product: R f The compound was purified using a method (=0.7) to obtain the title compound (45.0 g, yield 67%) as a yellow oily substance. 1 H NMR:(400 MHz,CDCl3)δ 9.93(s,1H),7.81(s,1H),7.60(d,2H),2.43(s,3H).

[0201] Process B': 1-Bromo-3-(difluoromethyl)-5-methylbenzene To a solution of 3-bromo-5-methylbenzaldehyde (42.0, 211 mmol, 1.0 equivalent) in DCM (500 mL), DAST (74.8 g, 464 mmol, 61.3 mL, 2.2 equivalents) was added, and the mixture was then stirred at 25°C for 10 hours. TLC (petroleum ether / ethyl acetate = 10 / 1, material R) f =0.500, product R f A reading of 0.700 indicated that the starting material had been consumed and new spots had formed. The reaction mixture was quenched with NaHCO3 (2000 mL) and extracted with DCM (3 × 1000 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (45.0 g, yield 97%) as a yellow oil, which was used in the next step without further purification.

[0202] Process C': 2-[3-(difluoromethyl)-5-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 1-bromo-3-(difluoromethyl)-5-methylbenzene (43.0 g, 194 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (59.3 g, 233 mmol, 1.1 equivalent), and Pd(dppf)Cl2 (14.2 g, 19.4 mmol, 0.05 equivalent) in dioxane (400 mL), AcOK (40.1 g, 408 mmol, 2.0 equivalent) was added, and the mixture was then stirred at 90°C for 2 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, material R f =0.8, product R f A reading of 0.7) indicated that the starting material had been consumed and new spots had formed. The reaction mixture was poured into H2O (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (53.0 g, crude) as a dark brown oily substance, which was used in the next step without further purification.

[0203] Process D': 3-(difluoromethyl)-5-methylphenol To a solution of 2-[3-(difluoromethyl)-5-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (52.0 g, 194 mmol, 1.0 equivalent) in THF (800 mL), NaOH (2.00 M, 291 mL, 3.0 equivalents) was added, followed by the addition of H2O2 (110 g, 970 mmol, 93.2 mL, 30% purity, 4.0 equivalents) at 0°C. The mixture was stirred at 25°C for 3 hours. The reaction mixture was then quenched with Na2SO3 (1000 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (0.1% NH3·H2O) to obtain the title compound (25.0 g, 82% yield) as a brown oil. LCMS:Rt =0.463 minutes, m / z=157.0[MH] + .

[0204] Process E': 5-(difluoromethyl)-2-iodo-3-methylphenol [ka] To a solution of 3-(difluoromethyl)-5-methylphenol (27.0 g, 171 mmol, 1.0 equivalent) in toluene (540 mL), NaH (13.7 g, 341 mmol, 60% purity, 2.0 equivalents) was added under N2 at 0°C. The mixture was stirred at 0°C for 0.5 hours, and then iodine (34.7 g, 136 mmol, 0.8 equivalents) was added. The mixture was stirred at 25°C for 1.5 hours. The reaction mixture was quenched with NH4Cl aqueous solution (1000 mL) and extracted with ethyl acetate (3 × 400 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (0.1% FA conditions) to obtain the desired compound and by-products (regional isomers) as a brown oily substance. The residue was purified by SFC (column: DAIEL CHIRALPAK AD (250mm*50mm, 10um); mobile phase: [Neu-IPA]; B%: 40%-40%, 2.2 mins) to obtain the title compound (28.0g, yield 73%) as a brown oily substance. LCMS:R t =0.499 minutes, m / z=283.0[MH] - ,ESI neg.

[0205] Process F': 1-Benzyloxy-5-(difluoromethyl)-2-iodo-3-methylbenzene [ka] To a solution of 5-(difluoromethyl)-2-iodo-3-methylphenol (19.0 g, 66.9 mmol, 1.0 equivalent) in DMF (190 mL), BnBr (17.2 g, 100 mmol, 11.9 mL, 1.5 equivalents) and K2CO3 (11.1 g, 80.3 mmol, 1.2 equivalents) were added. The mixture was stirred at 25°C for 12 hours. TLC (petroleum ether / ethyl acetate = 10 / 1, material R) was performed. f =0.4, product R f A reading of 0.7) indicated that the starting material had been consumed and new spots had formed. The reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layer was washed with H2O (3 × 300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain the title compound (22.0 g, yield 88%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 7.54(d,2H),7.40-7.44(m,2H),7.33-7.37(m,1H),7.03(s,1H),6.82(s,1H),6.44-6.72(m,1H),5.19(s,2H),2.54(s,3H).

[0206] Process G': 2-[2-benzyloxy-4-(difluoromethyl)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 1-benzyloxy-5-(difluoromethyl)-2-iodo-3-methylbenzene (9.00 g, 24.0 mmol, 1.0 equivalent) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.71 g, 36.1 mmol, 7.36 mL, 1.5 equivalents) in THF (90.0 mL), n-BuLi (2.50 M, 14.4 mL, 1.5 equivalents) was added under N2 at -70°C. The mixture was stirred at -60°C for 1 hour. TLC (petroleum ether / ethyl acetate = 10 / 1, material R) was performed. f =0.70, product R fA value of 0.65 indicated that the material had been completely consumed and new spots had formed. The reaction mixture was quenched with NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~20 / 1) to obtain the target compound (11.2 g, yield 60%, purity 97%) as a white solid. LCMS: m / z = 375.3 [M + H] + ,ESI pos.

[0207] Process H': 5-(difluoromethyl)-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol [ka] To a solution of 2-[2-benzyloxy-4-(difluoromethyl)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (800 mg, 2.14 mmol, 1.0 equivalent) and ethyl acetate (20 mL), palladium carbon (227.5 mg, 213.77 μmol, 0.1 equivalent) was added under argon. The black suspension was degassed under vacuum and purged several times with hydrogen. The reaction mixture was stirred under hydrogen (balloon) for 4 hours. The reaction mixture was filtered through two glass fiber filters, washed with ethyl acetate (3 × 20 mL), and evaporated to obtain the title compound (595 mg, yield 89%) as a colorless oil. LCMS: m / z 285.1 [M + H] + ,ESI pos.

[0208] Step B: 5-(difluoromethyl)-2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol [ka] Starting from 5-chloro-2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine (Example 17, Step A) and 5-(difluoromethyl)-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Example 26, Step H'), the title compound was produced as a pale yellow solid, LCMS: m / z 410.1 [M+H] using the same chemistry as described in Example 1, Step D. + It was obtained as ESI pos.

[0209] Example 27: 7-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-2,5,6,8-tetrahydro-2,7-naphthyridine-3-one [ka]

[0210] Process A: tert-butyl6-oxo-1,3,4,7-tetrahydro-2,7-naphthyridine-2-carboxylate Starting with tert-butyl6-benzyloxy-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate (Example 19, Step A), the title compound was obtained as a gray solid, LCMS: m / z 251.1 [M+H] using the same chemistry as described in Example 20, Step B. + It was obtained as ESI pos.

[0211] Process B: 5,6,7,8-tetrahydro-2H-2,7-naphthyridine-3-one hydrochloride Starting with tert-butyl 6-oxo-1,3,4,7-tetrahydro-2,7-naphthyridine-2-carboxylate (Example 27, Step A), the title compound was obtained as a gray solid, LCMS: m / z 151.1 [M+H] using the same chemistry as described in Example 20, Step C. + It was obtained as ESI pos.

[0212] Process C: 7-(5-chlorooxazolo[4,5-b]pyridine-2-yl)-2,5,6,8-tetrahydro-2,7-naphthyrizin-3-one Starting with 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2) and 5,6,7,8-tetrahydro-2H-2,7-naphthyrizin-3-one hydrochloride (Example 27, Step B), and using the same chemistry as described in Example 20, Step D, the title compound was produced as a light brown solid, LCMS: m / z 303.0 [M+H]. + It was obtained as ESI pos.

[0213] Process D: 7-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-2,5,6,8-tetrahydro-2,7-naphthyridine-3-one Starting from 7-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-2,5,6,8-tetrahydro-2,7-naphthyridine-3-one (Example 27, Step C) and (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (CAS No. 1207961-50-9), and using the same chemistry as described in Example 25, Step B, the title compound was produced as a white amorphous lyophilized solid, LCMS: m / z 409.1 [M+H]. + It was obtained as ESI pos.

[0214] Example 29: 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; formic acid [ka]

[0215] Process A: 3-Benzyloxy-6-bromopyrazine-2-amine To a mixture of BnOH (4.0 g, 36.99 mmol, 1.54 equivalents) in THF (100 mL), NaH (1.4 g, 35.0 mmol, P: 60% of mineral oil, 1.46 equivalents) was added in portions at 0°C, and the mixture was then heated to 70°C and stirred for 1 hour. The reaction mixture was cooled to 20°C, and 6-bromo-3-chloropyrazine-2-amine (CAS No. 1082843-72-8; 5.0 g, 24 mmol, 1.0 equivalent) was added. The mixture was stirred at 70°C for 16 hours. After the reaction was complete, the mixture was quenched with water (150 mL), extracted with ethyl acetate (150 mL x 3), the organic phase was washed with brine (30 mL x 2), dried on anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (PE / siRNA, 5:1) to obtain the title compound as a white solid (4.60 g, 67% yield). LCMS: m / z 280.0 [M+H] + ,ESI pos.

[0216] Process B: N-(3-benzyloxy-6-bromopyrazine-2-yl)-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide; 2,2,2-trifluoroacetic acid To a solution of 3-benzyloxy-6-bromopyrazine-2-amine (1.43 g, 5.11 mmol, 0.8 equivalents) in THF (20 mL), 1,4-nitrophenylcarbonochloride (CAS No. 7693-46-1; 1.29 g, 6.39 mmol, 1.0 equivalent) was added. The mixture was stirred at 60°C for 1 hour. After the reaction was complete, the mixture was concentrated under vacuum and dissolved in DCM (24 mL). Then, DIPEA (2.78 mL, 15.9 mmol, 2.5 equivalents) and 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine hydrochloride (CAS No. 6000-50-6; 1.0 g, 6.39 mmol, 1.0 equivalent) were added to the reaction mixture. The mixture was stirred at 20°C for 1 hour. Once the reaction was complete, saturated sodium bicarbonate (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined extract was washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was C18 The compound was purified by column chromatography (20 g, 0.1% TFA in water / acetonitrile, acetonitrile: 30%-50%) to obtain the title compound (900 mg, yield 33%) as a white solid. 1 H NMR(400 MHz,CD3OD)δ=8.82(s,1H),8.73(d,1H),8.02(s,1H),7.96(d,1H),7.46(d,2H) ,7.35-7.30(m,2H),7.29-7.23(m,1H),5.44(s,2H),5.09(s,2H),5.05(s,2H).

[0217] Process C: N-(6-bromo-3-hydroxypyrazine-2-yl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide A solution of N-(3-benzyloxy-6-bromopyrazine-2-yl)-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide; 2,2,2-trifluoroacetic acid (900 mg, 1.67 mmol, 1.0 equivalent) in TFA (9.0 mL, 121.2 mmol, 72.7 equivalents) was stirred at 20°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under vacuum to obtain a residue, which was dissolved in methanol (5 mL) and basicized to pH=9 by the addition of NH3·H2O to form a white precipitate. After filtration, the residue was air-dried to obtain the title compound (670.0 mg, yield 89%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=12.55(s,1H),8.96(s,1H),8.76(s,1H),8.66(d,1H),7.73(d,1H),7.31(s,1H),4.92(s,4H).

[0218] Process D: 5-bromo-2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine To a solution of N-(6-bromo-3-hydroxypyrazine-2-yl)-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide (200.0 mg, 0.44 mmol, 1.0 equivalent) in toluene (2 mL), POCl3 (0.81 mL, 8.89 mmol, 20.0 equivalents) was added. The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. This was slowly added to water (10 mL) using a pipette and basicized to pH=9 with NH3·H2O. During this time, a white precipitate formed. This precipitate was collected by filtration and air-dried to obtain the title compound (110.0 mg, yield 58%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.93(s,1H),8.81(d,1H),8.08(s,1H),7.96(d,1H),5.20(s,4H).

[0219] Process E: 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; formic acid To a solution of 5-bromo-2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine (50.0 mg, 0.16 mmol, 1.0 equivalent) in 1,4-dioxane (2 mL) and water (0.4 mL), CsF (95.5 mg, 0.63 mmol, 4.0 equivalents) and (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (23.4 mg, 0.13 mmol, 0.8 equivalents) were added to XPhos Pd G3 (26.6 mg, 0.03 mmol, 0.2 equivalents). The reaction mixture was stirred under N2 at 80°C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under vacuum to obtain the residue, which was then converted to C 18 The compound was purified by column chromatography (20 g, 0.1% FA in water / acetonitrile, acetonitrile: 30%-40%), and the eluent was freeze-dried to obtain the residue. The residue was polished in acetonitrile (2 mL) and stirred for 10 minutes to obtain the title compound (12.0 mg, 18%) as a white solid. LCMS: m / z 380.0 [M+H] + ,ESI pos.

[0220] Example 30: 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-(hydroxymethyl)phenol [ka]

[0221] Process A': Methyl 2-amino-5-chloro-3-methoxybenzoate To a solution of methyl 2-amino-3-methoxybenzoate (CAS No. 5121-34-6, 10.0 g, 55.2 mmol, 1.0 equivalent) in 100 mL of DMF at 25°C, NCS (7.59 g, 56.9 mmol, 1.03 equivalents) was added. The mixture was then stirred at 50°C for 2 hours. The mixture was poured into 100 mL of water and extracted with EA (3 × 50 mL). The combined organic layer was washed with brine (50 mL × 3), dried over Na₂SO₄, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0~5:1). 18 After purification by column chromatography (20 g, 0.1% TFA in water / MeCN), the compound was freeze-dried to obtain the title compound (10.8 g, 91% yield) as a pale yellow solid. 1 H NMR (CDCl3,400 MHz): δ 7.46(d,1H),6.79(d,1H),6.01(s,2H),3.87(s,6H).

[0222] Step B': Methyl 2-bromo-5-chloro-3-methoxybenzoate To a solution of methyl 2-amino-5-chloro-3-methoxybenzoate (10.0 g, 46.4 mmol, 1.0 equivalent) in MeCN (80 mL), CuBr2 (20.7 g, 92.8 mmol, 2.0 equivalents) and CuBr (665.5 mg, 4.64 mmol, 0.1 equivalent) were added to obtain a dark color. The mixture was stirred at 25°C for 20 minutes, and t-BuONO (8.61 g, 83.5 mmol, 1.8 equivalents) was added dropwise over 10 minutes. The reaction mixture was stirred for a further 30 minutes, and then heated at 60°C for 6 hours. The reaction mixture was concentrated under vacuum, and then water (150 mL) and siRNA (100 mL) were added. The resulting mixture was stirred at 25°C for 30 minutes. The organic phase turned brown, and the aqueous phase was green and contained insoluble material. The entire mixture was filtered through Celite and washed with dimethyl acetate (100 mL x 3). The organic layer was separated, washed with brine (100 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain the title compound (8.10 g, yield 62%) as a white solid. 1 H NMR (CDCl3,400 MHz): δ 7.28(d,1H),6.98(d,1H),3.94(s,3H),3.93(s,3H).

[0223] Process C': 2-Bromo-5-chloro-3-hydroxybenzoic acid (CAS 1889090-86-1) To a solution of methyl 2-bromo-5-chloro-3-methoxybenzoate (8.1 g, 28.98 mmol, 1.0 equivalent) in DCM (200 mL), BBr3 (8.38 mL, 86.93 mmol, 3.0 equivalent) was slowly added under N2 at -78°C, and the reaction mixture was then stirred at 25°C for 12 hours. MeOH (100 mL) was slowly added to the reaction mixture, and the resulting mixture was stirred at 20°C for 30 minutes. This was mixed with 500 mL of ice water at 0°C, and the organic phase was separated. The aqueous phase was extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (2 × 200 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain the title compound (6.5 g, yield 89%) as a white solid. 1 H NMR(400 MHz, CDCl3)δ=7.62(d,1H),7.28(s,1H),6.24-6.15(m,1H).

[0224] Process D': 2-Trimethylsilylethoxymethyl-2-bromo-5-chloro-3-(2-trimethylsilylethoxymethoxy)benzoate A mixture of Cs2CO3 (25 g, 77.6 mmol, 3.0 equivalents) and 2-bromo-5-chloro-3-hydroxybenzoic acid (6.50 g, 25.9 mmol, 1.0 equivalent) in DMF (40 mL) was degassed, purged three times with N2, and stirred for 30 minutes. Then, SEMCl (12928.7 mg, 77.6 mmol, 3.0 equivalents) was added to the mixture all at once. The mixture was stirred at 25°C for 2 hours. The mixture was poured into water (70 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (50 mL), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain the title compound (10.8 g, yield 82%) as a colorless oil. 1h nmr(400 mhz,cd3od)δ=7.35(d,1h),7.27(d,1h),5.47(s,2h),5.34(s,2h),3.88-3.76(m,4h),0.99-0.88(m,4h),0.00(s,9h),-0.04(s,9h).

[0225] Step E': 2-Bromo-5-chloro-3-(2-trimethylsilylethoxymethoxy)phenyl]methanol To a solution of 2-trimethylsilylethoxymethyl 2-bromo-5-chloro-3-(2-trimethylsilylethoxymethoxy)benzoate (10.7 g, 20.9 mmol, 1.0 equivalent) in THF (50 ml), 2M LIBH4 (20.9 ml, 41.8 mmol, 2.0 equivalent) in THF solution was added, and the reaction mixture was stirred at 25°C for 16 hours. The mixture was poured into water (100 ml), extracted with ethyl acetate (50 ml x 3), washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 10 / 1) to obtain the title compound (6.0 g, yield 76%) as a colorless oil. 1 h nmr(400 mhz,cd3od)δ=7.21(d,1h),7.13(d,1h),5.31(s,2h),4.63(s,2h),3.81(t,2h),0.98(t,2h),0.00(s,9h).

[0226] Process F': 2-[[2-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chlorophenoxy]methoxy]ethyl-trimethyl-silane A mixture of NaH (163.2 mg, 4.08 mmol, 60%, 1.5 equivalents) and [2-bromo-5-chloro-3-(2-trimethylsilylethoxymethoxy)phenyl]methanol (1000.0 mg, 2.72 mmol, 1.0 equivalent) in DMF (10 mL) was degassed, purged three times with N2, and stirred for 30 minutes. Then, TBSCl (614.79 mg, 4.08 mmol, 1.5 equivalents) was added to the mixture all at once. The mixture was stirred at 25°C for 3 hours. The mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with brine (50 mL), dried on 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 20 / 1), yielding the title compound (600.0 mg, yield 46%) as a colorless oil. 1 h nmr(400 mhz,cd3od)δ=7.22(s,1h),7.17(s,1h),5.36(s,2h),4.77(s,2h),3.88 (t,1h),1.02-0.98(s,9h),0.97-0.92(m,2h),0.19(s,6h),0.03(s,9h).

[0227] Process F': tert-butyl-[[5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilylethoxymethoxy)phenyl]methoxy]dimethylsilane [ka] To a solution of 2-[[2-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chlorophenoxy]methoxy]ethyl-trimethyl-silane (390.0 mg, 0.81 mmol, 1.0 equivalent) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (CAS No. 73183-34-3, 411.04 mg, 1.62 mmol, 2.0 equivalents) in 1,4-dioxane (4 mL), Cs2CO3 (527.3 mg, 1.62 mmol, 2.0 equivalents) and tris(4-methoxy-3,5-dimethylphenyl)phosphane (35.3 mg, 0.08 mmol, 0.1 equivalent) were added. Then, Pd(OAc)2 (18.2 mg, 0.08 mmol, 0.1 equivalent) was added to the mixture under N2 conditions. Finally, the mixture was stirred at 95°C for 5 hours. The reaction mixture was cooled to room temperature, then diluted with water (30 mL) and ethyl acetate (30 mL), filtered, and the filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 20:1) to obtain the title compound (400.0 mg, yield 75%) as a colorless oil. 1 H NMR(400 MHz,CD3OD)δ=7.08(s,1H),6.99(d,1H),5.20(s,2H),4.71(s,2H),3.81(t,2 H),1.37(s,12H),0.98-0.95(m,2H),0.94(s,9H),0.09(s,6H),0.00(s,9H).

[0228] Step A: tert-butyl-[[5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-(2-trimethylsilylethoxymethoxy)phenyl]methoxy]-dimethyl-silane XPhos Pd G3 (24.5 mg, 0.03 mmol, 0.2 equivalents) was added to a solution of 5-bromo-2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine (Example 29, Step D) (46.0 mg, 0.14 mmol, 1.0 equivalent) and tert-butyl-[[5-chloro-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilylethoxymethoxy)phenyl]methoxy]-dimethylsilane (Step F') (68.9 mg, 0.13 mmol, 0.9 equivalents), and Na2CO3 (38.3 mg, 0.36 mmol, 2.5 equivalents) in 1,4-dioxane (1 mL) / water (0.2 mL). The reaction mixture was stirred under N2 at 80°C for 4 hours. Once the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under vacuum to obtain the residue, which was then converted to C 18 The title compound (10.0 mg, 10% yield) was obtained as a colorless oil by purification by column chromatography (20 g, 0.1% NH3·H2O in water / acetonitrile, 100% acetonitrile) using LCMS. LCMS: m / z 640.5 [M+H] + ,ESI pos.

[0229] Step B: 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-(hydroxymethyl)phenol To a solution of tert-butyl-[[5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-(2-trimethylsilylethoxymethoxy)phenyl]methoxy]-dimethylsilane (Step A) (10.0 mg, 0.02 mmol, 1.0 equivalent) in DCM (0.5 mL), TFA (0.5 mL, 6.73 mmol, 431 equivalents) was added. The reaction mixture was stirred at 20°C for 1.5 hours. After the reaction was complete, the mixture was concentrated under vacuum. The residue was dissolved in methanol (0.5 mL), basicized to pH=8 with NH3·H2O, and then purified by preparative HPLC (Method: Column Waters Xbridge 150*25 mm*5 μm; Conditions: Water (NH4HCO3)-ACN; Start B: 20; End B: 50; Gradient time (min): 100% B; Retention time (min): 2; Flow rate (ml / min): 25) to obtain the title compound (4.0 mg, yield 64%) as a white solid. LCMS: m / z 396.0 [M+H] + ,ESI pos.

[0230] Examples 31-42 [ka] 5-(4-chloro-2-hydroxy-6-methylphenyl)-3H-oxazolo[4,5-b]pyridine-2-thion intermediate 1 (1320.0 mg, 4.51 mmol, 1.0 equivalent) was dissolved in DCM (50 mL), oxalyl chloride (5.8 mL, 67.64 mmol, 15.0 equivalents) was added, and then DMF (1.5 mL) was added. The mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The resulting residue was dissolved in DCM (45 mL) and saturated K2CO3 aqueous solution (15 mL) was added. The DCM layer was isolated, and the aqueous layer was back-extracted with DCM (30 mL). The combined organic extracts were dried using a phase separator. The resulting solution was diluted to 92 mL with DCM and used as a stock solution in a series of reactions using the following general procedure: [ka] Amine (5.41 mmol, 1.2 equivalents) was dissolved in DMF (0.1 mL), triethylamine (0.02 mL, 0.15 mmol, 3.0 equivalents) was added, and then 1 mL of stock solution of 5-chloro-2-(2-chlorooxazolo[4,5-b]pyridine-5-yl)-3-methylphenol (1 equivalent) was added. The mixture was shaken at room temperature for 20 minutes. The DCM was evaporated overnight, and the resulting residue was diluted to 1 mL with DMF and then filtered. The resulting filtrate was purified by preparative HPLC.

[0231] The following example "Ex." was synthesized by the method outlined above: [Table 4] TIFF2026514037000048.tif226170

[0232] Example 41: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-one [ka] 5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-3H-oxazolo[4,5-b]pyridine-2-thion intermediate 2 (156.0 mg, 0.33 mmol, 1.0 equivalent) was dissolved in DCM (2 mL), and oxalyl chloride (0.59 mL, 6.87 mmol, 21.1 equivalents) was added. The mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The resulting residue was dissolved in DCM (10 mL), diluted with saturated K2CO3 aqueous solution (10 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 × 10 mL), and the combined organic layers were then concentrated under vacuum. The resulting solution was dissolved in DCM (4 mL) to prepare the stock solution. Next, 2 mL of this stock solution was added to 5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidine-4-one;dihydrochloride (59.0 mg, 0.26 mmol, 1.6 equivalents), triethylamine (0.21 mL, 1.5 mmol, 9 equivalents), and DMF (0.1 mL). The reaction mixture was stirred at room temperature for 16 hours, and then concentrated under vacuum. The resulting product was dissolved in DMF (1 mL), filtered, and the filtrate was purified by preparative HPLC (25-100% MeCN in water) to obtain the title compound as a white solid. LCMS m / z 444.2 [M+H] + ,ESI pos.

[0233] Example 43: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-ol; 2,2,2-trifluoroacetic acid [ka]

[0234] Process A: N-(3-benzyloxy-6-chloropyrazine-2-yl)-6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide To a solution of 3-benzyloxy-6-chloropyrazine-2-amine (1.37 g, 5.79 mmol, 1.0 equivalent; CAS No. 2923540-12-7) in THF (13 mL), 4-nitrophenylcarbonochloride (1.28 g, 6.37 mmol, 1.1 equivalent; CAS No. 7693-46-1) was added. The mixture was stirred at 60°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (8 mL), and then DIPEA (1.87 g, 14.48 mmol, 2.5 equivalents) and 6-methoxy-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (870.0 mg, 5.79 mmol, 1.0 equivalent) (Example 12, Step A) were added to the reaction mixture, and stirring was continued at 20°C for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (20 mL), dried on 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 = 0 / 1 to 1 / 1) to obtain the title compound (1300.0 mg, yield 49%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 9.32(s,1H),8.16(s,1H),8.02(s,1H),7.52-7.42(m,3H),7.35-7.25(m,2H),6.83(s,1H),5.39(s,2H),4.90-4.60(m,4H),3.85(s,3H).

[0235] Process B: N-[3-benzyloxy-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazine-2-yl]-6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide XPhos Pd G3 (285.8 mg, 0.34 mmol, 0.2 equivalents) was added to a mixture of 1,4-dioxane (10 mL) and water (1 mL) containing CsF (1.03 g, 6.8 mmol, 4.0 equivalents), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (747.6 mg, 3.4 mmol, 2.0 equivalents; CAS number 2557358-38-8), and the aforementioned N-(3-benzyloxy-6-chloropyrazine-2-yl)-6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide (700.0 mg, 1.7 mmol, 1.0 equivalent). The mixture was stirred under N2 at 95°C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1~0 / 1) to obtain the title compound (360.0 mg, yield 38%) as a pale yellow solid. LCMS: m / z 552.1[M+H] + ,ESI + pos.

[0236] Process C: N-[3-benzyloxy-6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazine-2-yl]-6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide MeI (63.2 mg, 0.38 mmol, 1.0 equivalent) was added to a mixture of N-[3-benzyloxy-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazine-2-yl]-6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide (210.0 mg, 0.38 mmol, 1.0 equivalent) and K2CO3 (68.3 mg, 0.49 mmol, 1.3 equivalents) in DMF (3 mL). The mixture was stirred under nitrogen at 25°C for 12 hours. The mixture was then poured into water (10 mL) and extracted with Â(10 mL x 3). The combined organic layer was washed with brine (20 mL), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 2:1) to obtain the title compound (137.0 mg, yield 63%) as a pale yellow solid. LCMS: m / z 566.1 [M+H] + ,ESI + pos.

[0237] Process D: N-[3-hydroxy-6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazine-2-yl]-6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide A solution of N-[3-benzyloxy-6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazine-2-yl]-6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide (137.0 mg, 0.24 mmol, 1.0 equivalent) in TFA (3.0 mL) was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Gemini, 150 mm*30 mm*15 μm; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 22%-52%, 12 min) to obtain the title compound (100.0 mg, yield 88%) as a yellow solid. LCMS: m / z 476.1 [M+H] + ,ESI + pos.

[0238] Step E: 2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)-5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazine The above-mentioned solution of N-[3-hydroxy-6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazine-2-yl]-6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide (90.0 mg, 0.19 mmol, 1.0 equivalent) in POCl3 (5.0 mL) was stirred at 90°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then purified by preparative HPLC (column: Phenomenex Gemini, 150 mm*30 mm*15 μm; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 22%-52%, 12 min) to obtain the title compound (41.0 mg, yield 43%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 8.27(s,1H),7.84(s,1H),7.39(s,1H),7.29(s,1H),6.98(s,1H),5.12-5.00(m,4H),3.89(s,3H),3.76(s,3H),2.15(s,3H).

[0239] Step F: 2-[2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methyl-5-(trifluoromethyl)phenol To a solution of 2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)-5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazine (14.0 mg, 0.03 mmol, 1.0 equivalent) in DCM (0.5 mL), BBr3 (0.06 mL, 0.61 mmol, 20.0 equivalents) was added at 0°C. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was then quenched by the addition of MeOH (1 mL) and subsequently concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini, 150 mm*30 mm*15 μm; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 30%-52%, 10 min) to obtain the title compound (12.0 mg, yield 88%) as a yellow solid. 1 H NMR (400 MHz, CD3OD): δ 8.25(s,1H),7.81(s,1H),7.11(s,1H),7.01(s,1H),6.96(s,1H),5.11-5.00(m,4H),3.97(s,3H),2.22(s,3H).

[0240] Process G: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-ol; 2,2,2-trifluoroacetic acid A mixture of 2-[2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methyl-5-(trifluoromethyl)phenol (10.0 mg, 0.02 mmol, 1.0 equivalent) in HBr / AcOH (0.5 mL) was stirred at 80°C for 0.5 hours. After the reaction was complete, the mixture was cooled to 20°C and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini, 150 mm*30 mm*15 μm; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 30%-52%, 10 min) to obtain the title compound (1.56 mg, yield 16%) as a white solid. LCMS: m / z 430.2 [M+H] + ,ESI+ pos.

[0241] Example 44: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-1H-pyrrolo[3,4-d]pyrimidine-2,4-dione [ka]

[0242] Process A: 6-(5-chlorooxazolo[4,5-b]pyridine-2-yl)-5,7-dihydro-1H-pyrrolo[3,4-d]pyrimidine-2,4-dione To a solution of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 200 mg, 0.95 mmol, 1.0 equivalent) in 1,4-dioxane (2 mL), 1,5,6,7-tetrahydropyrrolo[3,4-d]pyrimidine-2,4-quinone hydrochloride (CAS No. 13931-24-3, 199 mg, 1.05 mmol, 1.1 equivalent) was added, followed by the addition of triethylamine (CAS No. 121-44-8, 211 mg, 0.29 mL, 2.08 mmol, 2.2 equivalents). The reaction mixture was stirred at 90°C for 16 hours. The solvent was then evaporated. The residue was dissolved in N-methyl-2-pyrrolidinone (CAS No. 872-50-4, 12 mL), and triethylamine (210 mg, 0.29 mL, 2.08 mmol, 2.2 equivalents) was added to the reaction mixture. The mixture was stirred at 130°C for 16 hours. The reaction mixture was then cooled to room temperature, adsorbed onto ISOLUTE HM-N, and purified by flash chromatography (ISCO, 12 g SiO2; 0%~10% MeOH in DCM) to obtain the title compound (340 mg, 99% yield) as a brown solid. LCMS: m / z 306.0 [M+H] + ,ESI pos.

[0243] Step B: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-1H-pyrrolo[3,4-d]pyrimidine-2,4-dione A mixture of 6-(5-chlorooxazolo[4,5-b]pyridine-2-yl)-5,7-dihydro-1H-pyrrolo[3,4-d]pyrimidine-2,4-quinone (Example 44, Step A) (50 mg, 0.14 mmol, 1.0 equivalent), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (72 mg, 0.215 mmol, 1.44 equivalents), cesium carbonate (137 mg, 0.42 mmol, 3.0 equivalents), and XPhos Pd G3 (12.4 mg, 0.015 mmol, 0.105 equivalents) in 1,4-dioxane (0.23 mL) and water (58 μL) was flushed with argon and stirred at 90°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with dichloromethane / methanol (19:1) and a semi-saturated aqueous solution of NH4Cl. The organic layer was washed with water and brine. The aqueous layer was back-extracted twice with a mixture of dichloromethane / methanol (19:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was then purified by preparative HPLC (column: YMC-Trail, 12 nm, 5 μm, 100 x 30 mm; conditions: ACN / water + 0.1% HCOOH; gradient: ACN in water, run time 4.5 min) to obtain the title compound (8 mg, yield 12%) as a pale gray solid. LCMS: m / z 446.1 [M+H] + ,ESI pos

[0244] Example A The compound of formula I can be used as an active ingredient in a manner known to itself to produce tablets of the following composition: per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20 mg 425mg

[0245] Example B The compound of formula I can be used as an active ingredient in a manner known to itself to produce capsules of the following composition: per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5 mg 220.0 mg

Claims

1. Equation I 【Chemistry 1】 (In the formula, R １ is H, alkyl, hydroxyalkyl, or alkoxyalkyl, R ２ These are halo, haloalkyl, or cyano, R ３ Is it H? or R ２ and R ３ , and the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom optionally substituted with one or two substituents independently selected from halo and alkyl, or R ２ and R ３ , and the atoms to which they are bonded form a 3- to 6-membered cycloalkyl ring optionally substituted with one or two substituents independently selected from halo and alkyl, A is CH or N, W is as follows: 【Chemistry 2】 And, p is either 1 or 2, q is either 1 or 2. m is either 0 or 1. Y １ is C=O, CH, CH ２ , C-R ｘ , N, or NH Y ２ C=O, CH, C-R ｙ , O, N, NH, or N-CH ３ And, Y ３ C=O, CH, CH ２ CR ｙ , N, NH, or NR ｚ and Y ４ C=O, CH, CR ｙ , N, NH, or N-CH ３ And, R ｘ H is H, and each R ｙ is independently selected from -OH, alkyl, alkoxy, cyano and halo, or R ｘ +R ｙ They form a heterocycle through the atoms to which they are bonded. R ｚ (It is H, alkyl, or hydroxyalkyl.) Compounds of and pharmaceutically acceptable salts thereof.

2. R １ The compound according to claim 1, wherein is alkyl or hydroxyalkyl.

3. R １ The compound according to claims 1 to 2, wherein the alkyl group is alkyl.

4. A compound according to any one of claims 1 to 3, wherein n is 1.

5. A compound according to any one of claims 1 to 4, wherein q is 1.

6. The compound according to any one of claims 1 to 5, wherein m is 1.

7. Y １ CH, C-R ｘ A compound according to any one of claims 1 to 6, wherein the compound is N or NH.

8. Y １ The compound according to any one of claims 1 to 7, wherein is CH, N, or NH.

9. Y １ The compound according to any one of claims 1 to 8, wherein is CH.

10. Y ２ However, C=O, CH, C-R ｙ A compound according to any one of claims 1 to 9, wherein the compound is N or NH.

11. Y ２ The compound according to any one of claims 1 to 10, wherein C=O or N.

12. Y ３ However, C=O, CH, C-R ｙ , N, NH or NR ｚ The compound according to any one of claims 1 to 11.

13. Y ３ is CH, N, NH or NR ｚ The compound according to any one of claims 1 to 12.

14. Y ３ is CH, NH or NR ｚ The compound according to any one of claims 1 to 13.

15. Each R ｙ The compound according to any one of claims 1 to 14, wherein the compound is independently selected from OH, alkyl, alkoxy, cyano, or halo.

16. Each R ｙ The compound according to any one of claims 1 to 15, wherein is alkyl.

17. Each R ｚ The compound according to any one of claims 1 to 16, wherein is H, alkyl, or hydroxyalkyl.

18. Each R ｚ The compound according to any one of claims 1 to 17, wherein is a hydroxyalkyl group.

19. R １ However, it is alkyl or hydroxyalkyl, R ２ However, it is halo, haloalkyl, or cyano, R ３ However, it is H, A is CH or N, p is 1 or 2, q is 1 or 2, m is 0 or 1, Y １ However, CH, C-R ｘ , N, or NH, Y ２ However, C=O, CH, C-R ｙ , N, or NH, Y ３ However, C=O, CH, CR ｙ , N, NH or NR ｚ And, Y ４ However, C=O, CH, CR ｙ , N, NH, or N-CH ３ And, R ｘ H is H, and each R ｙ is independently selected from OH, alkyl, alkoxy, cyano, or halo, or R ｘ +R ｙ These atoms form a heterocycle containing one or two oxygen heteroatoms via the atoms to which they are bonded. R ｚ is H, alkyl, or hydroxyalkyl. The compound according to claim 1 and a pharmaceutically acceptable salt thereof.

20. R １ However, it is alkyl, R ２ However, it is halo, haloalkyl, or cyano, R ３ However, it is H, A is CH or N, p is 1 or 2, q is 1, m is 0 or 1, Y １ However, it is CH, N, or NH, Y ２ However, C=O, CH, C-R ｙ , N, or NH, Y ３ However, CH, N, NH or NR ｚ And, Y ４ However, it is CH or N, Each R ｙ However, it is alkyl, R ｚ However, it is H, alkyl or hydroxyalkyl, A compound according to claim 1 or 19 and a pharmaceutically acceptable salt thereof.

21. R １ However, it is alkyl, R ２ However, it is halo, haloalkyl, or cyano, R ３ However, it is H, A is CH or N, p is 1 or 2, q is 1, m is 0 or 1, Y １ However, it is CH, N, or NH, Y ２ However, C=O, CH, C-R ｙ , N, or NH, Y ３ However, CH, N, NH or NR ｚ And, Y ４ However, it is CH or N, Each R ｙ However, it is alkyl, R ｚ However, it is a hydroxyalkyl, A compound according to any one of claims 1 or 19 to 20, and a pharmaceutically acceptable salt thereof.

22. R １ However, it is alkyl, R ２ However, it is halo, haloalkyl, or cyano, R ３ However, it is H, A is CH or N, p is 1, q is 1, m is 1, Y １ However, it is CH, Y ２ is C=O or N, Y ３ However, CH, NH or NR ｚ And, Y ４ However, it is CH, R ｚ However, it is a hydroxyalkyl, A compound according to claim 1 or any one of claims 19 to 21, and a pharmaceutically acceptable salt thereof.

23. below: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5-methyl-1,3-dihydropyrrololo[3,4-c]pyridine-6-one; 3-Hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-one; 5-Chloro-2-(2-isoindoline-2-yloxazolo[4,5-b]pyridine-5-yl)-3-methylphenol; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]isoindorin-5-ol; 5-Chloro-2-[2-(4-fluoroisoindorin-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 4-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-Chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 2-[2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; Formic acid; 5-Chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 3-hydroxy-4-(2-isoindoline-2-yloxazolo[4,5-b]pyridine-5-yl)-5-methyl-benzonitrile; 4-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-hydroxy-5-methyl-benzonitrile; 2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 7-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-2,5,6,8-tetrahydro-2,7-naphthyridine-3-one; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-1H-pyrrolo[3,4-b]pyridine-2-one; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1-methyl-5,7-dihydropyrrololo[3,4-b]pyridine-2-one; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-2-methyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-one; 2-[2-(5,7-dihydropyrrolo[3,4-b]pyrazine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 5-(difluoromethyl)-2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 7-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-2,5,6,8-tetrahydro-2,7-naphthyridine-3-one; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; Formic acid; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-(hydroxymethyl)phenol: 5-Chloro-2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol: 5-Chloro-2-[2-(2-methoxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol: 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-3,4-dihydro-1H-isoquinoline-5-carbonitrile; 5-Chloro-2-[2-(5-methoxy-3,4-dihydro-1H-isoquinoline-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(7-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridin-2-yl]-1,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-one: 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-1,5,7,8-tetrahydro-1,6-naphthyridine-2-one; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-2H-pyrrolo[3,4-c]pyridazin-3-one; 5-Chloro-2-[2-(7,8-dihydro-5H-pyrido[3,4-b]pyrazine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-one; 5-Chloro-2-(2-(6,8-dihydro-7H-[1,3]dioxolo[4,5-e]isoindole-7-yl)oxazolo[4,5-b]pyridine-5-yl)-3-methylphenol A compound according to any one of claims 1 to 22, selected from the above, and a pharmaceutically acceptable salt thereof.

24. below: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-ol; 2,2,2-trifluoroacetic acid; 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-ol; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-1H-pyrrolo[3,4-d]pyrimidine-2,4-dione A compound according to any one of claims 1 to 22, selected from the above, and a pharmaceutically acceptable salt thereof.

25. below: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-5-methyl-1,3-dihydropyrrololo[3,4-c]pyridine-6-one; 3-Hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-one; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; Formic acid; 5-Chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 5-Chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; Formic acid; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridin-2-yl]-1,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-one; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-2H-pyrrolo[3,4-c]pyridazine-3-one A compound according to any one of claims 1 to 23, selected from the above, and a pharmaceutically acceptable salt thereof.

26. below: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 3-Hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-one; 5-Chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methylphenol; 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)oxazolo[4,5-b]pyridine-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)oxazolo[4,5-b]pyridine-5-yl]phenol; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; formic acid; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridin-2-yl]-1,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-one; 6-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-5,7-dihydro-2H-pyrrolo[3,4-c]pyridazine-3-one A compound according to any one of claims 1 to 25, selected from the above, and a pharmaceutically acceptable salt thereof.

27. below: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 3-Hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyridine-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridine-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridine-6-one; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol; formic acid; 5-Chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridine-2-yl)oxazolo[4,5-b]pyrazine-5-yl]-3-methylphenol Selected from, A compound according to any one of claims 1 to 26 and a pharmaceutically acceptable salt thereof.

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

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27 and a therapeutically inert carrier.

30. Use of a compound according to any one of claims 1 to 27 for the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

31. A compound according to any one of claims 1 to 27 for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

32. A compound according to any one of claims 1 to 27 for the treatment or prevention of a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

33. Use of the compound according to any one of claims 1 to 27 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

34. Use of the compound according to any one of claims 1 to 27 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

35. A method for inhibiting NLRP3, comprising administering an effective amount of a compound according to any one of claims 1 to 27 to inhibit NLRP3.

36. A method for treating or preventing a disease, disorder, or condition, comprising administering an effective amount of a compound according to any one of claims 1 to 27, wherein the disease, disorder, or condition is selected from asthma or COPD.

37. A method for treating or preventing a disease, disorder or condition, comprising administering an effective amount of a compound according to any one of claims 1 to 27, wherein the disease, disorder or condition is selected from Parkinson's disease or Alzheimer's disease.

38. The invention as previously described herein.

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