NLRP3 inhibitors

Abstract

The present invention relates to: novel compounds having the general formula I (I) wherein R1, R2, R3, A and W are as described herein; comprising the compound; and methods of using the compounds.

Description

TECHNICAL FIELD

[0001] The present invention relates to organic compounds useful for therapy and / or prophylaxis in a mammal, and in particular to compounds that modulate NLRP3 inhibition.

[0002] The present invention provides novel compounds of Formula I,

[0003]

[0004] I

[0005] wherein,

[0006] R 1 is H, alkyl, hydroxyalkyl, or alkoxyalkyl;

[0007] R 2 is halo, haloalkyl, or cyano;

[0008] R 3 is H;

[0009] or R 2 and R 3 form, with the atom to which they are bonded, a 4- to 6-membered heterocyclic ring comprising a single heteroatom optionally substituted with one or two substituents independently selected from halo and alkyl, or R 2 and R 3 form, with the atom to which they are bonded, a 3- to 6-membered cycloalkyl ring optionally substituted with one or two substituents independently selected from halo and alkyl;

[0010] A is CH or N;

[0011] W is:

[0012]

[0013] p is 1 or 2;

[0014] q is 1 or 2;

[0015] m is 0 or 1;

[0016] Y1 is C=O, CH, CH2, C-R x , N, or NH

[0017] Y2 is C=O, CH, C-R y , O, N, NH, or N-CH3,

[0018] Y3 is C=O, CH, CH2, CR y , N, NH, or NRz

[0019] Y4 is C=0, CH, CR y , N, NH or N-CH3

[0020] wherein R x is H and each R y is independently selected from -OH, alkyl, alkoxy, cyano and halo, or R x + R y form a heterocyclic ring with the atom to which they are attached;

[0021] R z is H, alkyl or hydroxyalkyl;

[0022] and pharmaceutically acceptable salts thereof.

[0023] Furthermore, the present application includes all racemic mixtures, their entire corresponding enantiomers and / or optical isomers. BACKGROUND

[0024] The NOD-like receptor (NLR) family, the pyrin domain-containing protein 3 (NLRP3) inflammasome, is a component of inflammatory processes and its aberrant activity is pathogenic in genetic disorders such as Cryopyrin-associated Periodic Syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis.

[0025] NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental and host-derived factors. Upon activation, NLRP3 associates with the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form large aggregates called ASC specks. Polymerized ASC in turn interacts with the cysteine protease caspase-1 to form a complex called the inflammasome. This leads to activation of caspase-1, which cleaves the precursor forms of the proinflammatory cytokines IL-1 β and IL-18, called pro-IL-1 β and pro-IL-18, respectively, thereby activating these cytokines. Caspase-1 also mediates a type of inflammatory cell death called pyroptosis. ASC specks can also recruit and activate caspase-8, which can process pro-IL-1 β and pro-IL-18 and trigger apoptotic cell death.

[0026] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted by the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. Caspase-1 can also mediate the release of alarm molecules such as IL-33 and high mobility group protein 1 (HMGB1) by controlling the pyroptotic cell death pathway. Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and allowing IL-1α release. In human cells, caspase-1 can also control the processing and secretion of IL-37. Many other substrates of caspase-1 such as components of the cytoskeleton and glycolytic pathway can result in caspase-1 -dependent inflammation.

[0027] NLRP3-dependent ASC specks are released into the extracellular environment, where they can activate caspase-1, induce processing of caspase-1 substrates, and propagate inflammation.

[0028] Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to form the immune response to infection and damage. For example, IL-1β signaling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergize with IL-23 to induce memory CD4 Th17 cells and gd T cells to produce IL-17 in the absence of T cell receptor engagement. IL-18 and IL-12 also synergize to induce IFN-γ production from memory T cells and NK cells, driving a Th1 response.

[0029] The genetic CAPS diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID) are caused by gain-of-function mutations in NLRP3, thus defining NLRP3 as a key component of the inflammatory process. NLRP3 is also implicated in the pathogenesis of many complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout, among others.

[0030] The role of NLRP3 in central nervous system diseases is emerging, and lung diseases have also been shown to be affected by NLRP3. NLRP3 has also been implicated to play a role in many central nervous system pathologies including Parkinson’s disease (PD), Alzheimer’s disease (AD), dementia, Huntington’s disease, cerebral malaria, brain injury caused by 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 play a role in many lung diseases including chronic obstructive pulmonary disorder (COPD), asthma (including steroid resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 184: 42-54, 2014; and Kim et al. Am J Respir Crit Care Med. 2017 196(3): 283-97). In addition, NLRP3 has a role in the development of liver disease, kidney disease, and aging. Many of these associations are defined using Nlrp3 − / − mice, but there are also insights into NLRP3 specific activation in these diseases. In type 2 diabetes (T2D), deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1 β signaling, leading to cell death and inflammation.

[0031] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glibenclamide inhibits IL-1 β production at micromolar concentrations in response to activation of NLRP3 but not NLRC4 or NLRP1. Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), although these agents have limited potency and are non-specific.

[0032] Current treatments for NLRP3 related diseases include biopharmaceutical agents that target IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1 β antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. These approaches have been shown to successfully treat CAPS, and these biopharmaceutical agents have been used in clinical trials for other IL-1 β related diseases.

[0033] There is a need to provide compounds having improved pharmacological and / or physiological and / or physicochemical properties, and / or to provide compounds that are useful alternatives to known compounds. SUMMARY

[0034] The present invention provides novel compounds of Formula I,

[0035]

[0036] I

[0037] wherein,

[0038] R 1 is H, alkyl, hydroxyalkyl, or alkoxyalkyl;

[0039] R 2 is halo, haloalkyl, or cyano;

[0040] R 3 is H;

[0041] or R 2 and R 3 form, with the atoms to which they are bonded, a 4- to 6-membered heterocyclic ring comprising a single O heteroatom optionally substituted with one or two substituents independently selected from halo and alkyl, or R 2 and R 3 form, with the atoms to which they are bonded, a 3- to 6-membered cycloalkyl ring optionally substituted with one or two substituents independently selected from halo and alkyl;

[0042] A is CH or N;

[0043] W is:

[0044]

[0045] p is 1 or 2;

[0046] q is 1 or 2;

[0047] m is 0 or 1;

[0048] Y1 is C=O, CH, CH2, C-R x , N, or NH

[0049] Y2 is C=O, CH, C-R y , O, N, NH, or N-CH3,

[0050] Y3 is C=O, CH, CH2, CR y , N, NH, or NR z

[0051] Y4 is C=0, CH, CR y , N, NH, or N-CH3

[0052] wherein R x is H and each R y is independently selected from -OH, alkyl, alkoxy, cyano, and halo, or R x + R y forms a heterocycle with the atom to which they are attached;

[0053] R z is H, alkyl, or hydroxyalkyl;

[0054] and pharmaceutically acceptable salts thereof.

[0055] The term "alkyl" denotes a monovalent straight-chain or branched saturated hydrocarbon group having from 1 to 6 carbon atoms. In some embodiments, if not otherwise specified, alkyl comprises 1 to 6 carbon atoms (C 1-6 -alkyl) or 1 to 4 carbon atoms (C 1-4 -alkyl). Examples of C 1-6 -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and pentyl. A particular alkyl group is methyl.

[0056] The term "alkoxy" denotes a group of the formula -0-R', wherein R' is a C 1-6 -alkyl group. Examples of C 1-6 -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and t-butoxy. A particular alkoxy group is methoxy.

[0057] The term "alkoxyalkyl" denotes an alkyl group in which one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Examples of alkoxyalkyl are methoxymethyl and methoxyethyl.

[0058] The term "cycloalkyl" denotes a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise described, cycloalkyl comprises 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the like.

[0059] The terms "halogen", "halide", and "halo" are used interchangeably herein and denote fluorine, chlorine, bromine, or iodine. Particular examples of halo are fluorine and chlorine.

[0060] The term "haloalkyl" represents a C1-6alkyl group in which at least one hydrogen atom has been replaced with the same or different halogen atom. 1-6 The term "haloalkyl" represents a C1-6alkyl group in which at least one hydrogen atom has been replaced with the same or different halogen atom. 1-6 The term "haloalkyl" represents a C1-6alkyl group in which at least one hydrogen atom has been replaced with the same or different halogen atom. Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl. Particular examples of haloalkyl include trifluoromethyl and difluoromethyl.

[0061] The term "heterocycloalkyl" represents a C3-10cycloalkyl group in which at least one carbon atom has been replaced with the same or different heteroatom selected from N, O and S. Examples of heterocycloalkyl include azetidinyl, dinitrogenocycloheptyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl and piperazinyl.

[0062] The term "hydroxyl" represents a -OH group.

[0063] The term "hydroxyl" represents a -OH group.

[0064] The term "hydroxyl" represents a -OH group.

[0065] The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effect and properties of the free bases or acids, which are not biologically or otherwise undesirable. These salts are prepared from inorganic acids such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein. In addition, these salts can be prepared as condensates by adding inorganic or organic bases to free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and basic ion-exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. The compounds of formula I can also exist in a zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are the salts with formic acid and with hydrochloric acid, resulting in a hydrochloride, dihydrochloride or trihydrochloride.

[0066] The abbreviation uM means microMolar and is equivalent to the symbol µM.

[0067] The abbreviation uL means microliter and is equivalent to the symbol µL.

[0068] The abbreviation ug means microgram and is equivalent to the symbol µg.

[0069] The compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0070] According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms can be in the "R" or "S" configuration.

[0071] Another embodiment of the present application provides a compound according to formula I as described herein and pharmaceutically acceptable salts or esters thereof, in particular a compound according to formula I as described herein and pharmaceutically acceptable salts thereof, more particularly a compound according to formula I as described herein.

[0072] One embodiment of the present application provides a compound according to formula I as described herein, wherein R 1 is alkyl or hydroxyalkyl.

[0073] One embodiment of the present application provides a compound according to formula I as described herein, wherein R1 alkyl.

[0074] One embodiment of the present application provides compounds according to formula I as described herein, wherein n is 1.

[0075] One embodiment of the present application provides compounds according to formula I as described herein, wherein q is 1.

[0076] One embodiment of the present application provides compounds according to formula I as described herein, wherein m is 1.

[0077] One embodiment of the present application provides compounds according to formula I as described herein, wherein Y1 is CH, C-R x , N or NH.

[0078] One embodiment of the present application provides compounds according to formula I as described herein, wherein Y1 is CH, N or NH.

[0079] One embodiment of the present application provides compounds according to formula I as described herein, wherein Y1 is CH.

[0080] One embodiment of the present application provides compounds according to formula I as described herein, wherein Y2 is C=0, CH, C-R y , N or NH.

[0081] One embodiment of the present application provides compounds according to formula I as described herein, wherein Y2 is C=0 or N.

[0082] One embodiment of the present application provides compounds according to formula I as described herein, wherein Y3 is C=0, CH, C-R y , N, NH or NR z .

[0083] One embodiment of the present application provides compounds according to formula I as described herein, wherein Y3 is CH, N, NH or NR z .

[0084] One embodiment of the present application provides compounds according to formula I as described herein, wherein Y3 is CH, NH or NR z .

[0085] One embodiment of the present application provides compounds according to formula I as described herein, wherein Y4 is C=0, CH, CR y , N, NH or N-CH3, wherein R xH and each R y is independently selected from OH, alkyl, alkoxy, cyano, and halo, or R x + R y forms a heterocycle containing 1 or 2 oxygen heteroatoms with the atom to which they are attached.

[0086] One embodiment of the present application provides compounds according to Formula I as described herein, wherein each R y is independently selected from OH, alkyl, alkoxy, cyano, and halo.

[0087] One embodiment of the present application provides compounds according to Formula I as described herein, wherein each R Y is alkyl.

[0088] One embodiment of the present application provides compounds according to Formula I as described herein, wherein each R z is H, alkyl, or hydroxyalkyl.

[0089] One embodiment of the present application provides compounds according to Formula I as described herein, wherein each R z is hydroxyalkyl.

[0090] One embodiment of the present application provides compounds according to Formula I as described herein, wherein,

[0091] R 1 is alkyl or hydroxyalkyl;

[0092] R 2 is halo, haloalkyl, or cyano;

[0093] R 3 is H;

[0094] A is CH or N;

[0095] p is 1 or 2;

[0096] q is 1 or 2;

[0097] m is 0 or 1;

[0098] Y1 is CH, C-R x , N, or NH;

[0099] Y2 is C=O, CH, C-R y , N, or NH;

[0100] Y3 is C=O, CH, CR y , N, NH, or NR z ;

[0101] Y4 is C=0, CH, CR y , N, NH or N-CH3;

[0102] wherein R x is H and each R y is independently selected from OH, alkyl, alkoxy, cyano and halo, or R x + R y form, with the atom to which they are attached, a heterocyclic ring comprising 1 or 2 oxygen heteroatoms;

[0103] R z is H, alkyl or hydroxyalkyl;

[0104] and pharmaceutically acceptable salts thereof.

[0105] One embodiment of the present application provides a compound according to Formula I as described herein, wherein

[0106] R 1 is alkyl;

[0107] R 2 is halo, haloalkyl or cyano;

[0108] R 3 is H;

[0109] A is CH or N;

[0110] p is 1 or 2;

[0111] q is 1;

[0112] m is 0 or 1;

[0113] Y1 is CH, N or NH;

[0114] Y2 is C=0, CH, C-R y , N or NH;

[0115] Y3 is CH, N, NH or NR z ;

[0116] Y4 is CH or N;

[0117] wherein each R y is alkyl;

[0118] R z is H, alkyl or hydroxyalkyl;

[0119] and pharmaceutically acceptable salts thereof.

[0120] One embodiment of the present application provides a compound according to Formula I as described herein, wherein

[0121] R 1 is alkyl;

[0122] R 2 is halo, haloalkyl, or cyano;

[0123] R 3 is H;

[0124] A is CH or N;

[0125] p is 1 or 2;

[0126] q is 1;

[0127] m is 0 or 1;

[0128] Y1is CH, N, or NH;

[0129] Y2is C=0, CH, C-R y , N, or NH;

[0130] Y3is CH, N, NH, or NR z ;

[0131] Y4is CH or N;

[0132] wherein each R y is alkyl;

[0133] R z is hydroxyalkyl.

[0134] and pharmaceutically acceptable salts thereof.

[0135] One embodiment of the present application provides a compound according to Formula I as described herein, wherein,

[0136] R 1 is alkyl;

[0137] R 2 is halo, haloalkyl, or cyano;

[0138] R 3 is H;

[0139] A is CH or N;

[0140] p is 1;

[0141] q is 1;

[0142] m is 1;

[0143] Y1is CH;

[0144] Y2is C=0 or N;

[0145] Y3is CH, NH or NR z ;

[0146] Y4is CH;

[0147] R z is hydroxyalkyl;

[0148] and pharmaceutically acceptable salts thereof.

[0149] Particular examples of compounds of formula I as described herein are selected from

[0150] 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3,5- dihydro-1 H-pyrrolo[3,4-c]pyridin-6-one;

[0151] 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-5- methyl-1,3-dihydropyrrolo[3,4-c]pyridin-6-one;

[0152] 3-hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1 H-pyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5- b]pyridin-5-yl]benzonitrile;

[0153] 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-3,5-dihydro-1 H- pyrrolo[3,4-c]pyridin-6-one;

[0154] 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridin-6-one;

[0155] 5-chloro-2-(2-isoindolin-2-yl oxazolo[4,5-b]pyridin-5-yl)-3-methyl-phenol;

[0156] 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol;

[0157] 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]isoindolin-5-ol;

[0158] 5-chloro-2-[2-(4-fluoroisoindolin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl- phenol;

[0159] 4-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- hydroxy-5-methyl-benzonitrile;

[0160] 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl) oxazolo[4,5-b]pyridin-5-yl]phenol;

[0161] 2-[2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]- 3-methyl-5-(trifluoromethyl)phenol;

[0162] 5-chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]- 3-methyl-phenol; formic acid;

[0163] 5-chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]- 3-methyl-phenol;

[0164] 5-chloro-2-[2-(4,6-dihydro-1 H-pyrrolo[3,4-c]pyrazol-5-yl)oxazolo[4,5-b]pyridin-5-yl]- 3-methyl-phenol;

[0165] 5-chloro-2-[2-(3,4-dihydro-1 H-2,7-naphthyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol;

[0166] 3-hydroxy-4-(2-isoindolin-2-yl oxazolo[4,5-b]pyridin-5-yl)-5-methyl-benzonitrile;

[0167] 4-[2-(7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- hydroxy-5-methyl-benzonitrile;

[0168] 2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl- 5-(trifluoromethyl)phenol;

[0169] 7-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-2,5,6,8-tetrahydro-2,7-naphthyridin-3-one;

[0170] 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-5,7-dihydro-1H-pyrrolo[3,4-b]pyridin-2-one;

[0171] 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-1-methyl-5,7-dihydropyrrolo[3,4-b]pyridin-2-one;

[0172] 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;

[0173] 2-[2-(5,7-dihydropyrrolo[3,4-b]pyrazin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;

[0174] 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol;

[0175] 5-chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrrolo[4,3-c]pyridin-5-yl)oxazolo[4,5-b]pyridin-5-yl]phenol;

[0176] 5-(difluoromethyl)-2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol;

[0177] 7-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-2,5,6,8-tetrahydro-2,7-naphthyridin-3-one;

[0178] 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-phenol; formic acid;

[0179] 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-phenol;

[0180] 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- (hydroxymethyl)phenol:

[0181] 5-chloro-2-[2-(7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol:

[0182] 5-chloro-2-[2-(7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol:

[0183] 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-3,4-dihydro-1 H- isoquinoline-5-carbonitrile;

[0184] 5-chloro-2-[2-(7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol:

[0185] 5-chloro-2-[2-(7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol:

[0186] 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-1,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-one:

[0187] 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-1,5,7,8-tetrahydro-1,6- naphthyridin-2-one;

[0188] 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-5,7-dihydro-2H- pyrrolo[3,4-c]pyridazin-3-one;

[0189] 5-chloro-2-[2-(7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol:

[0190] 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3,5,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-one;

[0191] 5-chloro-2-(2-(6,8-dihydro-7H-[1,3]dioxolo[4,5-e]isoindol-7-yl)oxazolo[4,5- b]pyridin-5-yl)-3-methylphenol;

[0192] and pharmaceutically acceptable salts thereof.

[0193] Further particular examples of compounds of formula I as described herein are selected from

[0194] 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-1,3- dihydro pyrrolo[3,4-c]pyridin-6-one; 2,2,2-trifluoroacetic acid;

[0195] 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-1,3- dihydro pyrrolo[3,4-c]pyridin-6-one; 2,2,2-trifluoroacetic acid;

[0196] 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-5,7- dihydro-1 H-pyrrolo[3,4-d]pyrimidine-2,4-dione;

[0197] and pharmaceutically acceptable salts thereof.

[0198] Preferred examples of compounds of formula I as described herein are selected from

[0199] 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-1,3- dihydro pyrrolo[3,4-c]pyridin-6-one; 2,2,2-trifluoroacetic acid;

[0200] 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-1,3- dihydro pyrrolo[3,4-c]pyridin-6-one; 2,2,2-trifluoroacetic acid;

[0201] 3-hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1 H-pyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5- b]pyridin-5-yl]benzonitrile;

[0202] 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-3,5-dihydro-1 H- pyrrolo[3,4-c]pyridin-6-one;

[0203] 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridin-6-one;

[0204] 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol;

[0205] 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol;

[0206] 5-chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; formic acid;

[0207] 5-chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol;

[0208] 5-chloro-2-[2-(4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol;

[0209] 5-chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol;

[0210] 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5- (trifluoromethyl)phenol;

[0211] 5-chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrrolo[4,3-c]pyridin-5-yl)oxazolo[4,5-b]pyridin- 5-yl]phenol;

[0212] 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3- methyl-phenol; formic acid;

[0213] 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3- methyl-phenol;

[0214] 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]- 1,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-one;

[0215] 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]- 1,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-one;

[0216] and pharmaceutically acceptable salts thereof.

[0217] More preferred examples of compounds of formula 1 as described herein are selected from

[0218] 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;

[0219] 3-hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5- b]pyridin-5-yl]benzonitrile;

[0220] 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-3,5-dihydro- 1H-pyrrolo[3,4-c]pyridin-6-one;

[0221] 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridin-6-one;

[0222] 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol;

[0223] 5-chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol;

[0224] 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-5-(trifluoromethyl)phenol;

[0225] 5-chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrrolo[4,3-c]pyridin-5-yl)oxazolo[4,5- b]pyridin-5-yl]phenol;

[0226] 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; formic acid;

[0227] 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol;

[0228] 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-1,5,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-one;

[0229] 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-5,7-dihydro- 2H-pyrrolo[3,4-c]pyridazin-3-one;

[0230] and pharmaceutically acceptable salts thereof.

[0231] Most preferred examples of compounds of formula 1 as described herein are selected from

[0232] 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3,5- dihydro-1 H-pyrrolo[3,4-c]pyridin-6-one;

[0233] 3-hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1 H-pyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5- b]pyridin-5-yl]benzonitrile;

[0234] 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-3,5-dihydro-1 H- pyrrolo[3,4-c]pyridin-6-one;

[0235] 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridin-6-one;

[0236] 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; formic acid;

[0237] 5-chloro-2-[2-(l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3- methyl-phenol;

[0238] and pharmaceutically acceptable salts thereof.

[0239] Another embodiment of the application provides a pharmaceutical composition or medicament comprising a compound of the application and a therapeutically inert carrier, diluent or excipient, as well as a method for the use of the compounds of the application in the manufacture of such composition and medicament. In one example, a compound of Formula I can be formulated into galenical administration forms by mixing with physiologically acceptable carriers, i.e., carriers that are nontoxic to recipients at the dosages and concentrations employed in the formulation. The pH of the formulation depends mainly on the particular use and concentration of the compound but is preferably in the range of about 3 to about 8. In one example, a compound of Formula I is formulated in acetate buffer at pH 5. In another embodiment, a compound of Formula I is sterile. The compounds can be stored, for example, as solid or amorphous compositions, as lyophilized formulations or as aqueous solutions.

[0240] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the part of the body to be treated, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The compounds of the application can be administered by any appropriate route, including oral, local (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intramuscular, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0241] The compounds of the application can be administered by any appropriate route, including oral, local (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intramuscular, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0242] The compounds of the application can be administered in any convenient administration form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and other active agents.

[0243] Formulations are prepared by mixing a compound of the present application and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C. et al. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams and Wilkins, 2004; Gennaro, Alfonso R. et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams and Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Formulations can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents, and other known additives to provide an aesthetically pleasing and palatable (i.e., pharmaceutical) presentation of the compound of the present application or its pharmaceutical composition, or to further their manufacture.

[0244] The compounds of the formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used as such excipients for tablets, dragees and hard gelatin capsules, for example.

[0245] Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

[0246] Suitable excipients for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0247] Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0248] Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0249] Suitable excipients for topical ophthalmic formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

[0250] Furthermore, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

[0251] The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1 to 3 individual doses, which can consist, for example, of the same amounts, should be appropriate. In the case of topical administration, the formulations can contain 0.001% to 15% by weight of medicament, and the required dosage can be 0.1 mg to 25 mg, single administration per day or week, or multiple administration per day (2 to 4 times), or multiple administration per week. However, it is evident that the upper or lower limit given herein can be exceeded when this is deemed appropriate.

[0252] An embodiment of the present application is a compound according to Formula I as described herein for use as a therapeutically active substance.

[0253] An embodiment of the present application is a compound according to Formula I as described herein for use in the treatment or prophylaxis of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0254] An embodiment of the present application is a compound according to Formula I as described herein for use in the treatment or prophylaxis of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0255] As used herein, the term "NLRP3 inhibition" refers to a complete or partial reduction in the level of NLRP3 activity and includes, for example, inhibition of active NLRP3 and / or inhibition of the activation of NLRP3.

[0256] There is evidence that NLRP3 -induced IL-1 and IL-18 play a role in inflammatory responses associated with or caused by a variety of different disorders (Menu et al., Clinical and Experimental Immunology, 166: 1-15, 2011; Strowig et al., Nature, 481: 278-286, 2012).

[0257] In one embodiment, the disease, disorder or condition is selected from the group consisting of:

[0258] (i) inflammation;

[0259] (ii) autoimmune disease;

[0260] (iii) cancer;

[0261] (iv) infection;

[0262] (v) central nervous system disease;

[0263] (vi) metabolic disease;

[0264] (vii) cardiovascular disease;

[0265] (viii) respiratory disease;

[0266] (ix) liver disease;

[0267] (x) kidney disease;

[0268] (xi) ocular disease;

[0269] (xii) skin disease;

[0270] (xiii) lymphatic disorder;

[0271] (xiv) psychological disorder;

[0272] (xv) graft versus host disease;

[0273] (xvi) allodynia;

[0274] (xvii) a condition associated with diabetes; and

[0275] (xviii) any disease in which it has been determined that the individual carries a germline or somatic non-silent mutation in NLRP3

[0276] In another embodiment, the disease, condition or disorder is selected from:

[0277] (i) cancer;

[0278] (ii) infection;

[0279] (iii) central nervous system disease;

[0280] (iv) cardiovascular disease;

[0281] (v) liver disease;

[0282] (vi) ocular disease; and

[0283] (vii) skin disease.

[0284] In yet another exemplary embodiment of the application, the disease, condition or disorder is inflammation. Examples of inflammation that can be treated or prevented include inflammatory responses associated with or caused by:

[0285] (i) a skin disease 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;

[0286] (ii) a joint disease such as osteoarthritis, systemic juvenile idiopathic arthritis, adult onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout or a seronegative spondyloarthropathy (e.g. ankylosing spondylitis, psoriatic arthritis or Reiter's disease);

[0287] (iii) a muscle disease such as polymyositis or myasthenia gravis;

[0288] (iv) a gastrointestinal disease 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 a food-related allergy that can have effects outside the gut (e.g. migraine, rhinitis or eczema);

[0289] (v) a respiratory disease such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, and in particular chronic or intractable asthma such as late asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, rhinitis carbunculosa, rhinitis sicca, rhinitis medicamentosa, rhinitis membranacea, seasonal rhinitis such as hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, inflammation caused by volcanic ash, adult respiratory distress syndrome, hypersensitivity pneumonitis or idiopathic interstitial pneumonia;

[0290] (vi) a vascular disease such as atherosclerosis, Behcet's disease, vasculitis or Wegener's granulomatosis;

[0291] (vii) an autoimmune disease such as systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes mellitus, idiopathic thrombocytopenic purpura or Graves' disease;

[0292] (viii) an ocular disease such as uveitis, allergic conjunctivitis or vernal conjunctivitis;

[0293] (ix) neurological diseases, such as multiple sclerosis or encephalomyelitis;

[0294] (x) infections or infection-related diseases, such as acquired immune deficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (type A, B or C or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis (including tuberculosis and HIV co-infection), Mycobacterium intracellulare, Pneumocystis carinii pneumonia, orchitis / epididymitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis / aseptic meningitis or pelvic inflammatory disease;

[0295] (xi) kidney diseases, such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, obesity-related glomerulopathy, acute kidney failure, acute kidney injury, uremia, nephrotic syndrome, kidney fibrosis (including chronic crystal nephropathy) or renal hypertension;

[0296] (xii) lymphatic diseases, such as Castleman disease;

[0297] (xiii) diseases of the immune system or diseases involving the immune system, such as hyper IgE syndrome, leprosy, familial hemophagocytic lymphohistiocytosis or graft-versus-host disease;

[0298] (xiv) liver diseases, such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, liver fibrosis or liver failure;

[0299] (xv) cancer, including those listed above;

[0300] (xvi) burns, wounds, trauma, hemorrhage or stroke;

[0301] (xvii) radiation exposure;

[0302] (xviii) metabolic diseases, such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or

[0303] (xix) pain, such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain or cancer-induced bone pain.

[0304] One embodiment of the present application is a compound according to Formula I as described herein for use in the treatment or prophylaxis of a disease, disorder or condition selected from:

[0305] inflammation;

[0306] autoimmune diseases;

[0307] cancer;

[0308] infections;

[0309] diseases of the central nervous system;

[0310] metabolic diseases;

[0311] cardiovascular diseases;

[0312] diseases of the respiratory tract;

[0313] diseases of the liver;

[0314] diseases of the kidney;

[0315] diseases of the eye;

[0316] diseases of the skin;

[0317] lymphatic disorders;

[0318] psychiatric disorders;

[0319] graft-versus-host disease;

[0320] allodynia;

[0321] conditions associated with diabetes; and

[0322] any disease in which it has been determined that the individual carries a germline or somatic non-silent mutation in NLRP3.

[0323] One embodiment of the present application is the use of a compound according to Formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0324] One embodiment of the present application is the use of a compound according to Formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.

[0325] One embodiment of the present application is the use of a compound according to Formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

[0326] One embodiment of the application is the use of a compound according to Formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from asthma and COPD.

[0327] One embodiment of the application is the use of a compound according to Formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Cryopyrin Associated Periodic Syndromes.

[0328] One embodiment of the application is a compound according to Formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.

[0329] One embodiment of the application is a compound according to Formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

[0330] One embodiment of the application is a compound according to Formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from asthma and COPD.

[0331] One embodiment of the application is a compound according to Formula I as described herein for the treatment or prophylaxis of a disease, disorder or condition selected from Cryopyrin Associated Periodic Syndromes.

[0332] One embodiment of the application is the use of a compound according to Formula I as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Alzheimer’s disease and Parkinson’s disease.

[0333] One embodiment of the application is the use of a compound according to Formula I as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

[0334] One embodiment of the application is the use of a compound according to Formula I as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from asthma and COPD.

[0335] One embodiment of the application is the use of a compound according to Formula I as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Cryopyrin Associated Periodic Syndromes.

[0336] One embodiment of the application is a method of 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 as described herein.

[0337] One embodiment of the application is a method of treating or preventing a disease, disorder, or condition selected from multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), comprising administering an effective amount of a compound according to Formula I as described herein.

[0338] One embodiment of the application is a method of treating or preventing a disease, disorder, or condition selected from asthma and COPD, comprising administering an effective amount of a compound according to Formula I as described herein.

[0339] One embodiment of the application is a method of treating or preventing a disease, disorder, or condition selected from Cryopyrin Associated Periodic Syndromes, comprising administering an effective amount of a compound according to Formula I as described herein.

[0340] One embodiment of the application relates to a method of inhibiting NLRP3, comprising administering an effective amount of a compound according to Formula I as described herein.

[0341] Yet another embodiment of the application is a compound of Formula I as described herein, when manufactured according to any of the described methods.

[0342] One embodiment of the application is a pharmaceutical composition comprising a compound according to Formula I as described herein and a therapeutically inert carrier.

[0343] Assay procedure

[0344] NLRP3 and cell pyroptosis

[0345] It is well known that activation of NLRP3 leads to pyroptosis and this feature plays an important 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 and 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 prevent pyroptosis and the release of proinflammatory cytokines (e.g. IL-1 β) from cells.

[0346] THP-1 cells: culture and preparation

[0347] THP-1 cells (ATCC # TIB-202) were grown in RPMI containing L-glutamine (Gibco # 11835) supplemented with 1 mM sodium pyruvate (Sigma # S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma # P4333) in 10% fetal bovine serum (FBS) (Sigma # F0804). Cells were routinely passaged and grown to confluence (approximately 10 6THP-1 cells were harvested and resuspended in RPMI media (without FBS) on the day of the experiment. Cells were then counted and checked for viability (>90%) by trypan blue (Sigma # T8154). Appropriate dilutions were made to give a concentration of 625,000 cells / ml. To this diluted cell solution, LPS (Sigma # L4524) was added to give a final assay concentration (FAC) of 1 μg / ml. 40 μΐ of final preparation was aliquoted into each well of a 96 well plate. The plate thus prepared was used for compound screening.

[0348] THP-1 cell pyroptosis assay

[0349] Compound screening was performed in steps according to the following method.

[0350] THP-1 cells containing 1.0 μg / ml LPS (25,000 cells / well) were seeded in 40 μΐ RPMI media (without FBS) in a 96 well, black-walled, clear-bottomed cell culture plate coated with poly-D-lysine (VWR # 734-0317)

[0351] 5 μΐ of compound (8-point half-log dilution, 10 μΜ top dose) or vehicle (DMSO 0.1% FAC) was added to the appropriate wells

[0352] Incubate for 3 hours at 37°C, 5% C02

[0353] 5 μΐ Nigericin (Sigma # N7143) (FAC 5 μΜ) was added to all wells

[0354] Incubate for 1 hr at 37°C, 5% C02

[0355] At the end of the incubation period, the plate was spun at 300xg for 3 min and the supernatant removed

[0356] 50 μΐ Resazurin (Sigma # R7017) (FAC 100 μΜ Resazurin, dissolved in RPMI media without FBS) was then added and the plate incubated for a further 1-2 hours at 37°C and 5% C02

[0357] The plate was read in an Envision reader at Ex 560nm and Em 590nm

[0358] IC 50Data fit to a non-linear regression equation (log inhibitor vs. response variable slope 4 parameters)

[0359] Results of the pyroptosis assay are summarized in Table 1 below, as THP IC 50 .

[0360] Human whole blood IL-1 beta release assay

[0361] For systemic delivery, the ability to inhibit NLRP3 when the compound is present in the bloodstream is of great importance. For this reason, the NLRP3 inhibitory activity of a variety of compounds in human whole blood was investigated according to the following protocol.

[0362] Human whole blood in lithium heparin tubes was taken from healthy donors from a panel of volunteer donors.

[0363] 80 μΐ of whole blood containing 1 μg / ml LPS was placed into 96-well clear bottom cell culture plates (Corning #3585)

[0364] 10 μΐ of compound (8-point half-log dilution, 10 μΜ top dose) or vehicle (DMSO 0.1% FAC) was added to the appropriate wells

[0365] Incubate for 3 hours at 37°C, 5% C02

[0366] 10 μΐ of Nigericin (Sigma #N7143) (10 μΜ FAC) was added to all wells

[0367] Incubate for 1 hr at 37°C, 5% C02

[0368] At the end of the incubation period, spin the plates at 300xg for 5 min to pellet the cells and remove 20 μΐ of supernatant and add to 96-well V-bottom plates for IL-1 β analysis (Note: these plates containing supernatant can be stored at -80°C for later analysis)

[0369] IL-1 β was measured according to the manufacturer’s protocol (Perkin Elmer- AlphaLisa IL-1 Kit AL220F-5000)

[0370] IC 50 Data fit to a non-linear regression equation (log inhibitor vs. response variable slope 4 parameters)

[0371] Results of the human whole blood assay are summarized in Table 1 below, as HWB IC 50 .

[0372] Microsomal stability

[0373] Incubations were performed in 96-well plates at 37°C in a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system with 1 µM test compound (0.5 mg / mL) in microsomes plus co-factor NADPH. After a 10-minute pre-incubation of test compound with microsomes, the enzyme reaction was started by addition of co-factor. At 1, 3, 6, 9, 15, 25, 35, and 45 minutes, incubation aliquots were removed and quenched with 1:3 (v / v) acetonitrile containing internal standard. Samples were then cooled and centrifuged, and supernatants were then analyzed by LC-MS / MS 2.

[0374] Metabolic stability in hepatocytes

[0375] Assay description:

[0376] Biological materials. Cryopreserved hepatocytes [mouse, rat, rabbit, monkey, and human (male and female; pooled)] were obtained. Viability of hepatocytes after reconstitution was at least 80% throughout the study. Ready-to-use rat / human HepatoPac® cultures [long-term hepatocyte co-cultures; pooled (for humans, n=5 for males and n=5 for females)] with stromal mouse fibroblasts (negative control; pooled) were obtained and used for incubation with plates, application media, and maintenance media.

[0377] Metabolism by suspended hepatocytes. Primary pooled cryopreserved hepatocytes were reconstituted in pre-warmed William's E medium containing 10% FCS, 0.05 mg / mL streptomycin, and 50 U / mL penicillin and 0.4 mM L-glutamine, and 0.01 mg / mL gentamicin, 0.048 mg / mL hydrocortisone, and 0.004 mg / mL insulin to a final suspension density of 1 x 106 cells / mL. Incubations were performed fully automatically with a liquid handling system (Tecan) equipped with a CO2 incubator with orbital shaker. After addition of, for example, 1 µM (1 x 105 cells / well) test compound to the wells, 96-well hepatocyte suspension culture plates were incubated at 37°C in 5% CO2. At the indicated time points, samples were quenched by addition of acetonitrile (including internal standard) to the incubation wells for up to 2 hours.

[0378] ​​Metabolism by HepatoPac®. Incubation of test articles (at e.g. 1 µM, 0.1% v / v DMSO) as performed in the suspension assay was performed in 96-well plates containing co-cultures of adherent hepatocytes with mouse fibroblast control cells or single control cells (5% C02 atmosphere and 37°C). The incubation medium in human HepatoPac® was identical to the incubation medium in the suspended hepatocytes. At the prescribed time points (2, 18, 26, 48, 72 and 96 hours), the entire well was quenched with ice-cold acetonitrile containing internal standard.

[0379] The samples were then centrifuged appropriately and the supernatant was analyzed by LC-MS / MS. Incubations were performed with n = 1 or 2.

[0380] Table 1: NLRP3 inhibitory activity

[0381]

[0382] The application will now be demonstrated by the following examples, which are not limiting.

[0383] In case of preparation examples obtained as a mixture of enantiomers or diastereomers, the pure enantiomers or diastereomers can be obtained by the methods described herein or methods known to the skilled person, such as chiral chromatography or crystallization.

[0384] Experimental methods

[0385] Abbreviations

[0386]

[0387] Examples

[0388] All examples and intermediates were prepared under a nitrogen atmosphere, if not stated otherwise.

[0389] Preparation of intermediates

[0390] Intermediate 1:

[0391] 5-(4-Chloro-2-hydroxy-6-methyl-phenyl)-3H-oxazolo[4,5-b]pyridine-2-thione

[0392]

[0393] Step A: 2-amino-6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridin-3-ol

[0394] (4-Chloro-2-hydroxy-6-methylphenyl)boronic acid (CAS No. 1207961-50-9, 1972.4 mg, 10.6 mmol, 1.0 eq), XPhos Pd G3 (269.02 mg, 0.32 mmol, 0.03 eq), saturated aqueous NaHC03solution (5 mL), and 2-amino-6-bromopyridin-3-ol (CAS No. 934758-27-7, 2000.0 mg, 10.6 mmol, 1.0 eq) were suspended in dioxane (40 mL) and degassed with N2(5 min). The reaction mixture was heated to 80 °C and stirred for 18 h. The reaction mixture was filtered through a plug of celite, then dried down onto silica, and purified by silica gel flash chromatography (80 g column, 0% to 10% MeOH / DCM) to give the title compound (1001 mg, 37% yield) as a light brown solid. LCMS m / z 251.1 [M+H] + ESI pos.

[0395] Step B: 5-(4-chloro-2-hydroxy-6-methyl-phenyl)-3H-oxazolo[4,5-b]pyridine-2- thione

[0396] 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 eq) in DMF (20 mL) was added 1,1'-thiocarbonyldiimidazole (938.4 mg, 5.27 mmol, 1.2 eq) at room temperature and the reaction mixture was stirred for 18 h. The mixture was poured into 1 N aqueous HC1 (100 mL). The mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with 10 wt% aqueous LiCl (3 x 50 mL), dried (phase separator) and concentrated in vacuo to give the title compound (1102.0 mg, 77% yield) as a light brown solid. LCMS m / z 293.0 [M+H] + ESI pos.

[0397] Intermediate 2:

[0398] 5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-3H-oxazolopyridine-2-thione

[0399]

[0400] Step A: 2-amino-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridin-3-ol

[0401] A solution of 2-amino-6-bromopyridin-3-ol (250.0 mg, 1.32 mmol, 1.0 eq), 3-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (359.6 mg, 1.19 mmol, 0.9 eq), and XPhos Pd G3 (112.09 mg, 0.13 mmol, 0.1 eq) in 1,4-dioxane (1 mL) was bubbled with nitrogen for 5 min. Saturated aqueous Na2CO3 (0.5 mL) and water (0.1 mL) were added, then the reaction mixture was heated to 80 °C and stirred at this temperature for 18 h. The reaction mixture was cooled to room temperature, then it was concentrated in vacuo. The resulting residue was dissolved in EtOAc (20 mL) and filtered through a pad of celite. The filtrate was diluted with 1:1 water:brine (20 mL), then the layers were separated. The aqueous layer was extracted with EtOAc (2 x 20 mL), then the combined organics were concentrated in vacuo. The crude product was dry loaded onto celite and purified by silica gel chromatography (12 g cartridge, 0% to 100% (3:1 EtOAc:EtOH, containing 2% NH3OH) / isohexane) to give the title compound (119.0 mg, 31% yield) as a light grey solid. LCMS m / z 285.1 [M+H] + ESI pos.

[0402] Step B: 5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-3H-oxazolo[4,5-b]pyridine- 2-thione

[0403] 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), then the layers were separated. The aqueous layer was extracted with EtOAc (2 x 10 mL), then the combined organic phases were concentrated in vacuo. The crude product was triturated with isohexane (10 mL) to give the title compound (156 mg, 78% yield) as a light brown solid. LCMS m / z 327.1 [M+H] + ESI pos.

[0404] Preparation of Examples

[0405] Example 1:

[0406] 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

[0407]

[0408] Step A: 6-benzyloxy-tert-butyl 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxylate

[0409] 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 eq) and benzyl alcohol (603 mg, 0.58 mL, 5.58 mmol, 1.51 eq) in 1,4-dioxane (11 mL) was added potassium tert-butoxide (579 mg, 5.16 mmol, 1.40 eq). 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 layers were washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient: 0% to 20% ethyl acetate in heptane) to give the title compound (898 mg, yield 71%) as a purple solid. LCMS: m / z 327.2 [M+H] ESI pos. +

[0410] Step B: tert-butyl 6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxylate

[0411] ​A solution of tert-butyl 6-benzyloxy-l,3-dihydropyrrolo[3,4-c]pyridine-2-carboxylate (Example 1, Step A) (895 mg, 2.61 mmol, 1.00 eq) in ethyl acetate (10 mL) and methanol (10 mL) was evacuated and flushed with argon, alternating three times. Activated carbon supported palladium, 10% Pd on carbon (90 mg, 0.08 mmol, 0.03 eq) was carefully added. The reaction flask was evacuated and flushed with argon, alternating three times. 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 rinsed thoroughly with warm ethyl acetate / methanol. The filtrate was concentrated in vacuo to give the title compound (654 mg, 96% yield, 90% purity) as an off-white solid, which was used without further purification. LCMS: m / z 237.1 [M+H] + , ESI pos.

[0412] Step C: 2-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine- 6-one Step D: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-

[0413] To a solution of tert-butyl 6-oxo-3,5-dihydro-lH-pyrrolo[3,4-c]pyridine-2-carboxylate (Example 1, Step B) (60 mg, 0.24 mmol, 1.13 eq) in dichloromethane (0.70 mL) and methanol (0.30 mL) was added 4 M HC1 in dioxane (720 mg, 0.60 mL, 2.40 mmol, 11.3 eq) dropwise. Stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 1,4-dioxane (0.50 mL) and 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS Number 1783370-92-2, 45 mg, 0.21 mmol, 1.00 eq) was added followed by triethylamine (73 mg, 0.10 mL, 0.72 mmol, 3.37 eq). The reaction mixture was stirred at 90 °C for 25 hours and then left to stand at room temperature for 4 days. The reaction mixture was extracted with a mixture of dichloromethane / methanol (9: 1) and half-saturated aqueous NaHC03 three times (solid present in the aqueous phase). 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 give the title compound (20 mg, 31% yield) as a dark brown solid. LCMS: m / z 289.1 [M+H] + , ESI pos.

[0414] 3,5-dihydro-1H-pyrrolo[3,4-c]pyridine-6-one Step A: tert-butyl 5-methyl-6-oxo-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxylate

[0415] A mixture of 2-(5-chlorooxazolopyridin-2-yl)-3,5-dihydro-lH-pyrrolo[3,4- c]pyridin-6-one (Example 1, Step C) (20 mg, 0.07 mmol, 1.00 eq), 3-methyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS Number 2557358-38-8, 38 mg, 0.11 mmol, 1.72 eq, 90% purity), cesium carbonate (65 mg, 0.20 mmol, 3.03 eq), and XPhos Pd G3 (9 mg, 0.01 mmol, 0.16 eq) in 1,4-dioxane (0.60 mL) and water (0.15 mL) was flushed 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 half-saturated aqueous NH4C1. 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 in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in dichloromethane) to give the title compound (14 mg, 47% yield) as an off-white solid. LCMS: m / z 429.2 [M+H] + , ESI pos.

[0416] Example 2:

[0417] 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolopyridin-2-yl]-5-methyl- 1,3-dihydropyrrolo[3,4-c]pyridin-6-one

[0418]

[0419] Step B: 2-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-5-methyl-1,3-dihydropyrrolo[3,4-c]pyridine- 6-one

[0420] To a mixture of tert-butyl 6-oxo-3,5-dihydro-lH-pyrrolo[3,4-c]pyridine-2-carboxylate (Example 1, Step B) (170 mg, 0.68 mmol, 1.00 eq) in N,N-dimethylformamide (0.80 mL) was added potassium carbonate (222 mg, 1.61 mmol, 2.35 eq) followed by iodomethane (227 mg, 0.10 mL, 1.60 mmol, 2.34 eq). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was added to saturated aqueous NH4C1 and extracted with ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with saturated aqueous NH4C1 and water. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in dichloromethane) to give the title compound (144 mg, 80% yield) as an off-white solid. LCMS: m / z 251.1 [M+H] + , ESI pos.

[0421] Step C: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]- 5-methyl-1,3-dihydropyrrolo[3,4-c]pyridine-6-one

[0422] To a solution of tert-butyl 5-methyl-6-oxo-l,3-dihydropyrrolo[3,4-c]pyridine-2- carboxylate (Example 2, Step A) (106 mg, 0.40 mmol, 1.21 eq) in dichloromethane (1.0 mL) and methanol (0.50 mL) was added dropwise 4 M HC1 in dioxane (1.20 g, 1.0 mL, 4.00 mmol, 12.1 eq). Stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 1,4-dioxane (0.70 mL) and added 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 70 mg, 0.33 mmol, 1.00 eq) followed by triethylamine (112 mg, 0.154 mL, 1.10 mmol, 3.33 eq). The reaction mixture was stirred at 90 °C for 2 days. The reaction mixture was cooled to room temperature and extracted with a mixture of dichloromethane / methanol (9:1) and half-saturated aqueous NaHC03. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)) to give the title compound (20 mg, yield 19%) as an off-white solid. LCMS: m / z 303.1 [M+H] + , ESI pos.

[0423] Step A: 2-(5-bromooxazolo[4,5-b]pyridin-2-yl)-3,5-dihydro-1H-pyrrolo[3,4-c]pyridine- 6-one Step A`: 4-amino-3-methoxy-5-methyl-benzonitrile

[0424] A mixture of 2-(5-chlorooxazolopyridin-2-yl)-5-methyl-1,3-dihydropyrrolo[3,4- c]pyridin-6-one (Example 2, Step B) (27 mg, 0.08 mmol, 1.00 eq), 3-methyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS Number 2557358-38-8, 49 mg, 0.15 mmol, 1.72 eq, 90% purity), cesium carbonate (84 mg, 0.26 mmol, 3.04 eq), and XPhos Pd G3 (12 mg, 0.01 mmol, 0.17 eq) in 1,4-dioxane (0.80 mL) and water (0.20 mL) was flushed with argon and stirred at 100 °C for 3.5 h. The reaction mixture was cooled to room temperature and extracted with a mixture of dichloromethane / methanol (9:1) and half-saturated aqueous NH4Cl. 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 in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 5% methanol in dichloromethane) to give the title compound (25 mg, 63% yield) as an off-white solid. LCMS: m / z 443.2 [M+H] + , ESI pos.

[0425] Example 3:

[0426] 3-hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridin-2-yl)oxazolopyridin- 5-yl]benzonitrile

[0427]

[0428] Step B`: 4-bromo-3-methoxy-5-methyl-benzonitrile Step C`: 3-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0429] To a solution of tert-butyl 6-oxo-3,5-dihydro-lH-pyrrolo[3,4-c]pyridine-2-carboxylate (Example 1, Step B) (165 mg, 0.63 mmol, 1.16 eq, 90% purity) in dichloromethane (1.6 mL) and methanol (0.80 mL) was added dropwise 4 M HC1 in dioxane (1.80 g, 1.5 mL, 6.00 mmol, 11.1 eq). Stirred at room temperature for 3.5 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 1,4-dioxane (1.3 mL) and added 5-bromo-2-(methylthio)oxazolo[4,5-b]pyridine (CAS Number 1780768-09-3, 140 mg, 0.54 mmol, 1.00 eq) 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 half-saturated aqueous NaHC03solution. The mixture was sonicated, filtered, rinsed with a minimal 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, 37% yield, 90% purity) as a grey solid. LCMS: m / z 333.0 / 335.0 [M+H] ESI pos. + , ESI pos.

[0430] Step D`: (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid

[0431]

[0432] Two batches were run in parallel.

[0433] To a solution of commercially available 4-bromo-2-methoxy-6-methyl aniline (CAS No. 348169-39-1, 25.0 g, 115 mmol, 1.00 eq) in DMF (250 mL) was added Zn(CN)2 (13.5 g, 115 mmol, 7.34 mL, 1.0 eq) and Pd(PPh3)4 (66.8 g, 57.8 mmol, 0.5 eq). 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 Na2S04, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give the title compound (28.0 g, 75% yield) 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).

[0434] Step B: 3-hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]benzonitrile

[0435] To a solution of CuBr (46.4 g, 323 mmol, 9.86 mL, 1.50 eq) in MeCN (180 mL) was added t-BuONO (33.3 g, 323 mmol, 38.5 mL, 1.50 eq) and stirred at 65 °C. Then a solution of above intermediate 2B 4-bromo-3-methoxy-5-methyl-benzonitrile (35.0 g, 215 mmol, 1.00 eq) in MeCN (180 mL) was added at 65 °C. The mixture was stirred at 65 °C for 3.5 hours. Upon completion, saturated aqueous Na2S03 (400 mL) and saturated aqueous NH4CI (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 Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, Rf = 0.75) to give the title compound (20.7 g, yield 42%) as a white solid. f = 0.75) to give the title compound (20.7 g, yield 42%) as a white solid. 1H NMR (DMSO-d6) δ 7.43, 7.40 (2s, 1H each), 3.90 (s, 3H), 2.37 (s, 3H).

[0436] Step A: tert-butyl 5-(2-hydroxyethyl)-6-oxo-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxylate Step B: 2-(5-bromooxazolo[4,5-b]pyridin-2-yl)-5-(2-hydroxyethyl)-1,3-dihydropyrrolo[3,4-c]pyridine-6-one

[0437] To a solution of the above 4-bromo-3-methoxy-5-methyl-benzonitrile (18.0 g, 79.6 mmol, 1.00 eq) in DMF (180 mL) was added B2Pin2 (30.3 g, 119 mmol, 1.50 eq) and AcOK (35.1 g, 358 mmol, 4.50 eq). The mixture was stirred at 20 °C for 0.5 hour, and Pd(dppf)Cl2CH2Cl2(13.0 g, 15.9 mmol, 0.20 eq) was added. The mixture was stirred at 100 °C for 12 hours. The mixture was filtered with celite, 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 give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1, Rf= 0.30) to give the title compound (18.0 g, yield 83%) as a white solid. f = 0.30) to give the title compound (18.0 g, yield 83%) 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).

[0438] ​

[0439] A solution of the above 3-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzonitrile (17.0 g, 96.0 mmol, 1.00 eq) in dichloromethane (170 mL) was cooled to 0 °C and BBr3(38.9 g, 155 mmol, 2.50 eq) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was poured into H2O (200 mL), filtered, then the filter cake was collected and triturated with EtOAc (20 mL) to give the title compound as a grey solid (4.67 g, 42% yield). LCMS: m / z 178.1 [M+H] + , ESI pos.

[0440] ​ ​

[0441] A mixture of 2-(5-bromooxazol[4,5-b]pyridin-2-yl)-3,5-dihydro-lH-pyrrolo[3,4- c]pyridin-6-one (Example 3, Step A) (35 mg, 0.09 mmol, 1.00 eq, 90% purity), (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid (Step D`) (9 mg, 0.16 mmol, 1.73 eq), cesium carbonate (93 mg, 0.29 mmol, 3.02 eq), and XPhos Pd G3 (13 mg, 0.02 mmol, 0.16 eq) in 1,4-dioxane (1.0 mL) and water (0.25 mL) was flushed with argon and stirred at 95 °C for 2 h. The reaction mixture was cooled to room temperature and extracted with a mixture of dichloromethane / methanol (9:1) and half-saturated aqueous NH4C1. 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 in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 20% methanol in dichloromethane). The product-containing fractions were combined and concentrated in vacuo. The residue was triturated with ethyl acetate to give the title compound (7.7 mg, 20% yield) as an off-white powder. LCMS: m / z 386.1 [M+H] + , ESI pos.

[0442] Example 4:

[0443] 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-3,5- dihydro-1H-pyrrolo[3,4-c]pyridin-6-one

[0444]

[0445] A mixture of 2-(5-bromo oxazolo[4,5-b]pyridin-2-yl)-3,5-dihydro-1H-pyrrolo[3,4- c]pyridin-6-one (Example 3, Step A) (37 mg, 0.10 mmol, 1.00 eq, 90% purity), (4- chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS Number 1207961-50-9, 30 mg, 0.16 mmol, 1.61 eq), potassium carbonate (50 mg, 0.36 mmol, 3.62 eq), and 1,1'- bis(diphenylphosphino)ferrocene-palladium(ii) dichloromethane complex (13 mg, 0.02 mmol, 0.16 eq) in 1,4-dioxane (0.80 mL) and water (0.40 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 (19:1) and half-saturated aqueous 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 in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 4 g, gradient: 0% to 100% in dichloromethane:methanol:NH4OH 9:1:0.05). All fractions containing product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate to give the title compound (18 mg, 43% yield) as a light brown powder. LCMS: m / z 395.1 [M+H] + , ESI pos.

[0446] Example 5:

[0447] 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridin-6-one

[0448]

[0449] ​

[0450] To a suspension of tert-butyl 6-oxo-3,5-dihydro-lH-pyrrolo[3,4-c]pyridine-2- carboxylate (Example 1, Step B) (100 mg, 0.38 mmol, 1.00 eq, 90% purity) in N,N- dimethylformamide (0.50 mL) was added cesium carbonate (290 mg, 0.89 mmol, 2.34 eq) followed by 2-iodoethanol (132 mg, 0.06 mL, 0.77 mmol, 2.02 eq). The reaction mixture was stirred at 90 °C for 16 hours and was left to stand at room temperature for 16 hours. The reaction mixture was extracted with 5% aqueous LiCl and ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with 5% aqueous LiCl three times and with brine once. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (120 mg, 96% yield, 85% purity) as an off-white solid which was used without further purification. LCMS: m / z 281.1 [M+H] ESI pos. + , ESI pos.

[0451] ​ ​

[0452] To a solution of tert-butyl 5-(2-hydroxyethyl)-6-oxo-l,3-dihydropyrrolo[3,4- c]pyridine-2-carboxylate (Example 5, Step A) (117 mg, 0.35 mmol, 1.14 eq, purity 85%) in dichloromethane (0.92 mL) and methanol (0.46 mL) was added dropwise 4 M HC1 in dioxane (1.03 g, 0.86 mL, 3.44 mmol, 11.1 eq). Stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 1,4-dioxane (0.74 mL) and water (0.08 mL) and added 5-bromo-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1780768-09-3, 80 mg, 0.31 mmol, 1.00 eq) followed by N,N-diisopropylethylamine (129 mg, 0.17 mL, 1.00 mmol, 3.22 eq). 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 half-saturated aqueous NaHC03. The aqueous layer was back-extracted with a mixture of dichloromethane / methanol (9:1) five times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in dichloromethane) to give the title compound (54 mg, yield 42%, purity 90%) as an off-white solid. LCMS: m / z 377.0 / 379.0 [M+H] + , ESI pos.

[0453] Step C: 5-(2-Hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4, 5-b]pyridin-2-yl]-l,3-dihydropyrrolo[3,4-c]pyridin-6-one

[0454] A mixture of 2-(5-bromooxazolo[4,5-b]pyridin-2-yl)-5-(2-hydroxyethyl)-1,3- dihydropyrrolo[3,4-c]pyridin-6-one (Example 5, Step B) (53 mg, 0.13 mmol, 1.00 eq, 90% purity), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)phenol (CAS Number 2557358-38-8, 73 mg, 0.22 mmol, 1.72 eq, 90% purity), cesium carbonate (125 mg, 0.38 mmol, 3.03 eq), and XPhosPd G3 (17 mg, 0.02 mmol, 0.16 eq) in 1,4-dioxane (1.2 mL) and water (0.30 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 half-saturated aqueous NH4Cl. The aqueous layer was back-extracted twice with a mixture of dichloromethane / methanol (9:1). The organic layers were washed with water and brine (precipitation was present in the aqueous layer). The combined aqueous layers were filtered, rinsed with water and ethyl acetate. The filter cake was dried on a rotary evaporator and then placed under high vacuum to give the title compound (32 mg, 51% yield) as an off-white powder. LCMS: m / z 473.1 [M+H] + , ESI pos.

[0455] Example 6-9:

[0456] Intermediate 1 (1320.0 mg, 4.51 mmol, 1.0 eq) was dissolved in DCM (50 mL) and oxalyl chloride (5.8 mL, 67.6 mmol, 15.0 eq) was added followed by dropwise addition of DMF (1.5 mL). The mixture was stirred at room temperature for 30 min and then concentrated in vacuo. The resulting residue was taken up in DCM (45 mL) and saturated aqueous K2CO3 (15 mL) was added. The DCM layer was separated 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]pyridin-5-yl)-3-methylphenol) was made up to 92 mL and used as a stock solution in a series of reactions using the following general procedure:

[0457]

[0458] Dissolve the amine (5.41 mmol, 1.2 eq) in DMF (0.1 mL) and add triethylamine (0.02 mL, 0.15 mmol, 3.0 eq) followed by 1 mL of a stock solution of 5-chloro-2-(2-chlorooxazol[4,5-b]pyridin-5-yl)-3-methylphenol (1 eq.). Shake the mixture at room temperature for 20 min. Evaporate the DCM overnight and make up the resulting residue to 1 mL with DMF then filter. Purify the resulting filtrate by preparative HPLC.

[0459]

[0460] Example 10:

[0461] 4-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl- benzonitrile

[0462]

[0463] Step A: 5-Chloro-2-(l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridine

[0464] 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 eq) and 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine dihydrochloride (CAS No. 6000-50-6, 128 mg, 0.66 mmol, 1.40 eq) in 1,4-dioxane (0.90 mL) and water (0.10 mL) was added N,N-diisopropylethylamine (243 mg, 0.32 mL, 1.88 mmol, 3.97 eq). The reaction mixture was stirred at 90 °C for 72 hours. The reaction mixture was cooled to room temperature and extracted with semi-saturated aqueous NaHCO3 and extracted with a mixture of dichloromethane / methanol (19:1) three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 5% methanol in dichloromethane) to give the title compound (117 mg, yield 86%) as an off-white solid. LCMS: m / z 273.1 [M+H] + ESI pos.

[0465] Step B: 4-[2-(l,3-Dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- hydroxy-5-methyl-benzonitrile Step A: 5-Chloro-2-(2-methyl-7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxazolo[4,5-

[0466] The title compound was obtained as a white solid, LCMS: m / z 370.1 [M+H] + , ESI pos, prepared using a similar chemical procedure described in Example 3, Step B, starting from 5-chloro-2-(l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5- b]pyridine (Example 10, Step A) and (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid (Example 3, Step D’).

[0467] Example 11:

[0468] 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol

[0469]

[0470] b]pyridine Step B: 5-Chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxa

[0471] 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 eq) and 2-methyl-5,6,7,8-tetrahydropyrrolo[4,3-d]pyrimidine (CAS No. 676994-65-3, 74 mg, 0.50 mmol, 1.31 eq) in 1,4-dioxane (0.90 mL) and water (0.10 mL) was added N,N-diisopropylethylamine (106 mg, 0.14 mL, 0.82 mmol, 2.17 eq). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was cooled to room temperature and extracted with half-saturated aqueous NaHCO3 and extracted with a mixture of dichloromethane / methanol (19:1) three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 5% methanol in dichloromethane) to give the title compound (99 mg, yield 82%) as an off-white solid. LCMS: m / z 302.1 [M+H] + , ESI pos.

[0472] zolo[4,5-b]pyridin-5-yl]phenolStep A: 6-Methoxy-2,3-dihydro-lH-pyrrolo[3,4-c]pyridine

[0473] The title compound was obtained as off-white foam, LCMS: m / z 408.2 [M+H] + , ESI pos, starting from 5-chloro-2-(2-methyl-7,8-dihydro-5H-pyrrolo[4,3- d]pyrimidin-6-yl)oxazolo[4,5-b]pyridine (Example 11, Step A) and (4-chloro-2- hydroxy-6-methyl-phenyl)boronic acid (CAS Number 1207961-50-9), using a similar chemical process as described in Example 4.

[0474] Example 12:

[0475] 2-[2-(6-methoxy-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]- 3-methyl-5-(trifluoromethyl)phenol

[0476]

[0477] Step B: 5-Chloro-2-(6-methoxy-l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridine

[0478] To a mixture of 6-chloro-2,3-dihydro-lH-pyrrolo[3,4-c]pyridine (CAS Number 905273-90-7, 210 mg, 1.36 mmol, 1.00 eq) in 1,4-dioxane (2.8 mL) was added sodium methoxide solution (25 wt% in methanol) (1.42 g, 1.5 mL, 6.56 mmol, 4.83 eq) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, poured onto half-saturated aqueous NH4Cl solution, and extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.

[0479] The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 20% methanol in dichloromethane) to give the title compound (175 mg, yield 81%) as a purple solid. LCMS: m / z 151.1 [M+H] + , ESI pos.

[0480] Step C: 2-[2-(6-Methoxy-l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-5-(trifluoromethyl)phenol Step A: 5-Chloro-2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridine

[0481] 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 eq) and 6-methoxy-2,3-dihydro-lH-pyrrolo[3,4-c]pyridine (Example 12, Step A) (114 mg, 0.72 mmol, 1.32 eq) in 1,4-dioxane (1.3 mL) and water (0.14 mL) was added N,N-diisopropylethylamine (152 mg, 0.20 mL, 1.18 mmol, 2.16 eq). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and extracted with half-saturated aqueous NaHC03 and with a mixture of dichloromethane / methanol (19:1) three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 5% methanol in dichloromethane) to give the title compound (159 mg, yield 92%) as a pink solid. LCMS: m / z 303.1 [M+H] + , ESI pos.

[0482] Step B: 5-Chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol formate Step A: 5-Chloro-2-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)oxazolo[4,5-b]pyridine

[0483] The title compound was obtained as a light brown solid, LCMS: m / z 443.2 [M+H] + , ESI pos, starting from 5-chloro-2-(6-methoxy-l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridine (Example 12, Step B) and 3-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)phenol (CAS No. 2557358-38-8) using a similar chemical procedure described in Example 1, Step D.

[0484] Example 13:

[0485] 5-chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol formate

[0486]

[0487] Step B: 5-Chloro-2-[2-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol

[0488] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 200 mg, 1.00 mmol, 1.00 eq) and 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (CAS No. 53493-80-4, 133 mg, 1.10 mmol, 1.10 eq) in 1,4-dioxane (2.1 mL) was added triethylamine (113 mg, 0.16 mL, 1.12 mmol, 1.12 eq) under argon. The reaction mixture was stirred at 90 °C for 16 hours. Additional 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (CAS No. 53493-80-4, 121 mg, 1.00 mmol, 1.00 eq) 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 half-saturated aqueous NaHCO3 solution. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 80% ethyl acetate in heptane) to give the title compound (70 mg, yield 26%) as a brown solid. LCMS: m / z 274.0 [M+H] + , ESI pos.

[0489] Step A: 5-Chloro-2-(3,4-dihydro-lH-2,7-naphthyridin-2-yl)oxazolo[4,5-b]pyridine Step B: 5-Chloro-2-[2-(3,4-dihydro-lH-2,7-naphthyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol

[0490] The title compound was obtained as a white solid, LCMS: m / z 380.1 [M+H] + , ESI pos, prepared using a similar chemical process described in Example 4, starting from 5-chloro-2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridine (Example 13, Step A) and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS No. 1207961-50-9) and purified by reverse phase chromatography (column: YMC-Triart C18, eluent: water + acetonitrile containing 0.1% HCOOH).

[0491] Example 14:

[0492] 5-chloro-2-[2-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl- phenol

[0493]

[0494] Step A: 5-Chloro-2-isoindolin-2-yl-oxazolo[4,5-b]pyridine

[0495] 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 eq) and 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (67 mg, 0.61 mmol, 1.30 eq) in 1,4-dioxane (1.0 mL) and water (0.11 mL) was added N,N-diisopropylethylamine (135 mg, 0.178 mL, 1.05 mmol, 2.21 eq). 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 half-saturated aqueous NaHCO3 and extracted with a mixture of dichloromethane / methanol (19:1) three times and a mixture of dichloromethane / methanol (9:1) four times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM and purified by flash chromatography (silica gel, gradient: 0% to 5% methanol in dichloromethane) to give the title compound (77 mg, yield 56%, purity 90%) as a white solid. LCMS: m / z 262.1 [M+H] + ESI pos.

[0496] Step B: 3-Hydroxy-4-(2-isoindolin-2-yl oxazolo[4,5-b]pyridin-5-yl)-5-methyl-benzonitrile Step A: 5-Chloro-2-(7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridine

[0497] The title compound was obtained as an off-white solid, LCMS: m / z 368.2 [M+H] + ESI pos, which was prepared using a similar chemical process described in Example 4, starting from 5-chloro-2-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)oxazolo[4,5-b]pyridine (Example 14, Step A) and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS No. 1207961-50-9).

[0498] Example 15:

[0499] 5-chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl- phenol

[0500]

[0501] ​

[0502] 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 eq) and 1,2,3,4-tetrahydro-2,7- naphthyridine hydrochloride (CAS No. 1354940-72-9, 113 mg, 0.66 mmol, 1.40 eq) in 1,4-dioxane (0.90 mL) and water (0.10 mL) was added N,N- diisopropylethylamine (243 mg, 0.32 mL, 1.88 mmol, 3.97 eq). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was cooled to room temperature and extracted with half-saturated aqueous NaHCO3 and extracted with a mixture of dichloromethane / methanol (19:1) three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 5% methanol in dichloromethane) to give the title compound (116 mg, yield 81%) as a light yellow solid. LCMS: m / z 287.1 [M+H] + ESI pos.

[0503] ​ ​

[0504] The title compound was obtained as a white solid, LCMS: m / z 393.2 [M+H] + ESI pos, prepared using a similar chemical process as described in Example 4, starting from 5-chloro-2-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)oxazolo[4,5-b]pyridine (Example 15, Step A) and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS No. 1207961-50-9).

[0505] Example 16:

[0506] 3-hydroxy-4-(2-isoindolin-2-yl oxazolo[4,5-b]pyridin-5-yl)-5-methyl- benzonitrile

[0507]

[0508] ​

[0509] 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 eq) and isoindoline (CAS No. 496-12-8, 121 mg, 0.115 mL, 0.96 mmol, 1.30 eq) in 1,4-dioxane (1.8 mL) and water (0.20 mL) was added N,N-diisopropylethylamine (143 mg, 0.189 mL, 1.11 mmol, 1.50 eq). 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 layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, gradient: 0% to 20% ethyl acetate in dichloromethane) to give the title compound (151 mg, yield 71%) as a light gray solid. LCMS: m / z 272.0 [M+H] + , ESI pos.

[0510] ​

[0511] The title compound was obtained as an off-white solid, LCMS: m / z 369.2 [M+H] + , ESI pos, prepared using a similar chemical process as described in Example 3, Step B, starting from 5-chloro-2-isoindolin-2-yl-oxazolo[4,5-b]pyridine (Example 16, Step A) and (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid (Example 3, Step D’).

[0512] Example 17:

[0513] 4-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- hydroxy-5-methyl-benzonitrile

[0514]

[0515] ​

[0516] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 253 mg, 1.20 mmol, 1.00 eq) and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (CAS No. 192869-50-4, 227 mg, 1.68 mmol, 1.40 eq) in 1,4-dioxane (3.0 mL) was added triethylamine (218 mg, 0.30 mL, 2.16 mmol, 1.80 eq) 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 layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient: 0% to 10% methanol in dichloromethane) to give the title compound (270 mg, yield 74%) as a light yellow solid. LCMS: m / z 288.0 [M+H] + , ESI pos.

[0517] Step B: 4-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile Step B: 4-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile

[0518] The title compound was obtained as a white solid, LCMS: m / z 385.1 [M+H] + , ESI pos, prepared starting from 5-chloro-2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridine (Example 17, Step A) and (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid (Example 3, Step D’) using a chemical process analogous to that described in Example 3, Step B.

[0519] Example 18:

[0520] 2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5- (trifluoromethyl)phenol

[0521]

[0522] The title compound was obtained as an off-white solid, LCMS: m / z 414.1 [M+H] +, ESI pos, which was prepared using a similar chemical procedure to that described in Example 1, Step D, starting from 5-chloro-2-(5,7-dihydropyrrolo[3,4- d]pyrimidin-6-yl)oxazolo[4,5-b]pyridine (Example 13, Step A) and 3-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)phenol (CAS Number 2557358-38-8).

[0523] Example 19:

[0524] 7-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]- 2,5,6,8-tetrahydro-2,7-naphthyridin-3-one

[0525]

[0526] Step A: 6-benzyloxy-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylic acid tert-butyl ester

[0527] To a mixture of tert-butyl 6-chloro-3,4-dihydro-lH-2,7-naphthyridine-2-carboxylate (CAS Number 1396777-92-6, 150 mg, 0.56 mmol, 1.00 eq) and benzyl alcohol (91 mg, 0.087 mL, 0.84 mmol, 1.50 eq) in 1,4-dioxane (2.0 mL) was added potassium tert-butoxide (88 mg, 0.78 mmol, 1.40 eq). 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 with ethyl acetate twice. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, gradient: 0% to 30% ethyl acetate in heptane) to give the title compound (80 mg, 40% yield) as a colorless oil. LCMS: m / z 341.2 [M+H] + , ESI pos.

[0528] Step B: 6-benzyloxy-1,2,3,4-tetrahydro-2,7-naphthyridine hydrochloride

[0529] To a solution of 6-benzyloxy-3,4-dihydro-lH-2,7-naphthyridine-2-carboxylic acid tert-butyl ester (Example 19, Step A) (78 mg, 0.22 mmol, 1.00 eq) in dichloromethane (2.0 mL) and methanol (1.0 mL) was added 4 M HC1 in 1,4-dioxane (0.54 mL, 2.18 mmol, 10.00 eq) dropwise at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The white suspension was concentrated in vacuo to give the title compound (53 mg, 84% yield) as a white solid. LCMS: m / z 241.1 [M+H] + , ESI pos.

[0530] Step C: 2-(6-benzyloxy-3,4-dihydro-1H-2,7-naphthyridin-2-yl)-5-chloro- oxazolo[4,5-b]pyridine

[0531] 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 eq) and 6-benzyloxy-l,2,3,4-tetrahydro-2,7- naphthyridine hydrochloride (Example 19, Step B) (51 mg, 0.18 mmol, 1.10 eq) in 1,4-dioxane (1.0 mL) and water (0.10 mL) was added triethylamine (48 mg, 0.067 mL, 0.48 mmol, 3.00 eq) under argon. 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 NaHC03. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient: 0% to 50% ethyl acetate in heptane) to give the title compound (31 mg, 47% yield) as a light yellow foam. LCMS: m / z 393.1 [M+H] + , ESI pos.

[0532] Step D: 7-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-2,5,6,8-tetrahydro-2,7-naphthyridin-3-one Step A: 2-benzyloxy-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0533]

[0534] A mixture of 2-(6-benzyloxy-3,4-dihydro-lH-2,7-naphthyridin-2-yl)-5-chlorooxazolo[4,5- b]pyridine (Example 19, Step C) (30 mg, 0.07 mmol, 1.00 eq), 3-methyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS Number 2557358-38-8, 35 mg, 0.12 mmol, 1.60 eq) and cesium carbonate (71 mg, 0.22 mmol, 3.00 eq) in 1,4-dioxane (1.6 mL) and water (0.40 mL) was placed under argon and XPhos Pd G3 (9 mg, 0.01 mmol, 0.15 eq) was added. The reaction mixture was stirred at 95 °C for 3 hours. Additional XPhos Pd G3 (9 mg, 0.01 mmol, 0.15 eq) 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 equal amount of saturated aqueous NH4C1 solution, then extracted with ethyl acetate twice. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 50% in dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)) followed by crystallization with ethyl acetate / heptane 1:1 (v / v) to give the title compound (9 mg, yield 27%) as a white solid. LCMS: m / z 443.1 [M+H] + , ESI pos.

[0535] Example 20:

[0536] 6-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-5,7- dihydro-lH-pyrrolo[3,4-b]pyridin-2-one

[0537]

[0538] Step B: 2-oxo-5,7-dihydro-1H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0539] To a mixture of tert-butyl 2-chloro-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (CAS Number 1257854-60-6, 325 mg, 1.28 mmol, 1.00 eq) and benzyl alcohol (207 mg, 0.199 mL, 1.91 mmol, 1.50 eq) in 1,4-dioxane (5.0 mL) was added potassium tert-butoxide (200 mg, 1.79 mmol, 1.40 eq) at room temperature. 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 with ethyl acetate twice. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 25 g, gradient: 0% to 30% ethyl acetate in heptane) to give the title compound (305 mg, yield 69%) as a purple oil. LCMS: m / z 327.2 [M+H] + , ESI pos.

[0540] Step C: 1,5,6,7-tetrahydropyrrolo[3,4-b]pyridin-2-one hydrochloride

[0541] 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 eq) in ethyl acetate (10 mL) and methanol (10 mL) was evacuated and flushed with argon, alternating three times. Palladium on activated carbon (10% Pd base) (93 mg, 0.09 mmol, 0.10 eq) was carefully added. The reaction flask was evacuated, flushed with argon, evacuated, and flushed with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon) for 4 hours. The reaction mixture was filtered off and rinsed thoroughly with ethyl acetate / methanol. The filtrate was concentrated in vacuo to give the title compound (208 mg, yield 96%) as a white solid, which was used without further purification. LCMS: m / z 237.1 [M+H] + , ESI pos.

[0542] Step D: 6-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-5,7-dihydro-1H-pyrrolo[3,4- b]pyridine-2-one

[0543] To a solution of tert-butyl 2-oxo-5,7-dihydro-lH-pyrrolo[3,4-b]pyridine-6- carboxylate (Example 20, Step B) (97 mg, 0.41 mmol, 1.00 eq) in dichloromethane (2.0 mL) and methanol (1.0 mL) was added dropwise 4 M HC1 in 1,4-dioxane (1.23 g, 1.03 mL, 4.11 mmol, 10.0 eq) at ambient temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to afford the title compound (87 mg, 98% yield) as a light grey solid. LCMS: m / z 137.1 [M+H] + , ESI pos.

[0544] Step E: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-5,7-dihydro-1H-pyrrolo[3,4-b]pyridin-2-one Step A: 1-methyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0545] 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 eq) and l,5,6,7-tetrahydropyrrolo[3,4-b]pyridin-2-one hydrochloride (Example 20, Step C) (88 mg, 0.51 mmol, 1.20 eq) in 1,4-dioxane (1.0 mL) and water (0.10 mL) was added N,N-diisopropylethylamine (274 mg, 0.36 mL, 2.12 mmol, 5.00 eq). The reaction mixture was stirred in a sealed tube at 100 °C for 24 hours to give a grey suspension. The reaction mixture was cooled and diluted with a small amount of ethyl acetate, water and half-saturated aqueous NaHC03. The solid was filtered off, washed with a mixture of ethyl acetate / water and then the solid was rinsed with diethyl ether. The filter cake was placed under high vacuum and dried at 50 °C for 1 hour to afford the title compound (67 mg, 52% yield) as a grey solid. LCMS: m / z 287.0 [M-H] - , ESI pos.

[0546] Step B: 1-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-one hydrochloride Step C: 6-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-1-methyl-5,7-dihydropyrrolo[3,4- b]pyridin-2-one

[0547]

[0548] A mixture of 6-(5-chlorooxazolopyridin-2-yl)-5,7-dihydro-lH-pyrrolo[3,4- b]pyridin-2-one (Example 20, Step D) (66 mg, 0.23 mmol, 1.00 eq), 3-methyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS Number 2557358-38-8, 111 mg, 0.37 mmol, 1.60 eq) and cesium carbonate (223 mg, 0.69 mmol, 3.00 eq) in 1,4-dioxane (1.0 mL) and 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 eq) was added. The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature, quenched with water and equal amount of saturated aqueous NH4C1 solution. The mixture was extracted with ethyl acetate twice. The organic layer was washed with brine. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 50% in dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)) followed by crystallization with ethyl acetate / heptane 1:1 (v / v) to give the title compound (49 mg, yield 48%) as off-white solid. LCMS: m / z 429.1 [M+H] + , ESI pos.

[0549] Example 21:

[0550] 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolopyridin-2-yl]-l-methyl- 5,7-dihydropyrrolo[3,4-b]pyridin-2-one

[0551]

[0552] Step D: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-1-methyl-5,7-dihydropyrrolo[3,4-b]pyridin-2-one

[0553] The title compound was obtained as a light brown oil, LCMS: m / z 251.0 [M+H] + , ESI pos, prepared using a similar chemical process as described in Example 2, Step A, starting from tert-butyl 2-oxo-5,7-dihydro-lH-pyrrolo[3,4-b]pyridine-6-carboxylate (Example 20, Step B) and iodomethane.

[0554] Step A: 2-methyl-3-oxo-5,7-dihydropyrrolo[3,4-c]pyridazine-6-carboxylic acid tert-butyl ester

[0555] The title compound was obtained as a light brown solid, LCMS: m / z 151.0 [M+H] + , ESI pos, which was prepared using a similar chemical process described in Example 20, Step C, starting from tert-butyl 1-methyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (Example 21, Step A).

[0556] Step B: 2-methyl-6,7-dihydro-5H-pyrrolo[3,4-c]pyridazine-3-one hydrochloride Step C: 6-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-2-methyl-5,7-dihydropyrrolo[3,4- c]pyridazine-3-one

[0557] The title compound was obtained as a light grey solid, LCMS: m / z 303.0 [M+H] + , ESI pos, which was prepared using a similar chemical process described in Example 20, Step D, 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]pyridin-2-one hydrochloride (Example 21, Step B).

[0558] Step 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]pyridazine-3-one Step A: 5-chloro-2-(5,7-dihydropyrrolo[3,4-b]pyrazin-6-yl)oxazolo[4,5-b]pyridine

[0559] The title compound was obtained as an off-white foam, LCMS: m / z 443.1 [M+H] + , ESI pos, which was prepared using a similar chemical process described in Example 20, Step E, starting from 6-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-1-methyl-5,7-dihydropyrrolo[3,4-b]pyridin-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).

[0560] Example 22:

[0561] 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

[0562]

[0563] ​

[0564] The title compound was obtained as a dark brown solid, LCMS: m / z 252.1 [M+H] + , ESI pos, which was prepared using a similar chemical process described in Example 2, Step A, starting from tert-butyl 3-oxo-5,7-dihydro-2H-pyrrolo[3,4-c]pyridazine-6-carboxylate (CAS Number 1395493-25-0) and iodomethane.

[0565] ​

[0566] The title compound was obtained as a black solid, LCMS: m / z 152.0 [M+H] + , ESI pos, which was prepared using a similar chemical process described in Example 20, Step C, starting from tert-butyl 2-methyl-3-oxo-5,7-dihydropyrrolo[3,4-c]pyridazine-6-carboxylate (Example 22, Step A).

[0567] ​ ​

[0568] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS Number 1783370-92-2, 130 mg, 0.65 mmol, 1.00 eq) and 2-methyl-6,7-dihydro-5H-pyrrolo[3,4-c]pyridin-3-one hydrochloride (Example 22, Step B) (162 mg, 0.78 mmol, 1.20 eq, purity 90%) in 1,4-dioxane (2.6 mL) and water (0.26 mL) was added N,N-diisopropylethylamine (419 mg, 0.55 mL, 3.24 mmol, 5.00 eq). The reaction mixture was stirred at 100 °C in a sealed tube for 60 hours. The reaction mixture was quenched with water and extracted with ethyl acetate twice. The organic layer was washed with brine. The combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 50% dichloromethane:methanol:NH4OH 110:10:1 in dichloromethane) to give the title compound (32 mg, 15%) as a light brown solid. LCMS: m / z 304.0 [M+H] + , ESI pos.

[0569] ​ ​

[0570] The title compound was obtained as a white solid, LCMS: m / z 414.2 [M+H] + , ESI pos, which was prepared using a similar chemical process described in Example 20, Step E, starting from 6-(5-chlorooxazol[4,5-b]pyridin-2-yl)-2-methyl-5,7- dihydropyrrolo[3,4-c]pyridin-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 Number 2557358- 38-8).

[0571] Example 23:

[0572] 2-[2-(5,7-dihydropyrrolo[3,4-b]pyrazin-6-yl)oxazol[4,5-b]pyridin-5-yl]-3-methyl-5- (trifluoromethyl)phenol

[0573]

[0574] ​

[0575] To a mixture of 5-chloro-2-(methylthio)oxazol[4,5-b]pyridine (CAS Number 1783370-92-2, 140 mg, 0.69 mmol, 1.00 eq) and 6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine hydrochloride (CAS Number 1255099-34-3, 163 mg, 1.04 mmol, 1.50 eq) in 1,4-dioxane (2.0 mL) and water (0.20 mL) was added N,N-diisopropylethylamine (357 mg, 0.47 mL, 2.76 mmol, 4.00 eq). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate (2.0 mL) and water (2.0 mL). Stirred for 5 min. Then, the solid was filtered, rinsed with water and diethyl ether to give the title compound (148 mg, yield 74%) as a grey solid, which was used without further purification. LCMS: m / z 274.0 [M+H] + , ESI pos.

[0576] Step B: 2-[2-(5,7-dihydropyrrolo[3,4-b]pyrazin-6-yl)oxazolo[4,5-b]pyridin-5-yl]- 3-methyl-5-(trifluoromethyl)phenol

[0577] The title compound was obtained as a white solid, LCMS: m / z 414.2 [M+H] +The title compound was obtained as a white solid, LCMS: m / z 428.3 [M+H] + ESI pos, starting from 5-chloro-2-(7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)oxazolo[4,5-b]pyridine (Example 17, Step A) and 3-methyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS Number 2557358-38-8) using a chemical process analogous to that described in Example 1, Step D.

[0578] Example 24:

[0579] 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-5-(trifluoromethyl)phenol

[0580]

[0581] The title compound was obtained as a white solid, LCMS: m / z 428.3 [M+H] + The title compound was obtained as a white solid, LCMS: m / z 428.3 [M+H] + ESI pos, starting from 5-chloro-2-(7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)oxazolo[4,5-b]pyridine (Example 17, Step A) and 3-methyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS Number 2557358-38-8) using a chemical process analogous to that described in Example 1, Step D.

[0582] Example 25:

[0583] 5-chloro-3-methyl-2-[2-(2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)oxazolo[4,5- b]pyridin-5-yl]phenol

[0584]

[0585] Step A: 5-chloro-2-(2,4,6,7-tetrahydropyrano[4,3-c]pyridin-5-yl)oxazolo[4,5-b]pyridine

[0586] To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2, 200 mg, 0.95 mmol, 1.00 eq) and 4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridine (CAS No. 933742-87-1, 117 mg, 0.95 mmol, 1.00 eq) in 1,4-dioxane (2.0 mL) was added triethylamine (172 mg, 0.24 mL, 1.70 mmol, 1.80 eq) 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 aqueous NaHC03. The aqueous layer was back-extracted with ethyl acetate three times. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient: 0% to 10% methanol in dichloromethane) to give the title compound (178 mg, 65% yield) as a light yellow solid. LCMS: m / z 275.9 [M+H] + , ESI pos.

[0587] Step B: 5-chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrano[4,3-c]pyridin-5-yl)oxazolo[4, 5-b]pyridin-5-yl]phenol

[0588] In a sealed tube, 5-chloro-2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)oxazolo[4,5- b]pyridine (Example 25, Step A) (100 mg, 0.33 mmol, 1.00 eq) was dissolved in 1,4-dioxane (2.0 mL) and water (0.50 mL). Then, (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS No. 1207961-50-9, 103 mg, 0.55 mmol, 1.70 eq), cesium carbonate (319 mg, 0.98 mmol, 3.00 eq) and XPhos Pd G3 (41 mg, 0.05 mmol, 0.15 eq) were added under argon atmosphere. The reaction mixture was stirred at 95 °C for 16 h. The reaction mixture was quenched with half-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 in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (Si-amine, 25 g, gradient: 0% to 20% methanol in ethyl acetate) to give the title compound (75 mg, yield 57%) as a white solid. LCMS: m / z 382.1 [M+H] + , ESI pos.

[0589] Example 26:

[0590] 5-(Difluoromethyl)-2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]-3-methyl-phenol

[0591]

[0592] Step A: 3-bromo-5-methyl-benzaldehyde

[0593] Two batches were run in parallel. To a solution of compound 1 (50.0 g, 200 mmol, 1.0 eq) in THF (500 mL) was added dropwise n-BuLi (2.50 M, 96.0 mL, 1.50 eq) at -70 °C under N2, then DMF (43.9 g, 600 mmol, 46.2 mL, 2.00 eq) was added and the mixture was stirred at -70 °C for 1 h. TLC (petroleum ether / ethyl acetate = 10 / 1, material R f = 0.8, product R f= 0.7) showed that the starting material was consumed and a new spot was formed. The reaction mixture was quenched with water (1000 mL) and extracted with ethyl acetate (3 x 800 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1, product: Rf = 0.700) to give the title compound (45.0 g, yield 97%) as a yellow oil, which was used in the next step without further purification. f = 0.7) to give the title compound (45.0 g, yield 67%) as a yellow oil. 1 H NMR: (400 MHz, CDC13) δ 9.93 (s, 1H), 7.81 (s, 1H), 7.60 (d, 2H), 2.43 (s, 3H).

[0594] Step B: 1-bromo-3-(difluoromethyl)-5-methyl-benzene

[0595] To a solution of the above 3-bromo-5-methyl-benzaldehyde (42.0, 211 mmol, 1.0 eq) in DCM (500 mL) was added DAST (74.8 g, 464 mmol, 61.3 mL, 2.2 eq) and the mixture was stirred at 25 °C for 10 hours. TLC (petroleum ether / ethyl acetate = 10 / 1, material Rf = 0.700) showed that the starting material was consumed and a new spot was formed. The reaction mixture was quenched with NaHC03(2000 mL) and extracted with DCM (3 x 1000 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (45.0 g, yield 97%) as a yellow oil, which was used in the next step without further purification. f = 0.500, product Rf = 0.700) to give the title compound (45.0 g, yield 97%) as a yellow oil, which was used in the next step without further purification. f = 0.700) showed that the starting material was consumed and a new spot was formed. The reaction mixture was quenched with water (1000 mL) and extracted with ethyl acetate (3 x 800 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1, product: Rf = 0.700) to give the title compound (45.0 g, yield 97%) as a yellow oil, which was used in the next step without further purification.

[0596] Step C: 2-[3-(difluoromethyl)-5-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step D: 3-(difluoromethyl)-5-methyl-phenol

[0597] To a solution of 1-bromo-3-(difluoromethyl)-5-methyl-benzene (43.0 g, 194 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (59.3 g, 233 mmol, 1.1 eq) and Pd(dppf)Cl2(14.2 g, 19.4 mmol, 0.05 eq) in dioxane (400 mL) was added AcOK (40.1 g, 408 mmol, 2.0 eq) and the mixture was stirred at 90 °C for 2 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, material R f = 0.8, product R f = 0.7) showed that the starting material was consumed and a new spot was formed. The reaction mixture was poured into H2O (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (53.0 g, crude) as a black brown oil which was used in the next step without further purification.

[0598] Step E: 5-(difluoromethyl)-2-iodo-3-methyl-phenol

[0599] To a solution of 2-[3-(difluoromethyl)-5-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (52.0 g, 194 mmol, 1.0 eq) in THF (800 mL) was added NaOH (2.00 M, 291 mL, 3.0 eq) followed by H2O2(110 g, 970 mmol, 93.2 mL, purity 30%, 4.0 eq) at 0 °C and the mixture was stirred at 25 °C for 3 h. The reaction mixture was then quenched with Na2SO3(1000 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% NH3-H2O) to give the title compound (25.0 g, yield 82%) as a brown oil. LCMS: R t = 0.463 min, m / z = 157.0 [M-H] + .

[0600] Step F: 1-benzyloxy-5-(difluoromethyl)-2-iodo-3-methyl-benzene

[0601]

[0602] To a solution of 3-(difluoromethyl)-5-methyl-phenol (27.0 g, 171 mmol, 1.0 eq) in toluene (540 mL) was added NaH (13.7 g, 341 mmol, purity 60%, 2.0 eq) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h, then iodine (34.7 g, 136 mmol, 0.8 eq) was added. The mixture was stirred at 25 °C for 1.5 h. The reaction mixture was quenched with aqueous NH4Cl solution (1000 mL) and extracted with ethyl acetate (3 x 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 (conditions: 0.1% FA) to give the desired compound and a by-product (regioisomer) as brown oil. The residue was purified by SFC (Chromatographic column: DAICEL CHIRALPAK AD (250mm*50mm, 10um); Mobile phase: [Neu-IPA]; B%: 40% to 40%, 2.2 min) to give the title compound (28.0 g, yield 73%) as brown oil, LCMS: Rt= 0.499 min, m / z = 283.0 [M-H] t - ESI neg.

[0603] Step G: 2-[2-benzyloxy-4-(difluoromethyl)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane

[0604]

[0605] To a solution of 5-(difluoromethyl)-2-iodo-3-methyl-phenol (19.0 g, 66.9 mmol, 1.0 eq) in DMF (190 mL) was added BnBr (17.2 g, 100 mmol, 11.9 mL, 1.5 eq) and K2CO3 (11.1 g, 80.3 mmol, 1.2 eq). The mixture was stirred at 25 °C for 12 h. TLC (petroleum ether / ethyl acetate = 10 / 1, material R f Rf= 0.4, product R f ​= 0.7) showed that the starting material was consumed and a new spot was formed. The reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with H2O (3 x 300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give 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).

[0606] Step H: 5-(difluoromethyl)-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenol Step B: 5-(difluoromethyl)-2-[2-(7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]-3-methyl-phenol

[0607] Under N2, to a solution of 1-benzyloxy-5-(difluoromethyl)-2-iodo-3-methyl- benzene (9.00 g, 24.0 mmol, 1.0 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (6.71 g, 36.1 mmol, 7.36 mL, 1.5 eq) in THF (90.0 mL) at -70 °C was added n-BuLi (2.50 M, 14.4 mL, 1.5 eq). The mixture was stirred at -60 °C for 1 h. TLC (petroleum ether / ethyl acetate = 10 / 1, material R f = 0.70, product R f = 0.65) showed that the material was completely consumed and a new spot was formed. The reaction mixture was quenched with aqueous NH4CI solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to give the target compound (11.2 g, yield 60%, purity 97%) as a white solid. LCMS: m / z = 375.3 [M+H] + , ESI pos.

[0608] Step A: 6-oxo-1,3,4,7-tetrahydro-2,7-naphthyridine-2-carboxylic acid tert-butyl ester Step B: 5,6,7,8-tetrahydro-2H-2,7-naphthyridine-3-one hydrochloride

[0609]

[0610] To a solution of 2-[2-benzyloxy-4-(difluoromethyl)-6-methyl-phenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (800 mg, 2.14 mmol, 1.0 eq) and ethyl acetate (20 mL) under argon was added palladium on carbon (227.5 mg, 213.77 pmol, 0.1 eq). The black suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was stirred under hydrogen atmosphere (balloon) for 4 hours. The reaction mixture was filtered through two glass fibre filters, washed with ethyl acetate (3 x 20 mL) and evaporated to give the title compound (595 mg, yield 89%) as a colourless oil. LCMS: m / z 285.1 [M+H] + ESI pos.

[0611] Step C: 7-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-2,5,6,8-tetrahydro-2,7-naphthyridine-3-one Step D: 7-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-2,5,6,8- tetrahydro-2,7-naphthyridine-3-one

[0612]

[0613] The title compound was obtained as a light yellow solid, LCMS: m / z 410.1 [M+H] + ESI pos, which was prepared using a similar chemical process as described in Example 1 Step D, starting from 5-chloro-2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-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).

[0614] Example 27:

[0615] 7-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-2,5,6,8-tetrahydro- 2,7-naphthyridin-3-one

[0616]

[0617] Step A: 3-benzyloxy-6-bromo-pyrazin-2-amine

[0618] The title compound was obtained as a grey solid, LCMS: m / z 251.1 [M+H] +, ESI pos, which was prepared using a similar chemical procedure described in Example 20, Step B, starting from tert-butyl 6-benzyloxy-3,4-dihydro-lH-2,7-naphthyridine-2-carboxylate (Example 19, Step A).

[0619] Step B: N-(3-benzyloxy-6-bromo-pyrazin-2-yl)-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide; 2,2,2-trifluoroacetic acid

[0620] The title compound was obtained as a light yellow solid, LCMS: m / z 151.1 [M+H] + , ESI pos, which was prepared using a similar chemical procedure described in Example 20, Step C, starting from tert-butyl 6-oxo-l,3,4,7-tetrahydro-2,7-naphthyridine-2-carboxylate (Example 27, Step A).

[0621] Step C: N-(6-bromo-3-hydroxypyrazin-2-yl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2- carboxamide

[0622] The title compound was obtained as a light yellow solid, LCMS: m / z 151.1 [M+H] + , ESI pos, which was prepared using a similar chemical procedure described in Example 20, Step D, starting from 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS No. 1783370-92-2) and 5,6,7,8-tetrahydro-2H-2,7-naphthyridin-3-one hydrochloride (Example 27, Step B).

[0623] Step D: 5-bromo-2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazine Step E: 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5- yl]-3-methyl-phenol; formic acid

[0624] The title compound was obtained as a white amorphous lyophilized solid, LCMS: m / z 409.1 [M+H] + , ESI pos, which was prepared using a similar chemical procedure described in Example 25, Step B, starting from 7-(5-chlorooxazolo[4,5-b]pyridin-2-yl)-2,5,6,8-tetrahydro-2,7-naphthyridin-3-one (Example 27, Step C) and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS No. 1207961-50-9).

[0625] Example 29:

[0626] 5-chloro-2-[2-(l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3-methyl- phenol; formic acid

[0627]

[0628] Step A: 2-amino-5-chloro-3-methoxy-benzoic acid methyl ester

[0629] To a mixture of BnOH (4.0 g, 36.99 mmol, 1.54 eq) in THF (100 mL) was added NaH (1.4 g, 35.0 mmol, P: 60% in mineral oil, 1.46 eq) portionwise at 0 °C, then the mixture was heated to 70 °C and stirred for 1 h. The reaction mixture was cooled to 20 °C, and 6-bromo-3-chloro-pyrazin-2-amine (CAS No. 1082843-72-8; 5.0 g, 24 mmol, 1.0 eq) was added. The mixture was stirred at 70 °C for 16 hours. After the reaction was completed, the mixture was quenched with water (150 mL) and extracted with ethyl acetate (150 mL x 3), the organic phase was washed with brine (30 mL x 2), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE / EtOAc, 5:1) to give the title compound as a white solid (4.60 g, yield 67%). LCMS: m / z 280.0 [M+H] + ESI pos.

[0630] ​ ​

[0631] To a solution of 3-benzyloxy-6-bromo-pyrazin-2-amine (1.43 g, 5.11 mmol, 0.8 eq) in THF (20 mL) was added chloroformic acid 1,4-nitrophenyl ester (CAS No. 7693-46-1; 1.29 g, 6.39 mmol, 1.0 eq). The mixture was stirred at 60 °C for 1 h. After the reaction was completed, the mixture was concentrated under vacuum and dissolved in DCM (24 mL). Then DIPEA (2.78 mL, 15.9 mmol, 2.5 eq) and 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine hydrochloride (CAS No. 6000-50-6; 1.0 g, 6.39 mmol, 1.0 eq) were added to the reaction mixture. The mixture was stirred at 20 °C for 1 hour. After the reaction was completed, 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 extracts were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by column chromatography (PE / EtOAc, 5:1) to give the title compound as a white solid (1.0 g, yield 50%). LCMS: m / z 340.0 [M+H] 18Column chromatography (20 g, 0.1% TFA in water / acetonitrile, acetonitrile: 30% to 50%) purification to afford 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).

[0632] ​ ​

[0633] A solution of N-(3-benzyloxy-6-bromo-pyrazin-2-yl)-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide; 2,2,2-trifluoroacetic acid (900 mg, 1.67 mmol, 1.0 eq) in TFA (9.0 mL, 121.2 mmol, 72.7 eq) was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to give a residue, which was dissolved in methanol (5 mL) and basified to pH = 9 by the addition of NH3·H2O, resulting in the formation of a white precipitate. After filtration, the residue was air-dried to afford 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).

[0634] ​

[0635] To a solution of N-(6-bromo-3-hydroxy-pyrazin-2-yl)-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide (200.0 mg, 0.44 mmol, 1.0 eq) in toluene (2 mL) was added POCl3 (0.81 mL, 8.89 mmol, 20.0 eq). The reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature. It was slowly transferred to water (10 mL) and basified to pH = 9 by NH3·H2O. During this period, a white precipitate was formed. It was collected by filtration and air dried to give 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).

[0636] ​ ​

[0637] To a solution of 5-bromo-2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5- b]pyrazine (50.0 mg, 0.16 mmol, 1.0 eq) in 1,4-dioxane (2 mL) and water (0.4 mL), CsF (95.5 mg, 0.63 mmol, 4.0 eq) and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (23.4 mg, 0.13 mmol, 0.8 eq) was added XPhos Pd G3 (26.6 mg, 0.03 mmol, 0.2 eq). The reaction mixture was stirred at 80 °C under N2 for 4 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under vacuum to give a residue, which was purified by column chromatography (20 g, water with 0.1% FA / acetonitrile, acetonitrile: 30% to 40%) and the eluent was lyophilized to give a residue. The residue was triturated in acetonitrile (2 mL) and stirred for 10 min to give the title compound (12.0 mg, 18%) as a white solid. LCMS: m / z 380.0 [M+H] ESI pos. 18 , ESI pos. +

[0638] Example 30:

[0639] ​5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3- (hydroxymethyl)phenol

[0640]

[0641] ​

[0642] To a solution of methyl 2-amino-3-methoxy-benzoate (CAS No. 5121-34-6, 10.0 g, 55.2 mmol, 1.0 eq) in DMF (100 mL) was added NCS (7.59 g, 56.9 mmol, 1.03 eq) at 25 °C. Then the mixture was stirred at 50 °C for 2 h. The mixture was poured into water (100 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (50 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 5:1) and further purified by C 18 column chromatography (20 g in 0.1% TFA in water / MeCN), followed by lyophilization to give the title compound (10.8 g, yield 91%) as a light yellow solid. 1 H NMR (CDC13, 400 MHz): δ 7.46 (d, 1H), 6.79 (d, 1H), 6.01 (s, 2H), 3.87 (s, 6H).

[0643] Step B: 2-bromo-5-chloro-3-methoxy-benzoic acid methyl ester

[0644] To a solution of 2-amino-5-chloro-3-methoxy-benzoic acid methyl ester (10.0 g, 46.4 mmol, 1.0 eq) in MeCN (80 mL) was added CuBr2(20.7 g, 92.8 mmol, 2.0 eq) and CuBr (665.5 mg, 4.64 mmol, 0.1 eq) to give a dark color. The mixture was stirred at 25 °C for 20 min, and t-BuONO (8.61 g, 83.5 mmol, 1.8 eq) was added dropwise over 10 min. The reaction mixture was stirred for another 30 min, and then heated to 60 °C for 6 h. The reaction mixture was concentrated in vacuo, and then water (150 mL) and EtOAc (100 mL) were added. The resulting mixture was stirred at 25 °C for 30 min. The organic phase turned brown, and the aqueous phase was green with insoluble material. The whole mixture was filtered through celite and washed with EtOAc (100 mL x 3). The organic layer was separated and washed with brine (100 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the title compound (8.10 g, yield 62%) as a white solid. 1 H NMR (CDC13, 400 MHz): δ 7.28 (d, 1H), 6.98 (d, 1H), 3.94 (s, 3H), 3.93 (s, 3H).

[0645] Step C: 2-bromo-5-chloro-3-hydroxy-benzoic acid (CAS 1889090-86-1)

[0646] To a solution of methyl 2-bromo-5-chloro-3-methoxy-benzoate (8.1 g, 28.98 mmol, 1.0 eq) in DCM (200 mL) was added BBr3(8.38 mL, 86.93 mmol, 3.0 eq) slowly at -78 °C under N2, then the reaction mixture was stirred at 25 °C for 12 h. To the reaction mixture was added MeOH (100 mL) slowly, and the resulting mixture was stirred at 20 °C for 30 min. It was mixed with 500 mL ice water at 0 °C, and the organic phase was separated. The aqueous phase was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (2 x 200 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give the title compound (6.5 g, yield 89%) as a white solid. 1 HNMR (400 MHz, CDCl3) δ = 7.62 (d, 1H), 7.28 (s, 1H), 6.24 - 6.15 (m, 1H).

[0647] Step D: 2-trimethylsilylethoxymethyl-2-bromo-5-chloro-3-(2-trimethylsilylethoxymethoxy) benzoate Step E: 2-bromo-5-chloro-3-(2-trimethylsilylethoxymethoxy)phenyl]methanol

[0648] A mixture of Cs2C03(25 g, 77.6 mmol, 3.0 eq) and 2-bromo-5-chloro-3-hydroxy- benzoic acid (6.50 g, 25.9 mmol, 1.0 eq) in DMF (40 mL) was degassed and purged with N2three times, and stirred for 30 min. Then SEMCl (12928.7 mg, 77.6 mmol, 3.0 eq) was added to the mixture in one portion. The mixture was stirred at 25 °C for 2 h. The mixture was poured into water (70 mL), and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Then the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 10:1) to give 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).

[0649] Step F: 2-[[2-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chloro-phenoxy]methoxy]ethyl- trimethyl-silane

[0650] To a solution of 2-bromo-5-chloro-3-(2-trimethylsilylethoxymethyl- oxymethoxy)benzoic acid 2-trimethylsilylethoxymethyl ester (10.7 g, 20.9 mmol, 1.0 eq) in THF (50 mL) was added a solution of 2 M LiBH4 in THF (20.9 mL, 41.8 mmol, 2.0 eq) and the reaction mixture was stirred at 25 °C for 16 h. The mixture was poured into water (100 ml) and extracted with ethyl acetate (50 mL * 3), the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 10 / 1) to give 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).

[0651] Step F: tert-butyl-[[5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2- trimethylsilylethoxymethoxy)phenyl]methoxy]-dimethyl-silane Step A: tert-butyl-[[5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5- yl]-3-(2-trimethylsilylethoxymethoxy)phenyl]methoxy]-dimethyl-silane

[0652] A mixture of NaH (163.2 mg, 4.08 mmol, 60%, 1.5 eq) and [2-bromo-5-chloro-3-(2- trimethylsilylethoxymethoxymethyl)phenyl]methanol (1000.0 mg, 2.72 mmol, 1.0 eq) in DMF (10 mL) was degassed and purged with N2 three times and stirred for 30 min. Then, TBSCl (614.79 mg, 4.08 mmol, 1.5 eq) was added to the mixture in one portion. The mixture was stirred at 25 °C for 3 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0 / 1 to 20 / 1) to give 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).

[0653] Step B: 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3- (hydroxymethyl)phenol Step A: N-(3-benzyloxy-6-chloro-pyrazin-2-yl)-6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide

[0654]

[0655] To a solution of 2-[[2-bromo-3-[[tert-butyl(dimethyl)methylsilyl]oxymethyl]-5- chloro-phenoxy]methoxy]ethyl-trimethyl-silane (390.0 mg, 0.81 mmol, 1.0 eq) 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 eq) in 1,4-dioxane (4 mL) was added Cs2CO3 (527.3 mg, 1.62 mmol, 2.0 eq) and tris(4-methoxy-3,5-dimethylphenyl)phosphane (35.3 mg, 0.08 mmol, 0.1 eq). And to the mixture was added Pd(OAc)2 (18.2 mg, 0.08 mmol, 0.1 eq) under N2. Finally, the mixture was stirred at 95 °C for 5 hours. The above 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 give 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, 2H), 1.37 (s, 12H), 0.98 - 0.95 (m, 2H), 0.94 (s, 9H), 0.09 (s, 6H), 0.00 (s, 9H).

[0656] Step B: N-[3-benzyloxy-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazin-2-yl]-6-methoxy- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide Step C: N-[3-benzyloxy-6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazin-2-yl]-6-methoxy- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide

[0657] To a solution of 5-bromo-2-(l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5- b]pyrazine (Example 29, Step D) (46.0 mg, 0.14 mmol, 1.0 eq) and tert-butyl-[[5- chloro-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilylethoxymethoxy)phenyl] methoxy]-dimethyl-silane (Step F) (68.9 mg, 0.13 mmol, 0.9 eq), Na2CO3(38.3 mg, 0.36 mmol, 2.5 eq) in 1,4-dioxane (1 mL) / water (0.2 mL) was added XPhos Pd G3 (24.5 mg, 0.03 mmol, 0.2 eq). The reaction mixture was stirred at 80 °C for 4 h under N2. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under vacuum to get a residue which was purified by column chromatography (20 g, 0.1% NH3H2O in water / acetonitrile, acetonitrile: 100%) to get the title compound (10.0 mg, 10% yield) as a colorless oil. LCMS: m / z 640.5 [M+H] 18 ESI pos. + , ESI pos.

[0658] Step D: N-[3-hydroxy-6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazin-2-yl]-6-methoxy- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide Step E: 2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)-5-[2-methoxy-6-methyl-4- (trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazine

[0659] To a solution of tert-butyl-[[5-chloro-2-[2-(l,3-dihydropyrrolo[3,4-c]pyridin-2- yl)oxazolo[4,5-b]pyrazin-5-yl]-3-(2-trimethylsilylethoxymethylmethoxy)phenyl]methoxy]- dimethyl-silane (Step A) (10.0 mg, 0.02 mmol, 1.0 eq) in DCM (0.5 mL) was added TFA (0.5 mL, 6.73 mmol, 431 eq). The reaction mixture was stirred at 20 °C for 1.5 h. After completion of the reaction, the mixture was concentrated under vacuum. The residue was dissolved in methanol (0.5 mL) and basified to pH=8 by NH3H2O, then purified by preparative HPLC (Method: Column Waters xbridge 150*25 mm*5 um; Conditions: water (NH4HCO3)-ACN; Start B: 20; End B: 50; Gradient time (min): 100%B; Hold time (min): 2; Flow rate (ml / min): 25) to give the title compound (4.0 mg, yield 64%) as a white solid. LCMS: m / z 396.0 [M+H] ESI pos. +

[0660] Examples 31 to 42

[0661]

[0662] Intermediate 1 (1320.0 mg, 4.51 mmol, 1.0 eq) was dissolved in DCM (50 mL) and oxalyl chloride (5.8 mL, 67.64 mmol, 15.0 eq) was added followed by dropwise addition of DMF (1.5 mL). The mixture was stirred at room temperature for 30 min and then concentrated in vacuo. The resulting residue was taken up in DCM (45 mL) and saturated aqueous K2CO3solution (15 mL) was added. The DCM layer was separated 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 made up to 92 mL and used as a stock solution in a series of reactions using the following general procedure:

[0663]

[0664] ​The amine (5.41 mmol, 1.2 eq) was dissolved in DMF (0.1 mL) and triethylamine (0.02 mL, 0.15 mmol, 3.0 eq) was added followed by 1 mL of a stock solution of 5-chloro-2-(2-chlorooxazol[4,5-b]pyridin-5-yl)-3-methylphenol (1 eq.). The mixture was shaken at room temperature for 20 min. DCM was evaporated overnight and the resulting residue was made up to 1 mL with DMF and then filtered. The resulting filtrate was purified by preparative HPLC.

[0665] The following examples "Ex." were synthesized by the methods outlined above:

[0666]

[0667]

[0668] Example 41:

[0669] 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3,5,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-one

[0670]

[0671] Dissolve 5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-3H-oxazolo[4,5- b]pyridine-2-thione, Intermediate 2 (156.0 mg, 0.33 mmol, 1.0 eq) in DCM (2 mL) and add oxalyl chloride (0.59 mL, 6.87 mmol, 21.1 eq). Stir the mixture at room temperature for 30 min, then concentrate in vacuo. Take up the resulting residue in DCM (10 mL), dilute with saturated aqueous K2CO3solution (10 mL), then allow the layers to separate. Extract the aqueous layer with DCM (2x 10 mL), then concentrate the combined organics in vacuo. Dissolve the resulting solution in DCM (4 mL) to make a stock solution. Then add 2 mL of this stock solution to 5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one; dihydrochloride (59.0 mg, 0.26 mmol, 1.6 eq), triethylamine (0.21 mL, 1.5 mmol, 9 eq), and DMF (0.1 mL). Stir the reaction mixture at room temperature for 16 hours, then concentrate it in vacuo. Dissolve the resulting product in DMF (1 mL), filter, and purify the resulting filtrate by preparative HPLC (25% to 100% MeCN in water) to give the title compound as a white solid. LCMS m / z 444.2 [M+H] + ESI pos.

[0672] Example 43:

[0673] 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazin-2-yl]-1,3- dihydropyrrolo[3,4-c]pyridine-6-ol; 2,2,2-trifluoroacetic acid

[0674]

[0675] Step F: 2-[2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3-methyl- 5-(trifluoromethyl)phenol Step G: 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazin-2-yl]-1,3- dihydropyrrolo[3,4-c]pyridin-6-ol; 2,2,2-trifluoroacetic acid

[0676] To a solution of 3-benzyloxy-6-chloro-pyrazin-2-amine (1.37 g, 5.79 mmol, 1.0 eq; CAS No. 2923540-12-7) in THF (13 mL) was added 4-nitrophenyl chloroformate (1.28 g, 6.37 mmol, 1.1 eq; CAS No. 7693-46-1). The mixture was stirred at 60 °C for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (8 mL), then DIPEA (1.87 g, 14.48 mmol, 2.5 eq) and 6-methoxy-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (870.0 mg, 5.79 mmol, 1.0 eq) (Example 12, Step A) were added to the above reaction mixture, and stirring was continued at 20 °C for 1 hour. The mixture was poured into water (20 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0:1 to 1:1) to give 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).

[0677] ​ ​

[0678] To a mixture of CsF (1.03 g, 6.8 mmol, 4.0 eq), 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 eq; CAS No. 2557358-38-8) and above N-(3-benzyloxy-6-chloro-pyrazin-2-yl)-6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide (700.0 mg, 1.7 mmol, 1.0 eq.) in 1,4-dioxane (10 mL) and water (1 mL) was added XPhos Pd G3 (285.8 mg, 0.34 mmol, 0.2 eq). The mixture was stirred at 95 °C under N2 for 5 hours. After the reaction was completed, it was cooled to room temperature and filtered. Then, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1 to 0 / 1) to give the title compound (360.0 mg, yield 38%) as a light yellow solid. LCMS: m / z 552.1 [M+H] + , ESI + pos.

[0679] ​ ​

[0680] To a mixture of above N-[3-benzyloxy-6-[2-hydroxy-6-methyl-4- (trifluoromethyl)phenyl]pyrazin-2-yl]-6-methoxy-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide (210.0 mg, 0.38 mmol, 1.0 eq) and K2CO3 (68.3 mg, 0.49 mmol, 1.3 eq) in DMF (3 mL) was added Mel (63.2 mg, 0.38 mmol, 1.0 eq). The mixture was stirred at 25 °C under nitrogen for 12 hours. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 2:1) to give the title compound (137.0 mg, yield 63%) as a light yellow solid. LCMS: m / z 566.1 [M+H] + , ESI + pos.

[0681] ​ ​

[0682] A solution of the above N-[3-hydroxy-6-[2-methoxy-6-methyl-4- (trifluoromethyl) phenyl] pyrazin-2-yl] -6-methoxy-1, 3-dihydropyrrolo [3, 4- c] pyridine-2-carboxamide (90.0 mg, 0.19 mmol, 1.0 eq) in POCl3(5.0 mL) was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini, 150mm*30mm*15um; mobile phase: [water (0.1% TFA, V / V) - MeCN]; B%: 22% to 52%, 12 min) to afford the title compound (41.0 mg, yield 43%) as a light yellow solid. + ESI + pos.

[0683] ​ ​

[0684] A solution of the above N-[3-hydroxy-6-[2-methoxy-6-methyl-4- (trifluoromethyl) phenyl] pyrazin-2-yl] -6-methoxy-1, 3-dihydropyrrolo [3, 4- c] pyridine-2-carboxamide (90.0 mg, 0.19 mmol, 1.0 eq) in POCl3(5.0 mL) was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini, 150mm*30mm*15um; mobile phase: [water (0.1% TFA, V / V) - MeCN]; B%: 22% to 52%, 12 min) to afford the title compound (41.0 mg, yield 43%) as a light yellow solid. 1 H NMR (400 MHz, 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).

[0685] ​​

[0686] To a solution of 2-(6-methoxy-l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)-5-[2-methoxy-6- methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazine (14.0 mg, 0.03 mmol, 1.0 eq) in DCM (0.5 mL) was added BBr3 (0.06 mL, 0.61 mmol, 20.0 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. Then, the reaction mixture was quenched by the addition of MeOH (1 mL), followed by concentration under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini, 150mm*30mm*15um; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 30% to 52%, 10 min) to give 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).

[0687] ​ ​

[0688] A mixture of 2-[2-(6-methoxy-l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5- yl]-3-methyl-5-(trifluoromethyl)phenol (10.0 mg, 0.02 mmol, 1.0 eq) in HBr / AcOH (0.5 mL) was stirred at 80 °C for 0.5 h. After the reaction was completed, the mixture was cooled to 20 °C, then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini, 150mm*30mm*15um; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 30% to 52%, 10 min) to give the title compound (1.56 mg, yield 16%) as a white solid. LCMS: m / z 430.2 [M+H] + , ESI + pos.

[0689] Example 44:

[0690] 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]- 5,7-dihydro-lH-pyrrolo[3,4-d]pyrimidine-2,4-dione

[0691]

[0692] Step A: 6-(5-chlorooxazolopyridin-2-yl)-5,7-dihydro-lH-pyrrolo[3,4- d]pyrimidine-2,4-dione Step B: 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolopyridin-2-yl]-

[0693] 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 eq) in 1,4-dioxane (2 mL) was added 1,5,6,7- tetrahydropyrrolo[3,4-d]pyrimidine-2,4-dione; hydrochloride (CAS No. 13931-24-3, 199 mg, 1.05 mmol, 1.1 eq) followed by triethylamine (CAS No. 121-44-8, 211 mg, 0.29 mL, 2.08 mmol, 2.2 eq). The reaction mixture was stirred at 90 °C for 16 h. Then, the solvent was evaporated. The residue was dissolved in N-methyl-2-pyrrolidone (CAS No. 872-50-4, 12 mL) and triethylamine (210 mg, 0.29 mL, 2.08 mmol, 2.2 eq) was added to the reaction mixture and stirring was continued at 130 °C for 16 h. Then, the reaction mixture was cooled to room temperature, adsorbed on ISOLUTE HM-N and purified by flash chromatography (ISCO, 12 g Si02, 0% to 10% MeOH in DCM) to give the title compound (340 mg, yield 99%) as a brown solid. LCMS: m / z 306.0 [M+H] ESI pos. + , ESI pos.

[0694] 5,7-dihydro-lH-pyrrolo[3,4-d]pyrimidine-2,4-dione Example A

[0695] A mixture of 6-(5-chlorooxazol[4,5-b]pyridin-2-yl)-5,7-dihydro-1H-pyrrolo[3,4- d]pyrimidine-2,4-dione (Example 44, Step A) (50 mg, 0.14 mmol, 1.0 eq), 3-methyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (72 mg, 0.215 mmol, 1.44 eq), cesium carbonate (137 mg, 0.42 mmol, 3.0 eq), and XPhos Pd G3 (12.4 mg, 0.015 mmol, 0.105 eq) in 1,4-dioxane (0.23 mL) and water (58 µL) was flushed with argon and stirred at 90 °C for two hours. The reaction mixture was cooled to room temperature and extracted with dichloromethane / methanol (19:1) and half-saturated aqueous 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 in vacuo. The crude product was then purified by preparative HPLC (column: YMC-Trail, 12 nm, 5 um, 100 x 30 mm; conditions: ACN / water + 0.1% HCOOH; gradient: ACN in water, run time 4.5 min) to give the title compound (8 mg, yield 12%) as a light grey solid. LCMS: m / z 446.1 [M+H] + ESI pos

[0696] each tablet

[0697] The compounds of the formula I can be used as active ingredients for the production of tablets of the following composition in a manner known per se:

[0698] 20 mg

[0699] Active ingredient 200 mg

[0700] Microcrystalline cellulose 155 mg

[0701] Corn starch 25 mg

[0702] Talc 25 mg

[0703] Hydroxypropyl methylcellulose Example B

[0704] 425 mg

[0705] each capsule

[0706] The compounds of the formula I can be used as active ingredients in the production of capsules of the following composition in a manner known per se:

[0707] 0.5 mg

[0708] Active ingredient 100.0 mg

[0709] Corn starch 20.0 mg

[0710] Lactose 95.0 mg

[0711] Talc 4.5 mg

[0712] Magnesium stearate ​

[0713] 220.0 mg.

Claims

1. A compound of formula I I in, R 1 R is H, alkyl, hydroxyalkyl or alkoxyalkyl; R 2 R is halo, haloalkyl or cyano; R 3 R is H; or R 2 and R 3 form, with the atom to which they are bonded, a 4- to 6-membered heterocyclyl ring containing a single O heteroatom optionally substituted with one or two substituents independently selected from halo and alkyl; or R 2 and R 3 form, with the atom to which they are bonded, 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: p is 1 or 2; q is 1 or 2; m is 0 or 1; Y1is C=0, CH, CH2, C-R x , N or NH Y2 is C=0, CH, C-R y , O, N, NH or N-CH3, Y3 is C=0, CH, CH2, CR y , N, NH or NR z Y4 is C=0, CH, CR y , N, NH or N-CH3 wherein R x is H and each R y is independently selected from -OH, alkyl, alkoxy, cyano, and halo, or R x + R y forms a heterocyclic ring with the atom to which they are attached; R z R is H, alkyl or hydroxyalkyl; And its medicinal salts.

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

3. The compound of claim 1-2, wherein R 1 is alkyl.

4. The compound according to claims 1 to 3, wherein n is 1.

5. The compound according to claims 1 to 4, wherein q is 1.

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

7. The compound according to claims 1 to 6, wherein Y1 is CH, C-R x , N or NH.

8. The compound according to claims 1 to 7, wherein Y1 is CH, N or NH.

9. The compound according to claims 1 to 8, wherein Y1 is CH.

10. The compound according to claims 1 to 9, wherein Y2 is C=0, CH, C-R y , N or NH.

11. The compound according to claims 1 to 10, wherein Y2 is C=O or N.

12. The compound according to claims 1 to 11, wherein Y3is C=0, CH, C-R y , N, NH or NR z .

13. The compound of claims 1-12, wherein Y3 is CH, N, NH, or NR z .

14. The compound of claims 1-13, wherein Y3 is CH, NH, or NR z .

15. The compound of claims 1 to 14, wherein each R y is independently selected from OH, alkyl, alkoxy, cyano, or halo.

16. The compound of claims 1-15, wherein each R y is alkyl.

17. The compound of claims 1-16, wherein each R z is H, alkyl, or hydroxyalkyl.

18. The compound of claims 1-17, wherein each R z is hydroxyalkyl.

19. The compound according to claim 1, wherein, R 1 R is hydrogen, alkyl, or hydroxyalkyl; R 2 halo, haloalkyl or cyano; R 3 R is H; A is CH or N; p is 1 or 2; q is 1 or 2; m is 0 or 1; Y1 represents CH and CR x , N or NH; Y2is C=0, CH, C-R y , N or NH; Y3 is C=0, CH, CR y , N, NH or NR z ; Y4 is C=0, CH, CR y , N, NH or N-CH3; wherein R x is H and each R y is independently selected from OH, alkyl, alkoxy, cyano, or halo, or R x + R y forms a heterocyclic ring with the atom to which they are attached containing 1 or 2 oxygen heteroatoms; R z R is H, alkyl or hydroxyalkyl; And its medicinal salts.

20. The compound according to claim 1 or 19, wherein, R 1 R is alkyl; R 2 halo, haloalkyl or cyano; R 3 R is H; A is CH or N; p is 1 or 2; q is 1; m is 0 or 1; Y1 is CH, N, or NH; Y2is C=0, CH, C-R y , N or NH; Y3 is CH, N, NH or NR z ; Y4 is CH or N; wherein each R y is alkyl; R z R is H, alkyl or hydroxyalkyl; And its medicinal salts.

21. The compound according to claim 1 or 19 to 20, wherein, R 1 R is H, alkyl, cycloalkyl, cycloalkylalkyl, R 2 halo, haloalkyl or cyano; R 3 R is H; A is CH or N; p is 1 or 2; q is 1; m is 0 or 1; Y1 is CH, N, or NH; Y2is C=0, CH, C-R y , N or NH; Y3 is CH, N, NH or NR z ; Y4 is CH or N; wherein each R y is alkyl; R z R is hydroxyalkyl. And its medicinal salts.

22. The compound according to claim 1 or 19 to 21, wherein, R 1 R is H, alkyl, cycloalkyl, cycloalkylalkyl, R 2 R is halo, haloalkyl or cyano; R 3 R 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 ; Y4 is CH; R z R is hydroxyalkyl; And its medicinal salts.

23. The compound according to any one of claims 1 to 22, wherein the compound is selected from... 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]pyridin-2-yl]-5-methyl-1,3-dihydropyrrolo[3,4-c]pyridin-6-one; 3-Hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-3,5-dihydro-1H-pyrrolo[3,4-c]pyridin-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridin-6-one; 5-chloro-2-(2-isindolin-2-yl oxazolo[4,5-b]pyridin-5-yl)-3-methyl-phenol; 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]isoindolin-5-ol; 5-chloro-2-[2-(4-fluoroisoindolin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 4-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5- methyl-benzonitrile; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 2-[2-(6-methoxy-1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-5-(trifluoromethyl)phenol; 5-chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; formic acid; 5-chloro-2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; 5-chloro-2-[2-(4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; 5-chloro-2-[2-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; 3-hydroxy-4-(2-isindolin-2-yl oxazolo[4,5-b]pyridin-5-yl)-5-methyl-benzonitrile; 4-[2-(7,8-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- hydroxy-5-methyl-benzonitrile; 2-[2-(5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5- (trifluoromethyl)phenol; 7-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-2,5,6,8- tetrahydro-2,7-naphthyridin-3-one; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-5,7- dihydro-1 H-pyrrolo[3,4-b]pyridin-2-one; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-1 -methyl- 5,7-dihydropyrrolo[3,4-b]pyridin-2-one; 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; 2-[2-(5,7-dihydropyrrolo[3,4-b]pyrazin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5- (trifluoromethyl)phenol; 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5- (trifluoromethyl)phenol; 5-chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrrolo[4,3-c]pyridin-5-yl)oxazolo[4,5-b]pyridin- 5-yl]phenol; 5-(difluoromethyl)-2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5- yl]-3-methyl-phenol; 7-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-2,5,6,8-tetrahydro- 2,7-naphthyridin-3-one; 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3- methyl-phenol; formic acid; 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3- methyl-phenol; 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3- (hydroxymethyl)phenol: 5-chloro-2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol: 5-chloro-2-[2-(2-methoxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin- 5-yl]-3-methyl-phenol: 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-3,4-dihydro-1 H- isoquinoline-5-carbonitrile; 5-chloro-2-[2-(5-methoxy-3,4-dihydro-1 H-isoquinolin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; 5-chloro-2-[2-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-1,5,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-one: 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-1,5,7,8- tetrahydro-1,6-naphthyridin-2-one; 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-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]pyrazin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3,5,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-one; 5-chloro-2-(2-(6,8-dihydro-7H-[1,3]dioxolo[4,5-e]isoindol-7-yl)oxazolo[4,5-b]pyridin-5-yl)- 3-methylphenol; and pharmaceutically acceptable salts thereof.

24. The compound according to any one of claims 1 to 22, selected from 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazin-2-yl]-1,3- dihydropyrrolo[3,4-c]pyridin-6-ol; 2,2,2-trifluoroacetic acid; 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyrazin-2-yl]-1,3- dihydropyrrolo[3,4-c]pyridin-6-ol; 6-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-5,7- dihydro-1H-pyrrolo[3,4-d]pyrimidine-2,4-dione; pharmaceutically acceptable salts thereof.

25. The compound according to any one of claims 1 to 23, selected from 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3,5- dihydropyrrolo[3,4-c]pyridin-6-one; 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-5-methyl- 1,3-dihydropyrrolo[3,4-c]pyridin-6-one; 3-hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-1H-pyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5- b]pyridin-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-3,5- dihydro-1 H-pyrrolo[3,4-c]pyridin-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridin-6-one; 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3- methyl-phenol; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-1,5,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-one; 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-5,7-dihydro-2H- pyrrolo[3,4-c]pyridazin-3-one; and pharmaceutically acceptable salts thereof.

26. The compound according to any one of claims 1 to 25, which is selected from 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3,5- dihydro-lH-pyrrolo[3,4-c]pyridin-6-one; 3-hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-lH-pyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5- b]pyridin-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-3,5-dihydro-lH- pyrrolo[3,4-c]pyridin-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-l,3-dihydropyrrolo[3,4-c]pyridin-6-one; 5-chloro-3-methyl-2-[2-(2-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 5-chloro-2-[2-(3,4-dihydro-lH-2,7-naphthyridin-2-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl- phenol; 2-[2-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5- (trifluoromethyl)phenol; 5-chloro-3-methyl-2-[2-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)oxazolo[4,5- b]pyridin-5-yl]phenol; 5-chloro-2-[2-(l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3-methyl- phenol; formic acid; 5-chloro-2-[2-(l,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3-methyl- phenol; 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-l,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-one; 6-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-5,7-dihydro-2H- pyrrolo[3,4-c]pyridazin-3-one; and pharmaceutically acceptable salts thereof.

27. The compound according to any one of claims 1 to 26, which is selected from 2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]-3,5- dihydro-lH-pyrrolo[3,4-c]pyridin-6-one; 3-hydroxy-5-methyl-4-[2-(6-oxo-3,5-dihydro-lH-pyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5- b]pyridin-5-yl]benzonitrile; 2-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]-3,5- dihydro-1 H-pyrrolo[3,4-c]pyridin-6-one; 5-(2-hydroxyethyl)-2-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b]pyridin-2-yl]-1,3-dihydropyrrolo[3,4-c]pyridin-6-one; 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3- methyl-phenol; formic acid; 5-chloro-2-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)oxazolo[4,5-b]pyrazin-5-yl]-3- methyl-phenol; and pharmaceutically acceptable salts 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 use in 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 use in the treatment or prevention of a disease, disorder, or condition selected from Parkinson’s disease or Alzheimer’s disease.

33. Use of a 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 a 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 of 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 the treatment or prevention of 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 the treatment or prevention of 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 application as hereinbefore described.

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